aglycone solanidine and solasodine derivatives: a natural ... 2017 - aglyco… · review aglycone...

Biomedicine & Pharmacotherapy 94 (2017) 446–457

Review

Aglycone solanidine and solasodine derivatives: A natural approachtowards cancer

Abdul Hameeda, Shakeel Ijaza, Imran Shair Mohammadb,*, Kiran Sher Muhammadc,Naveed Akhtara, Haji Muhammad Shoaib Khana

aDepartment of Pharmacy, Faculty of Pharmacy and Alternative Medicines, The Islamia University of Bahawalpur, Bahawalpur, Punjab, 63100, PakistanbDepartment of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR ChinacDepartment of Zoology, University of Agriculture, Faisalabad, Pakistan

A R T I C L E I N F O

Article history:Received 5 June 2017Received in revised form 26 July 2017Accepted 27 July 2017

Keywords:Natural compoundsGlycoalkaloidsChemotherapeuticApoptosis

A B S T R A C T

Over the past few years, it was suggested that a rational approach to treat cancer in clinical settingsrequires a multipronged approach that augments improvement in systemic efficiency along withmodification in cellular phenotype leads to more efficient cell death response. Recently, the combinatorydelivery of traditional chemotherapeutic drugs with natural compounds proved to be astonishing to dealwith a variety of cancers, especially that are resistant to chemotherapeutic drugs. The natural compoundsnot only synergize the effects of chemotherapeutics but also minimize drug associated systemic toxicity.In this review, our primary focus was on antitumor effects of natural compounds. Previously, the drugsfrom natural sources are highly precise and safer than drugs of synthetic origins. Many naturalcompounds exhibit anti-cancer potentials by inducing apoptosis in different tumor models, in-vitro andin-vivo. Furthermore, natural compounds are also found equally useful in chemotherapeutic drugresistant tumors. Moreover, these Phyto-compounds also possess numerous other pharmacologicalproperties such as antifungal, antimicrobial, antiprotozoal, and hepatoprotection. Aglycone solasodineand solanidine derivatives are the utmost important steroidal glycoalkaloids that are present in variousSolanum species, are discussed here. These natural compounds are highly cytotoxic against differenttumor cell lines. As the molecular weight is concerned; these are smaller molecular weightchemotherapeutic agents that induce cell death response by initiating apoptosis through both extrinsicand intrinsic pathways.

© 2017 Elsevier Masson SAS. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4472. Steroidal alkaloids/Glycoalkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4483. Aglycone solanidine alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448

3.1. Solanine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4483.1.1. Toxic effects of solanine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4483.1.2. Antitumor effects of solanine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448

3.2. Chaconine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4493.2.1. Anticancer activity of chaconine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4493.2.2. Antimetastasis of chaconine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450

4. Aglycone solasodine alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4504.1. Solamargine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450

4.1.1. Anticancer effect of solamargine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4504.1.2. Cytotoxicity in human hepatic cell line . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452

Available online at

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* Corresponding author.E-mail address: [email protected] (I.S. Mohammad).

http://dx.doi.org/10.1016/j.biopha.2017.07.1470753-3322/© 2017 Elsevier Masson SAS. All rights reserved.

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A. Hameed et al. / Biomedicine & Pharmacotherapy 94 (2017) 446–457 447

4.1.3. The activity of solamargine against breast cell carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4524.2. Solasonine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453

5. Solasodine rhamnose glycoside (SRGs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4536. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4547. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454

Authors contribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455

1. Introduction

Recently, Cancer is a principal cause of death [1], associatedwith the development of solid masses known as tumors. In clinics,the management of cancer includes chemotherapy, radiotherapyand surgical removal of tumor masses. In chemotherapy, low-molecular-weight cytotoxic agents are used to be administered.Unfortunately, these cytotoxic agents kill not only the tumor cellsbut also the healthy cells which result in hair loss, bone marrowsuppression, nausea and gastrointestinal tract lesion [2].

Previously, the majority of chemotherapeutic drugs showed celldeath response through the induction of programmed cell death(Apoptosis) [3], however; apoptosis is not the only mean to kill anderadicate cancer cells [4,5]. Apoptosis can characterize by cellshrinkage, dilatation of endoplasmic reticulum, DNA fragmenta-tion, chromatin condensation and the formation of apoptoticbodies [6,7] by extrinsic and intrinsic pathway or both. Theextrinsic pathway (receptor mediated pathway) results in theactivation of cell surface ligand death receptors such as TNFR, Fasand TRAIL receptors while the intrinsic (mitochondrial mediatedpathway) pathway associated with the release of cytochrome-Cinto the cytoplasm, following the mitochondrial disruption and

Fig. 1. Apoptosis; intrinsic i.e mitochondrial-mediated pathway

initiate caspase cascade by converting procaspase-9 to caspase-9and caspase-9 further activate caspase-3 that cause irreversiblecell death (apoptosis) [8] (Fig. 1).

Previously, many Phytocompounds and their synthetic andsemi-synthetic derivatives are the potential sources of cytotoxicagents [9]. Furthermore, clinical trials for new chemical entities(NCE) or drugs for assessment of their anticancer potentials; about50% of these come from natural origin [10]. Solanum nigrum is aversatile member of Solanaceae family [11] and predominantlybreeds in temperate climate region [12]. It is an annual branchingherb having dull dark green leaves and small white flowers [13]. Atmaturation, the berries or fruits of this plant are small in size, blackin color and globular in shape [14]. Traditionally, grinded leaves ofyoung plant applied externally for the treatment of sores,carbuncles, swelling and injuries [15]. It has diuretic andantipyretic effect and exploits in the management of edema,inflammation [12] and mastitis [16]. It also used to treat stomachache, jaundice, liver problems, toothache and many skin diseases[17]. In China and Japan, the entire plant was used in differenttypes of cancer [18] such as liver [12], lungs, urinary bladder,larynx, and carcinoma of vocal cords [19]. Plant also illustrates anumber of other pharmacological actions such as;

and extrinsic or death receptor-mediated pathways [106].

448 A. Hameed et al. / Biomedicine & Pharmacotherapy 94 (2017) 446–457

hepatoprotective [20–22], anti-ulcerogenic [23], anti-seizure [24],cytoprotective [25], antifungal [26], neuro-pharmacological [27],antioxidative [28,29], antimicrobial [30], larvicidal, molluscicideand acaricidal [31–33]. However, amongst a lot of reportedpharmacological studies, the anticancer effects of this plantexpand a high priority [34]. Anticancer phytochemicals presentin Solanum nigrum include glycoproteins, polysaccharides, steroi-dal alkaloids and glycoalkaloids [12]. These glycoalkaloids includesolanine, solamargine, solasonine and solasodine [35,36].

In this review, we studied different steroidal glycoalkaloidspresent inSolanum nigrum concerning theirchemical structures andhydrolysis, the level of cytotoxicity, along with their mode of action.

2. Steroidal alkaloids/Glycoalkaloids

Glycoalkaloids are present in more than 350 plant species. Eachspecies has a pair of glycoalkaloids, which has a similar aglyconemoiety but different carbohydrate side-chain [37]. Several Solanumspecies also synthesize steroidal alkaloids, and their glycoalkaloidsare natural toxins which demonstrate antitumor, teratogenic,antifungal, antiviral and anti-estrogen activities [38,39].The acidhydrolysis of these alkaloids yields alkamines [40]. These Glyco-alkaloids offer protection toplants against fungi, herbivores, insects,and pests. Interestingly, total glycoalkaloids level (TGA) of 2–5 mg/kg (body weight) is toxic to humans because, at this level, theyproduce systemic and gastrointestinal effects and also down-regulate acetylcholinesterase’s [41]. These glycoalkaloids producetoxicity by making a complex with sterol of cellular membranes anddisrupt cells [42]. Neurological signs and symptoms of toxicity dueto glycoalkaloids include; weakness, depression, coma, convul-sions, partial paralysis and mental confusion [43]. It has beenreported that some glycoalkaloids from Solanum species such asa-solasonine, a-solamargine, and aglycone solasodine showantitumor activity against several tumor cell lines [44].

3. Aglycone solanidine alkaloids

3.1. Solanine

Solanine is a steroidal alkaloid, mostly found in all parts ofSolanum nigrum (nightshade). Along with solanine, Solanum

Fig. 2. Chemical structure of a-

nigrum also contains other steroidal alkaloids such as solasodinei.e. solamargine [45] and solasonine [15]. Solanine was firstisolated by Defosses from the leaves of Solanum nigrum in 1820[46]. Solanine also found in tuber of Solanum tuberosum Linn. [15].Typically unripe, green and small sized potatoes contain a highamount of solanine as compared to fully ripe and large sizepotatoes [47]. Its molecular mass is 868 Da [48] (Fig. 2).

3.1.1. Toxic effects of solanineAbout 0.02% concentration of solanine in potatoes have a toxic

effect on humans [46]. The first toxic effect of solanine poisoningwas observed in 1932, when a Greek family of eight persons, had ameal of young potatoes shoots and broad beans. At first, there wasno sign of toxicity, but after 12 h, symptoms of toxicity revealed,including; headache, colic pain, hot skin, nausea, and vomiting. Theother symptoms included weakness, depression, convulsions,diarrhea, abdominal pain and difficulty in breathing [14,47]. Inanother observation, it was observed that, solanine at a low dose of200 mg/p.o (per oral) causes itchiness in the neck region, dyspnea,drowsiness, and hyperesthesia. While at higher doses it initiatesvomiting and diarrhea. Chemically, solanine has structuralresemblance with cardiac glycosides, for this reason, it showspositive inotropic effect [46].

3.1.2. Antitumor effects of solanineSolanine, at different concentrations, initiates programmed cell

death (Apoptosis) in tumor cell lines which include humanhepatocarcinoma cell line (HepG2), human gastric carcinoma cellline (SGC-7901) and human large intestine cancer cell line (LS-174). The cytotoxic effects of solanine can be observed bymeasuring different parameters such as morphology, cell cyclephase analysis and rate of apoptosis. In each cell line here, the rateof apoptosis is usually dose dependent. It was observed that HepG2tumor cells are more sensitive to solanine than other tumor cells.Solanine inhibits the development of HepG2 tumor cells byinterfering with S phase of the cell cycle which prevents cells fromentering into G2 phase thus prevent cell division. Furthermore, italso inhibits the gene expression of Bcl-2 protein in HepG2 cellsand boosts the expression of Bax in HepG2 tumor cells and finallyraise Bax/Bcl-2 ratio [15,49]. Bcl-2 family is an anti-apoptoticprotein (Mueller, Voigt et al., 2003), mostly localized at the inner

solanine [42,43,45,111,117].


mitochondrial membrane, nucleus membrane and membrane ofendoplasmic reticulum [50,51]. Bcl-2, with the molar size of1500 Da, is present in mitochondria and located near tomitochondrial permeability transition (MPT) pores [52], whichtransport both anionic and cationic molecules [53–55]. Any changein the permeability of these pores results in apoptosis. Bcl-2prevents any change in permeability of these pores and act as anti-apoptotic agent [52]. Bcl-2 also inhibits the release of cytochrome-C. Cytochrome-C plays an imperative role in the activation ofcaspase cascade (cysteine-aspartic-proteases), which is crucial forapoptosis [15].

Solanine also helps in lowering the membrane potential ofHepG2 tumor cells in a dose-dependent manner which initiatesthe opening of mitochondrial permeability transition pores (MPT).The opening of these MPT pores leads to swelling and rupturing ofthe mitochondrial membrane which releases Ca++ ions frommitochondria into cytoplasm results in high accumulation of Ca++

in the cytosol. These events end in tumor cell death induced byapoptosis [45].

3.2. Chaconine

Saponins are classified as triterpenoids, steroids or steroidalglycoalkaloids (chaconine and solanine) [56], which are present inmore than 100 plant species. Chaconine and solanine moleculesdisrupt cellular membrane and leakage of electrolyte from the cellby forming a complex with plasma membrane sterol at 3b-OH site[57]. The trisaccharide of a-chaconine composed of one glucoseand two rhamnose molecules attached to aglycone solanidinemoiety at 3-OH position [56]. a-chaconine synthesized in thoseparts of plants that are naturally bioactive, that is why it offers anenvironmental protection to plants from fungi, pests, andherbivores. Its molecular weight is 852 Da, and it is ten timesmore toxic than solanine [38,48]. However, the level of toxicityreduced with the removal of glucose unit from primary structurei.e. gradual elimination of glucose unit from b1-, b2-, g-chaconine

Fig. 3. Structure of chaconine a

and solanidine with the order of toxicity b1- chaconine and b2-chaconine > g-chaconine > solanidine [56] (Fig. 3).

3.2.1. Anticancer activity of chaconine`Chaconine induces apoptosis by activating caspases-3 and is

also responsible for the transfer of phosphatidylserine to plasmamembrane; which results in condensation of nuclear chromatinand cytoplasmic contents in human colon carcinoma cells (HT-29).In induction of apoptosis, chaconine is a potent apoptosis inducerthan solanine which is due to the presence of side chain glucosemolecules attached to the 3-OH position of aglycone solanidinemoiety.

Chaconine also hampers phosphorylation of ERK-1 (Extracellu-lar signal-regulated kinases-1) to ERK-2 (Extracellular signal-regulated kinases-2) [58]. Activated ERK-1 and two signalingpathways are important for cell survival, inhibition of apoptosis,cell motility, cell proliferation, differentiation and metabolism[59–61]. This pathway is simply described as Ras-Raf-MEK-ERK/MAPK (Ras-Raf-MEK-Extracellular signal-regulated kinases/Mito-gen-activated protein kinases) pathway that conveys a signal inresponse to external stimuli such as growth factor or hormonesand regulates gene transcription, which controls several cellularevents [62].

When extracellular factors such as paracrine growth factors,autocrine growth factors, and adhesion factors are attached to itsreceptor e.g. tyrosine kinases (RTK) at the surface of the plasmamembrane, it leads to autophosphorylation and dimerization oftyrosine. Phosphotyrosine provides a docking site for growth-factor-receptor bound protein-2 (Grb2) and adaptor protein (Shc).Grb2 drags GDP/GTP exchange factor son of sevenless (SOS) to theplasma membrane, and SOS causes activation of Ras GTPase [63].Ras is small GTPase present at the membrane, and it has threeisoforms i.e. Ha-Ras, N-Ras and Ki-Ras [64]. Ki-Ras isoform isprimarily allied with activation of Raf/MEK/ERK signaling path-way; while Ha-Ras isoform activates Pl3K/Akt signaling pathway[60] and N-Ras isoform chiefly linked with the pathogenesis of

nd its hydrolysis [56,118].


melanoma [64]. Ras binding activates and translocates Raf serine/threonine kinase to the plasma membrane. The Raf consists ofthree isoforms i.e. A-Raf, B-Raf and Raf-1(C-Raf), these effectorstrigger MEK-ERK/MAPK kinase pathway [61,65]. Raf isoformsactivate and phosphorylate MEK isoforms MEK-1 and MEK-2 withdifferent potencies i.e. B-Raf > Raf-1 > A-Raf, respectively [65].Activated MEK, initiates phosphorylation of ERK, followingactivation shift to nucleus and facilitates the phosphorylation ofother transcription factors such as Elk-1, globin transcriptionfactor-1, cAMP response element-binding protein and Fos thathinder apoptosis and after binding with growth factor and cytokinegene, work as a cell growth regulators [64,66,67]. Du et al. [67], alsoreported that activation of this pathway also upregulatesintracellular anti-apoptotic proteins (Fig. 4).

3.2.2. Antimetastasis of chaconineMatrix metalloproteinase (MMPs) family is the endopeptidases

that have the zinc-binding capacity [68]. It comprises of 14members of enzymes divided into four sub-groups i.e. collage-nases, gelatinases, stromelysins and the membrane-type MMPs.The over expression of these enzymes degrades most of thecomponents of extracellular matrix (ECM) and therefore, helps inthe invasion of tumor cells at different sites and metastasis [69].There are many MMPs inhibitors available in clinical practice thatreduce the expression of MMPs proteins and inhibit tumor cellsmigration [70]. It was noted that chaconine showed theantimetastatic effects on human lung adenocarcinoma A549 cellsby inhibiting the expression of proteolytic enzymes such as ofMMPs family (MMP-2 and MMP-9). The expression of MMP-2 andMMP-9 is related to various cellular and physiological events suchas cell motility, adhesion, differentiation, proliferation, activation,invasion, growth, and metastasis. The a-chaconine inhibits theactions of MMP-2 and MMP-9 and reduces the migration of humanlung adenocarcinoma cells. It inhibits the translocation andbinding efficiency of transcriptional factor NF-kB from cytosol tothe nucleus and also inhibits the phosphorylation of JNK1/2 and

Fig. 4. Action of Chaconine on Ras-Raf-ME

PI3K/Akt in A549 tumor cells [71]. The inhibition of JNK1/2 andPI3K/Akt signaling pathways and transcriptional factor NF-kB;results in down-regulation of MMP-2 and 9 results in inhibition ofcancer metastasis [72] (Fig. 5).

4. Aglycone solasodine alkaloids

4.1. Solamargine

Solamargine is of 828 Da molecular weight steroidal glycoalka-loid [73,74]. It is present in nearly 100 Solanum species. Previously,many tumor cells such as lung, hepatoma, breast, prostate, andcolon cells were sensitive to solamargine [12]. It has been observedthat solamargine also possess hepatoprotective activity againstcarbon tetrachloride (CCL4) induced hepatotoxicity [75]. At smalldoses, solamargine initiates apoptosis while at high doses, it causesnecrosis. It was found that rhamnose moiety, present in thecarbohydrate side chain of solamargine was essential for tumor celldeath [76,77] (Fig. 6).

4.1.1. Anticancer effect of solamargineRecently, lung cancer is a primary focus of researchers because

lung cancer associated deaths are increasing gradually [78]. Lungcancer is classified into two groups, small cells lung carcinoma(SCLC) and non-small cells lung carcinoma (NSCLC). Type II i.e.NSCLC; constitutes 75–80% of lung cancer and is furthersubdivided into three subtypes namely adenocarcinoma, squa-mous cells carcinoma and large cells carcinoma [79].

Previously, Liu et al., [3] reported the cytotoxic effects ofsolamargine against non-small cell lung carcinoma cell lines(H441, H661, and H520) and small cell lung carcinoma cell line(H69). It was observed that solamargine induces dose-dependentapoptosis by;

1. Increasing binding of tumor necrosis factors (TNFs) to tumornecrosis factor receptors (TNFRs).

K-ERK (MAPK) signaling pathway [63].

Fig. 5. Ras involved in the activation of ERK and PI3K signaling pathway (Downward, 2008).

Fig. 6. Chemical structure of Solamargine [5,110,111,119].


2. Downregulation of anti-apoptotic proteins (Bcl-2).3. Activation of the caspase cascade.

Tumor necrosis factor (TNF) is a group or family of cytokines,present as proteins with molecular weights in the range of 40–70 kDa [80–84]. Human TNFs have a molecular weight of 17 kDaand play a major role in acute and chronic inflammation; cancer-related inflammation, autoimmune diseases, programmed cell

death (apoptosis) and necroptosis (necrosis) [85]. Among all TNF-a, TNF-b, CD40L, FasL, TNF-related apoptosis-inducing ligand(TRAIL) and LIGHT are most important [86]. TNFs initiate apoptosisby binding to tumor necrosis factor receptors TNFRs, TNFR-I, andTNFR-II [87]. These receptors are present on different types of cellssuch as human fibroblasts, endothelial cells, adipocytes, livermembranes and monocytes, different tumor cell lines andhematopoietic cells [88–91]. Their numbers on each cell type


from 1000–10,000 per cell with affinity constant ranging between3 � 10�11 to 2 � 10�10M with a molecular weight of 55 kDa (TNFR-1) and 75 kDa (TNFR-11) [85,92,93]. These receptors are calleddeath receptors which play a major role in receptor-mediatedapoptosis or extrinsic pathway of programmed cell death.

When a specific ligand (TNF-a, FasL, TRAIL) comes in contactwith death receptors (TNFR1, Fas, TRAIL receptors), the receptorsdimerization is initiated. TNFR-1 contains death domains, thesedeath domains (TRADD) interact with FADD (Fas-associated deathdomain) and help in activation and cleavage of pro-caspase-8 tocaspase-8. Caspases-8 causes further cleavage and activation ofcaspases-3, which induces irreversible programmed cell death orapoptosis [8].

In normal lung cells these receptors are upregulated, but duringcancer development, these receptors loss or trim down theirresponse to stimulus or down-regulation of receptors occur [94].Solamargine induces apoptosis in lung cancer cells by initiating thegene expression of TNFR-I and TNFR-II and also enhances thebinding of TNFs to TNFRs. Activation of TNFRs and upregulation ofapoptotic TRADD and FADD, during lung cancer, is an importantmechanism of action of solamargine and it also boosts thesensitivity of lung cancer cells to TNF-a and TNF-b [3].

Bcl-2 (B-cell lymphoma 2) is encoded by Bcl-2 gene, a foundingmember of Bcl-2 family of regulatory proteins and showsantiapoptotic and antiproliferative activities. Bcl-2 family com-prises of 20 members some of these show antiapoptotic activity(Bcl-2, Bcl-xL, Bcl-w, A1 and Mcl 1) while others show pro-apoptotic activity (Bax, BH3, and Bid) [95,96] (Fig. 7).

Bcl-2 family is an important regulator of the intrinsic pathwayof apoptosis [8]. During stress, Bax and Bid relocate in themitochondrial outer membrane and is responsible for the releaseof cytochrome-c into the cytoplasm [97–105].

Cytochrome-c along with apoptotic protease activating factor I(Apaf 1), forms apoptosome complex by binding with initiatorcaspases-9 [106]. This complex activates other caspases such ascaspases-3 and �7 which leads to apoptosis [86]. However,upregulation or overexpression of Bcl-2 and Bcl-xL restrains the

Fig. 7. Bcl-2 related

release of cytochrome-c from mitochondria, inhibit the Bax andavert the cell death [8,107,108]. It was reported that Solamargineinhibits the expression of Bcl-2 and Bcl-xL and upregulates Baxwhich causes the release of cytochrome-c and results in apoptosis[8] (Fig. 8).

4.1.2. Cytotoxicity in human hepatic cell lineDing et al., [12] observed the effects of solamargine in human

hepatic carcinoma cells line (SMMC-7721, Hep3B), respectively.The solamargine induces apoptosis in a dose-dependent mannerby;

1. Arresting the cells at the G2/M phase and induces apoptosis inthis cell cycle phase.

2. Activation of caspase-33. Initiation or expression of TNF receptors.

Kuo et al. [109], found that steroidal glycoalkaloids (solamar-gine) exert their cytotoxic effects by diffusion into cells, where thismolecule irreversibly bounds and activates intracellular receptorsthat result in transcription of particular genes.

4.1.3. The activity of solamargine against breast cell carcinomaIn breast tumor cell lines (HBL-100, SK-BR-3, and ZR-75-1)

Solamargine induces apoptosis following extrinsic and intrinsicpathways by shrinking the size, membrane hemorrhage andchromatin condensation of nuclei. The mechanism by whichsolamargine induces apoptosis in these breast carcinoma cells issimilar to other carcinoma cell lines. It has been reported thatsolamargine induces apoptosis by arresting the cells at G2/M phaseof cell cycle through initiating the expression of TNFR, TRADD,FADD and Fas receptors, downregulating of anti-apoptotic proteinsBcl-2 and Bcl-xL, increasing the expression of pro-apoptoticprotein Bax, activating caspases 8, 9 and 3 and finally the releaseof cytochrome-c [8].

It was also reported that solamargine at 2.9 and 7.7 mMconcentration produces 50% and 80% cell death in A549 lung

proteins [95].

Fig. 8. Extrinsic and intrinsic pathways of apoptosis [95].


adenocarcinoma cell line, respectively. Solamargine showed a doseand time-dependent inhibitory effects in these lung cancer cells[74].

4.2. Solasonine

The Molecular formula of solasonine is C45H73NO16 with amolecular weight of 884.04 Da [110]. Solasonine and solamarginehave the same steroidal part, aglycone solasodine but solasoninediffers from solamargine at its carbohydrate side chain composi-tion. The trisaccharide of solasonine molecule has a solatriose (L-rhamnopyranose-D-glucopyranosyl-galactopyranose) structure,identical to the corresponding side chain of a-solanine. Hydrolyticelimination of carbohydrate side chain from solasonine, yieldssolasodine which is readily converted into 16-dehydropregneno-lone; an efficient remedy in steroidal medicine [111]. Solasonineexhibits weak antiviral, antifungal, insecticidal and molluscicidaleffects [112]. It also shows a concentration-dependent cytotoxicityagainst human K562 leukemic cells and antiproliferative actionagainst Ehrlich carcinoma cells [113], human colon (HT29) andhuman liver (HepG2) cancer cells. Cytotoxicity of solasonine is

mainly due to the presence of glucose moiety in its main structure[10]. Like other glycoalkaloids, solasonine has no inhibitory effectson acetylcholinesterases [37] (Fig. 9).

5. Solasodine rhamnose glycoside (SRGs)

SRGs are the innovative class of chemotherapeutic agents inwhich solasodine glycosides, solasonine and solamargine contrib-ute equally. SRGs have the ability to devastate cancer cells due toapoptosis and also show antineoplastic effects with peculiarbehavior. The rhamnopyranose component in SRGs binds tospecific receptor Endogenous Endocytic Lectins (EELs), presentonly in cancerous cells as compared to normal cells that’s why SRGsspecifically kill cancer cells but imparts no harmful effects onnormal healthy cells. Once rhamnose binding glycoprotein isidentified and binds to these receptors, it forms SRGs-EELscomplex, which internalized into cancer cells through endosomesvia receptor-mediated endocytosis. In the cells, SRGs demonstrateanti-mitochondrial and anti-lysosomal activities. Solasodinebranch of SRGs ruptures lysosomes. As a result, lysosomal contents(mainly hydrolytic enzymes) released into cytosol that causes the

Fig. 9. Chemical structure of solasonine [110,112].


death of tumor cells. SRGs trigger apoptosis in cancer cells byincreasing the expression of death receptors such as Fas and Fas-associated death domain and TNFR receptors and its death domain.SRGs also decrease the Bcl-2/Bax ratio by downregulating theexpression of anti-apoptotic proteins (Bcl-2) and increase theexpression of pro-apoptotic proteins (Bax). These outcomes leadthe activation of Caspases-8, 9 and 3 in tumor cells. Thus SRGsinitiate apoptosis via both extrinsic and intrinsic pathways incancer cells.

SRGs in combination with cisplatin proved more effectiveagainst cisplatin-resistant tumor cells, including lung and breastcancer cells [114], as compared to the sensitive phenotypes.Interestingly, it was observed that as a chemotherapeutic agentSRGs are more efficient than Taxol, Cisplatin, Vinblastine,Methotrexate, 5-fluorouracil, Epirubicin, Cyclophosphamide andGemcitabine [73].

SRGs are commercially available as a topical formulation for thetreatment of skin cancer without destroying healthy skin cells[114]. It was first formulated in Australia, licensed in 1991 andmarketed as “Curaderm” [115]. Curaderm contains 33% solasonine,33% solamargine and 34% di- and mono-glycosides, which arepresent in a topical cream formulation that contains 0.005%glycoalkaloids BEC (a mixture of SRGs). At this low concentration toattain efficacy, keratolytic agents such as salicylic acid (10%) andurea (5%) have to be added to the formulation which assistsabsorption of BEC to cancer cells. After the application offormulation, keratolytic agents gave slightly burning and stingingsensations, but it has no side effects on liver, kidneys and systemiccirculation [116].

6. Conclusion

Studies have shown that steroidal glycoalkaloids, aglyconesolanidine (solanine, chaconine) and aglycone solasodine (sol-amargine, solasonine) have antitumor activity against many tumorcell lines. In many cancer cell lines these compounds triggerapoptosis in two ways, (1) Death receptor-mediated apoptosis (2)Mitochondrial mediate apoptosis. Both depend mainly on thestructural modification of carbohydrate moiety attached toaglycone part of these steroidal glycoalkaloids. The molecular

mechanism by these steroidal glycoalkaloid initiates cells deathare similar to the currently available chemotherapeutic drugs inclinics. These steroidal glycoalkaloids induce apoptosis by regu-lating the expression of TNFRs, down-regulating the expression ofanti-apoptotic proteins (Bcl-2), increasing the expression ofapoptotic proteins (Bax), decreasing the Bcl-2/Bax ratio, disruptionmitochondrial and lysosomal membrane and activation of caspasescascade. Furthermore, inhibiting the phosphorylation of ERK1/2,JNK1/2, PI3K/Akt signaling pathways and inhibit the expression ofMMPs. According to all these molecular mechanisms of steroidalglycoalkaloids; SRGs (solasodine rhamnose glycoside) formulationwas formulated to treat skin cancers successfully. In conclusion,these natural compounds can be a breakthrough for the develop-ment of effective chemotherapy in respect of their efficacy andpromising specificity.

7. Future directions

Concerning the molecular mechanism, toxicity, molecular sizeand specificity of chemotherapeutic agents; we can suggest somefuture directions for the development of effective chemother-apeutics.

1. The chemotherapeutic drug should be small enough(


can be proved more accurate and efficient chemotherapyregimen.

4. The main disadvantage associated with chemotherapy is non-specificity. Due to this, they can destroy normal healthy cellsalong with tumor cells. The specific receptors are present on thesurface of tumor cells to bind with drugs. So, to achievespecificity, SRGs incorporated formulation should be developedthat has potential to bind specifically with EELs, present only ontumor cells.

5. Finally, authors encourage the use of natural compounds astherapeutic agents because of their excellent safety, highefficacy and promising specificity to kill tumor cells.

Authors contribution

Abdul Hameed is a Ph.D. student. He contributed to the writingsection and prepared the figures of this review.

Shakeel Ijaz is a Ph.D. student. He contributed to the writingsection of this review.

Imran Shair Mohammad is a Ph.D. student. He contributed tothe writing section and prepared the figures of this review. He alsoworked to finalize the manuscript.

Kiren Sher Muhammad is a Masters Student. She helped in theliterature search.

Haji Muhammad Shoaib Khan is an assistant professor. Hedirected/instructed and guided us to complete this review.

Naveed Akhtar is a Professor. He supervised all the work andreviewed the manuscript.

Conflict of interest

All authors declared no conflict of interest.

Acknowledgement

The author’s thanks, Dr. Haji Muhammad Shoaib Khan and Dr.Naveed Akhtar for their guidance and support to complete thisproject.

References

[1] D. Chanda, S. Bhushan, S.K. Guru, K. Shanker, Z. Wani, B. Rah, S. Luqman, D.M. Mondhe, A. Pal, A.S. Negi, Anticancer activity, toxicity andpharmacokinetic profile of an indanone derivative, Eur. J. Pharm. Sci. 47 (5)(2012) 988–995.

[2] S. Nussbaumer, P. Bonnabry, J.-L. Veuthey, S. Fleury-Souverain, Analysis ofanticancer drugs: a review, Talanta 85 (5) (2011) 2265–2289.

[3] L.-F. Liu, C.-H. Liang, L.-Y. Shiu, W.-L. Lin, C.-C. Lin, K.-W. Kuo, Action ofsolamargine on human lung cancer cells–enhancement of the susceptibilityof cancer cells to TNFs, FEBS Lett. 577 (1) (2004) 67–74.

[4] E. Finkel, Does cancer therapy trigger cell suicide? Science 286 (5448) (1999)2256–2258.

[5] L. Sun, Y. Zhao, H. Yuan, X. Li, A. Cheng, H. Lou, Solamargine, a steroidalalkaloid glycoside, induces oncosis in human K562 leukemia and squamouscell carcinoma KB cells, Cancer Chemother. Pharmacol. 67 (4) (2011) 813–821.

[6] J.D. Ly, D. Grubb, A. Lawen, The mitochondrial membrane potential (DCm) inapoptosis; an update, Apoptosis 8 (2) (2003) 115–128.

[7] Y. Suárez, L. González, A. Cuadrado, M. Berciano, M. Lafarga, A. Muñoz, F.Kahalalide, A new marine-derived compound, induces oncosis in humanprostate and breast cancer cells, Mol. Cancer Ther. 2 (9) (2003) 863–872.

[8] L. Shiu, L. Chang, C. Liang, Y. Huang, H. Sheu, K. Kuo, Solamargine inducesapoptosis and sensitizes breast cancer cells to cisplatin, Food Chem. Toxicol.45 (11) (2007) 2155–2164.

[9] M.L. de Mesquita, J.E. de Paula, C. Pessoa, M.O. de Moraes, L.V. Costa-Lotufo, R.Grougnet, S. Michel, F. Tillequin, L.S. Espindola, Cytotoxic activity of BrazilianCerrado plants used in traditional medicine against cancer cell lines, J.Ethnopharmacol. 123 (3) (2009) 439–445.

[10] C.C. Munari, P.F. de Oliveira, J.C.L. Campos, S.d.P.L. Martins, J.C. Da Costa, J.K.Bastos, D.C. Tavares, Antiproliferative activity of Solanum lycocarpumalkaloidic extract and their constituents, solamargine and solasonine, intumor cell lines, J. Nat. Med. 68 (1) (2014) 236–241.

[11] S. Patel, N. Gheewala, A. Suthar, A. Shah, In-vitro cytotoxicity activity ofSolanum nigrum extract against Hela cell line and Vero cell line, Int. J. Pharm.Pharm. Sci. 1 (1) (2009) 38–46.

[12] X. Ding, F.-S. Zhu, M. Li, S.-G. Gao, Induction of apoptosis in human hepatomaSMMC-7721 cells by solamargine from Solanum nigrum L, J.Ethnopharmacol. 139 (2) (2012) 599–604.

[13] F. Atanu, U. Ebiloma, E. Ajayi, A review of the pharmacological aspects ofSolanum nigrum Linn, Biotech. Mol. Biol. Rev. 6 (1) (2011) 001–007.

[14] R. Alexander, G. Forbes, E. Hawkins, A fatal case of solanine poisoning, Br.Med. J. 2 (4575) (1948) 518.

[15] Y. Ji, S. Gao, C. Ji, X. Zou, Induction of apoptosis in HepG 2 cells by solanine andBcl-2 protein, J. Ethnopharmacol. 115 (2) (2008) 194–202.

[16] J. Li, Q. Li, T. Feng, K. Li, Aqueous extract of Solanum nigrum inhibit growth ofcervical carcinoma (U14) via modulating immune response of tumor bearingmice and inducing apoptosis of tumor cells, Fitoterapia 79 (7) (2008) 548–556.

[17] P. Gogoi, M. Islam, Phytochemical screening of solanum nigrum L. and S.myriacanthus dunal from districts of upper assam, India, IOSR J. Pharm. 23 (2)(2012) 455–459.

[18] T. Ikeda, H. Tsumagari, T. Nohara, Steroidal oligoglycosides from Solanumnigrum, Chem. Pharm. Bull. Tokyo 48 (7) (2000) 1062–1064.

[19] K. Hu, H. Kobayashi, A. Dong, Y. Jing, S. Iwasaki, X. Yao, Antineoplastic agents.III: steroidal glycosides from solanum nigrum, Planta Med. 65 (1) (1999) 35–38.

[20] S. Sultana, S. Perwaiz, M. Iqbal, M. Athar, Crude extracts of hepatoprotectiveplants, Solanum nigrum and Cichorium intybus inhibit free radical-mediatedDNA damage, J. Ethnopharmacol. 45 (3) (1995) 189–192.

[21] K. Raju, G. Anbuganapathi, V. Gokulakrishnan, B. Rajkapoor, B. Jayakar, S.Manian, Effect of dried fruits of Solanum nigrum LINN against CCl4-inducedhepatic damage in rats, Biol. Pharm. Bull. 26 (11) (2003) 1618–1619.

[22] H.-M. Lin, H.-C. Tseng, C.-J. Wang, J.-J. Lin, C.-W. Lo, F.-P. Chou,Hepatoprotective effects of Solanum nigrum Linn extract against CCl 4-iduced oxidative damage in rats, Chem. Biol. Interact.171 (3) (2008) 283–293.

[23] M. Jainu, C.S.S. Devi, Antiulcerogenic and ulcer healing effects of Solanumnigrum (L.) on experimental ulcer models: possible mechanism for theinhibition of acid formation, J. Ethnopharmacol. 104 (1) (2006) 156–163.

[24] N.N. Wannang, J.A. Anuka, H.O. Kwanashie, S. Gyang, A. Auta, Anti-seizureactivity of the aqueous leaf extract of Solanum nigrum linn (solanaceae) inexperimental animals, Afr. Health Sci. 8 (2) (2008).

[25] V.P. Kumar, S. Shashidhara, M. Kumar, B. Sridhara, Cytoprotective role ofSolanum nigrum against gentamicin-induced kidney cell (Vero cells) damagein vitro, Fitoterapia 72 (5) (2001) 481–486.

[26] S. Shamim, S.W. Ahmed, I. Azhar, Antifungal activity of allium, aloe, andsolanum species, Pharm. Biol. 42 (7) (2004) 491–498.

[27] R.M. Perez, J.A. Perez, L.M. Garcia, H. Sossa, Neuropharmacological activity ofSolanum nigrum fruit, J. Ethnopharmacol. 62 (1) (1998) 43–48.

[28] K.-S. Heo, K.-T. Lim, Antioxidative effects of glycoprotein isolated fromSolanum nigrum L, J. Med. Food 7 (3) (2004) 349–357.

[29] F. Abas, N.H. Lajis, D. Israf, S. Khozirah, Y.U. Kalsom, Antioxidant and nitricoxide inhibition activities of selected Malay traditional vegetables, FoodChem. 95 (4) (2006) 566–573.

[30] P. Rani, N. Khullar, Antimicrobial evaluation of some medicinal plants fortheir anti-enteric potential against multi-drug resistant Salmonella typhi,Phytother. Res. 18 (2) (2003) 670–673.

[31] A. Ahmed, I. Kamal, R. Ramzy, Studies on the molluscicidal and larvicidalproperties of Solanum nigrum L. leaves ethanol extract, J. Egypt. Soc.Parasitol. 31 (3) (2001) 843–852.

[32] A. Ahmed, M. Rifaat, Molluscicidal and cercaricidal efficacy of Acanthusmollis and its binary and tertiary combinations with Solanum nigrum and Irispseudacorus against Biomphalaria alexandrina, J. Egypt. Soc. Parasitol. 34 (3)(2004) 1041–1050.

[33] A. Ahmed, M. Rifaat, Effects of Solanum nigrum leaves water extract on thepenetration and infectivity of Schistosoma mansoni cercariae, J. Egypt. Soc.Parasitol. 35 (1) (2005) 33–40.

[34] Z.A. Zakaria, H.K. Gopalan, H. Zainal, N.H. Mohd Pojan, N.A. Morsid, A. Aris, M.R. Sulaiman, Antinociceptive, anti-inflammatory and antipyretic effects ofSolanum nigrum chloroform extract in animal models, Pharm. Soc. Japan 126(11) (2006) 1171–1178.

[35] R. Saijo, K. Murakami, T. Nohara, T. Tomimatsu, A. Sato, K. Matsuoka, Studieson the constituents of Solanum plants. II. On the constituents of theimmature berries of Solanum nigrum L.(author’s transl), Yakugaku zasshi, J.Pharm. Soc. Japan 102 (3) (1982) 300–305.

[36] E.A. Eltayeb, A.S. Al-Ansari, J.G. Roddick, Changes in the steroidal alkaloidsolasodine during development of Solanum nigrum and Solanum incanum,Phytochemistry 46 (3) (1997) 489–494.

[37] J.G. Roddick, M. Weissenberg, A.L. Leonard, Membrane disruption andenzyme inhibition by naturally-occurring and modified chacotriose-containing Solanum steroidal glycoalkaloids, Phytochemistry 56 (6) (2001)603–610.

[38] L. Bejarano, E. Mignolet, A. Devaux, N. Espinola, E. Carrasco, Y. Larondelle,Glycoalkaloids in potato tubers: the effect of variety and drought stress on thea-solanine and a-chaconine contents of potatoes, J. Sci. Food Agric. 80 (14)(2000) 2096–2100.

[39] X. Zha, H. Sun, J. Hao, Y. Zhang, Efficient synthesis of solasodine, O-Acetylsolasodine, and soladulcidine as anticancer steroidal alkaloids, Chem.Biodivers. 4 (1) (2007) 25–31.

http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0005http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0005http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0005http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0005http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0010http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0010http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0015http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0015http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0015http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0020http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0020http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0025http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0025http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0025http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0025http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0030http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0030http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0035http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0035http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0035http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0040http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0040http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0040http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0045http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0045http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0045http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0045http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0050http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0050http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0050http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0050http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0055http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0055http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0055http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0060http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0060http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0060http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0065http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0065http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0070http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0070http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0075http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0075http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0080http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0080http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0080http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0080http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0085http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0085http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0085http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0090http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0090http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0095http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0095http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0095http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0100http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0100http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0100http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0105http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0105http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0105http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0110http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0110http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0110http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0115http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0115http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0115http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0120http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0120http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0120http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0125http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0125http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0125http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0130http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0130http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0135http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0135http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0140http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0140http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0145http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0145http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0145http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0150http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0150http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0150http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0155http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0155http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0155http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0160http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0160http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0160http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0160http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0165http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0165http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0165http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0170http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0170http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0170http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0170http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0175http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0175http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0175http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0175http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0180http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0180http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0180http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0185http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0185http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0185http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0185http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0190http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0190http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0190http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0190http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0195http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0195http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0195


[40] J. Barbosa Filho, M. Agra, R. Oliveira, M. Paulo, G. Trolin, E. Cunha, J. Ataide, J.Bhattacharyya, Chemical and pharmacological investigation of Solanumspecies of Brazil: a search for solasodine and other potentially usefultherapeutic agents, Memórias do Instituto Oswaldo Cruz 86 (1991) 189–191.

[41] S. Langkilde, T. Mandimika, M. Schrøder, O. Meyer, W. Slob, A. Peijnenburg, M.Poulsen, A 28-day repeat dose toxicity study of steroidal glycoalkaloids,a-solanine and a-chaconine in the Syrian Golden hamster, Food Chem.Toxicol. 47 (6) (2009) 1099–1108.

[42] J.G. Roddick, A.L. Rijnenberg, S.F. Osman, Synergistic interaction betweenpotato glycoalkaloids a-solanine and a-chaconine in relation todestabilization of cell membranes: ecological implications, J. Chem. Ecol. 14(3) (1988) 889–902.

[43] D.B. Smith, J.G. Roddick, J.L. Jones, Potato glycoalkaloids: some unansweredquestions, Trends Food Sci. Technol. 7 (4) (1996) 126–131.

[44] Y.I. Korpan, E.A. Nazarenko, I.V. Skryshevskaya, C. Martelet, N. Jaffrezic-Renault, V. Anna, Potato glycoalkaloids: true safety or false sense of security?Trends Biotechnol. 22 (3) (2004) 147–151.

[45] S.-Y. Gao, Q.-J. Wang, Y.-B. Ji, Effect of solanine on the membrane potential ofmitochondria in HepG2 cells and [Ca2 +] i in the cells, World J. Gastroenterol.:WJG 12 (21) (2006) 3359–3367.

[46] K. Nishie, M. Gumbmann, A. Keyl, Pharmacology of solanine, Toxicol. Appl.Pharmacol. 19 (1) (1971) 81–92.

[47] S. Willimott, An investigation of solanine poisoning, Analyst 58 (689) (1933)431–439.

[48] S. Sinden, R.E. Webb, Effect of Environment on Glycoalkaloid Content of SixPotato Varieties at 39 Locations, Agricultural Research Service, US Dept. ofAgriculture, 1974.

[49] J.I. Y.-b, G.A.O. S.-y, Antihepatocarcinoma effect of solanine and itsmechanisms, Chin. Herbal Med. 4 (2) (2012) 126–135.

[50] D. Hockenbery, G. Nuñez, C. Milliman, R.D. Schreiber, S.J. Korsmeyer, Bcl-2 Isan Inner Mitochondrial Membrane Protein That Blocks Programmed CellDeath, (1990) .

[51] R.M. Kluck, E. Bossy-Wetzel, D.R. Green, D.D. Newmeyer, The release ofcytochrome c from mitochondria: a primary site for Bcl-2 regulation ofapoptosis, Science 275 (5303) (1997) 1132–1136.

[52] S. Orrenius, Mitochondrial regulation of apoptotic cell death, Toxicol. Lett.149 (1) (2004) 19–23.

[53] J.J. Lemasters, A.-L. Nieminen, T. Qian, L.C. Trost, S.P. Elmore, Y. Nishimura, R.A.Crowe, W.E. Cascio, C.A. Bradham, D.A. Brenner, The mitochondrialpermeability transition in cell death: a common mechanism in necrosis,apoptosis and autophagy, Biochim. Biophys. Acta (BBA)-Bioenergetics 1366(1) (1998) 177–196.

[54] A.P. Halestrap, G.P. McStay, S.J. Clarke, The permeability transition porecomplex: another view, Biochimie 84 (2) (2002) 153–166.

[55] Y. Tsujimoto, Cell death regulation by the Bcl-2 protein family in themitochondria, J. Cell. Physiol. 195 (2) (2003) 158–167.

[56] Y. Oda, K. Saito, A. Ohara-Takada, M. Mori, Hydrolysis of the potatoglycoalkaloid a-chaconine by filamentous fungi, J. Biosci. Bioeng. 94 (4)(2002) 321–325.

[57] K.-M. Weltring, J. Wessels, R. Geyer, Metabolism of the potato saponinsa-chaconine and a-solanine by Gibberella pilicaris, Phytochemistry 46 (6)(1997) 1005–1009.

[58] S.-A. Yang, S.-H. Paek, N. Kozukue, K.-R. Lee, J.-A. Kim, a-Chaconine, a potatoglycoalkaloid, induces apoptosis of HT-29 human colon cancer cells throughcaspase-3 activation and inhibition of ERK 1/2 phosphorylation, Food Chem.Toxicol. 44 (6) (2006) 839–846.

[59] B.-J. Tan, G.N. Chiu, Role of oxidative stress, endoplasmic reticulum stress andERK activation in triptolide-induced apoptosis, Int. J. Oncol. 42 (5) (2013)1605–1612.

[60] F. Chang, L. Steelman, J. Lee, J. Shelton, P. Navolanic, W. Blalock, R. Franklin, J.McCubrey, Signal transduction mediated by the Ras/Raf/MEK/ERK pathwayfrom cytokine receptors to transcription factors: potential targeting fortherapeutic intervention, Leukemia 17 (7) (2003) 1263–1293.

[61] C. Song, W. Wang, M. Li, Y. Liu, D. Zheng, Tax1 enhances cancer cellproliferation via Ras–Raf–MEK–ERK signaling pathway, IUBMB Life 61 (6)(2009) 685–692.

[62] W. Kolch, Coordinating ERK/MAPK signalling through scaffolds andinhibitors, Nat. Rev. Mol. Cell Biol. 6 (11) (2005) 827–837.

[63] F. Meier, B. Schittek, S. Busch, C. Garbe, K. Smalley, K. Satyamoorthy, G. Li, M.Herlyn, The Ras/Raf/MEK/ERK and PI3 K/AKT signaling pathways presentmolecular targets for the effective treatment of advanced melanoma, Front.Biosci. 10 (2986-3001) (2005) 2986–3001.

[64] A.B. Uzdensky, S.V. Demyanenko, M.Y. Bibov, Signal transduction in humancutaneous melanoma and target drugs, Curr. Cancer Drug Targets 13 (8)(2013) 843–866.

[65] J.A. McCubrey, L.S. Steelman, S.L. Abrams, J.T. Lee, F. Chang, F.E. Bertrand, P.M.Navolanic, D.M. Terrian, R.A. Franklin, A.B. D’Assoro, Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drugresistance, Adv. Enzyme Regul. 46 (1) (2006) 249–279.

[66] L. Steelman, R. Franklin, S. Abrams, W. Chappell, C. Kempf, J. Bäsecke, F.Stivala, M. Donia, P. Fagone, F. Nicoletti, Roles of the Ras/Raf/MEK/ERKpathway in leukemia therapy, Leukemia 25 (7) (2011) 1080–1094.

[67] K. Du, Q. Zheng, M. Zhou, L. Zhu, B. Ai, L. Zhou, Chlamydial antiapoptoticactivity involves activation of the Raf/MEK/ERK survival pathway, Curr.Microbiol. 63 (4) (2011) 341–346.

[68] Y. Tsunezuka, H. Kinoh, T. Takino, Y. Watanabe, Y. Okada, A. Shinagawa, H.Sato, M. Seiki, Expression of membrane-type matrix metalloproteinase 1(MT1-MMP) in tumor cells enhances pulmonary metastasis in anexperimental metastasis assay, Cancer Res. 56 (24) (1996) 5678–5683.

[69] J. Hua, R.J. Muschel, Inhibition of matrix metalloproteinase 9 expression by aribozyme blocks metastasis in a rat sarcoma model system, Cancer Res. 56(22) (1996) 5279–5284.

[70] R.S. Herbst, S. Yano, H. Kuniyasu, F.R. Khuri, C.D. Bucana, F. Guo, D. Liu, B.Kemp, J.J. Lee, W.K. Hong, Differential expression of E-cadherin and type IVcollagenase genes predicts outcome in patients with stage I non-small celllung carcinoma, Clin. Cancer Res. 6 (3) (2000) 790–797.

[71] Y.-W. Shih, P.-S. Chen, C.-H. Wu, Y.-F. Jeng, C.-J. Wang, a-Chaconine-reducedmetastasis involves a PI3 K/Akt signaling pathway with downregulation ofNF-kB in human lung adenocarcinoma A549 cells, J. Agric. Food Chem. 55(26) (2007) 11035–11043.

[72] C.-L. Kuo, K.-C. Lai, Y.-S. Ma, S.-W. Weng, J.-P. Lin, J.-G. Chung, Gallic acidinhibits migration and invasion of SCC-4 human oral cancer cells throughactions of NF-kB, Ras and matrix metalloproteinase-2 and-9, Oncol. Rep. 32(1) (2014) 355–361.

[73] K.-W. Kuo, C.-N. Lin, Pharmacological composition for treating cancer cells,Google Patents, 2001.

[74] C.-H. Liang, L.-F. Liu, L.-Y. Shiu, Y.-S. Huang, L.-C. Chang, K.-W. Kuo, Action ofsolamargine on TNFs and cisplatin-resistant human lung cancer cells,Biochem. Biophys. Res. Commun. 322 (3) (2004) 751–758.

[75] C.-N. Lin, M.-I. Chung, K.-H. Gan, Novel antihepatotoxic principles of Solanumincanum, Planta Med. 54 (3) (1988).

[76] L.-C. Chang, T.-R. Tsai, J.-J. Wang, C.-N. Lin, K.-W. Kuo, The rhamnose moiety ofsolamargine plays a crucial role in triggering cell death by apoptosis,Biochem. Biophys. Res. Commun. 242 (1) (1998) 21–25.

[77] S.-y. Li, D.-j. He, X. Zhang, W.-h. Ni, Y.-f. Zhou, L.-p. Zhang, Modification ofsugar chains in glycoalkaloids and variation of anticancer activity, Chem. Res.Chin. Univ. 23 (3) (2007) 303–309.

[78] M.M. Ho, A.V. Ng, S. Lam, J.Y. Hung, Side population in human lung cancer celllines and tumors is enriched with stem-like cancer cells, Cancer Res. 67 (10)(2007) 4827–4833.

[79] A.K. Virmani, K.M. Fong, D. Kodagoda, D. McIntire, J. Hung, V. Tonk, J.D. Minna,A.F. Gazdar, Allelotyping demonstrates common and distinct patterns ofchromosomal loss in human lung cancer types, Genes, Chromosom. Cancer21 (4) (1998) 308–319.

[80] N. Matthews, J. Watkins, Tumour-necrosis factor from the rabbit I. Mode ofaction, specificity and physicochemical properties, Br. J. Cancer 38 (2) (1978)302.

[81] D. Männel, R. Moore, S. Mergenhagen, Macrophages as a source oftumoricidal activity (tumor-necrotizing factor), Infect. Immun. 30 (2)(1980) 523–530.

[82] N. Matthews, Production of an anti-tumour cytotoxin by human monocytes,Immunology 44 (1) (1981) 135.

[83] F.C. Kull, P. Cuatrecasas, Necrosin: purification and properties of a cytotoxinderived from a murine macrophage-like cell line, Proc. Natl. Acad. Sci. 81 (24)(1984) 7932–7936.

[84] H.C. Kelker, J.D. Oppenheim, D. Stone-Wolff, D. Henriksen-DeStefano, B.B.Aggarwal, H.C. Stevenson, J. Vil9cek, Characterization of human tumornecrosis factor produced by peripheral blood monocytes and its separationfrom lymphotoxin, Int. J. Cancer 36 (1) (1985) 69–73.

[85] R. Munker, H.P. Koeffler, Tumor necrosis factor: recent advances, Klin.Wochenschr. 65 (8) (1987) 345–352.

[86] W.-M. Chu, Tumor necrosis factor, Cancer Lett. 328 (2) (2013) 222–225.[87] L.A. Tartaglia, R.F. Weber, I.S. Figari, C. Reynolds, M.A. Palladino, D.V. Goeddel,

The two different receptors for tumor necrosis factor mediate distinctcellular responses, Proc. Natl. Acad. Sci. 88 (20) (1991) 9292–9296.

[88] F.C. Kull, S. Jacobs, P. Cuatrecasas, Cellular receptor for 125I-labeled tumornecrosis factor: specific binding, affinity labeling, and relationship tosensitivity, Proc. Natl. Acad. Sci. 82 (17) (1985) 5756–5760.

[89] M. Tsujimoto, Y. Yip, J. Vilcek, Tumor necrosis factor: specific binding andinternalization in sensitive and resistant cells, Proc. Natl. Acad. Sci. 82 (22)(1985) 7626–7630.

[90] P.P. Nawroth, D.M. Stern, Modulation of endothelial cell hemostaticproperties by tumor necrosis factor, J. Exp. Med. 163 (3) (1986) 740–745.

[91] B. Beutler, J. Mahoney, N. Le Trang, P. Pekala, A. Cerami, Purification ofcachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin-induced RAW 264.7 cells, J. Exp. Med. 161 (5) (1985) 984–995.

[92] B.B. Aggarwal, B. Moffat, R.N. Harkins, Human lymphotoxin. Production by alymphoblastoid cell line, purification, and initial characterization, J. Biol.Chem. 259 (1) (1984) 686–691.

[93] K. KouWha, H. ShuHui, L. YunPing, L. WeiLing, L. LiFeng, C. LiChing, L.ChihChao, L. ChunNan, S. HammMing, Anticancer activity evaluation of theSolanum glycoalkaloid solamargine, Biochem. Pharmacol. 60 (12) (2000)1865–1873.

[94] H. Shimomoto, Y. Hasegawa, Y. Nozaki, N. Takagi, T. Shibagaki, A. Nakao, K.Shimokata, Expression of tumor necrosis factor receptors in human lungcancer cells and normal lung tissues, Am. J. Respir. Cell Mol. Biol.13 (3) (1995)271–278.

[95] S. Cory, J.M. Adams, The Bcl2 family: regulators of the cellular life-or-deathswitch, Nat. Rev. Cancer 2 (9) (2002) 647–656.

http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0200http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0200http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0200http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0200http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0205http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0205http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0205http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0205http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0210http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0210http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0210http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0210http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0215http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0215http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0220http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0220http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0220http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0225http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0225http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0225http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0230http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0230http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0235http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0235http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0240http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0240http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0240http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0245http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0245http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0250http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0250http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0250http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0255http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0255http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0255http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0260http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0260http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0265http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0265http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0265http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0265http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0265http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0270http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0270http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0275http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0275http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0280http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0280http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0280http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0285http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0285http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0285http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0290http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0290http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0290http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0290http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0295http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0295http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0295http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0300http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0300http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0300http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0300http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0305http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0305http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0305http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0310http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0310http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0315http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0315http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0315http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0315http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0320http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0320http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0320http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0325http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0325http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0325http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0325http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0330http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0330http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0330http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0335http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0335http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0335http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0340http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0340http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0340http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0340http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0345http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0345http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0345http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0350http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0350http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0350http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0350http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0355http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0355http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0355http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0355http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0360http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0360http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0360http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0360http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0370http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0370http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0370http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0375http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0375http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0380http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0380http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0380http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0385http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0385http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0385http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0390http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0390http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0390http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0395http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0395http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0395http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0395http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0400http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0400http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0400http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0405http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0405http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0405http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0410http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0410http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0415http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0415http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0415http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0420http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0420http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0420http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0420http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0425http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0425http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0430http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0435http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0435http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0435http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0440http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0440http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0440http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0445http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0445http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0445http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0450http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0450http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0455http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0455http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0455http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0460http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0460http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0460http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0465http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0465http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0465http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0465http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0470http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0470http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0470http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0470http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0475http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0475


[96] M. Degli Esposti, J.T. Erler, J.A. Hickman, C. Dive, Bid, a widely expressedproapoptotic protein of the Bcl-2 family, displays lipid transfer activity, Mol.Cell. Biol. 21 (21) (2001) 7268–7276.

[97] D.T. Chao, S.J. Korsmeyer, BCL-2 family: regulators of cell death, Annu. Rev.Immunol. 16 (1) (1998) 395–419.

[98] X. Luo, I. Budihardjo, H. Zou, C. Slaughter, X. Wang, Bid, a Bcl2 interactingprotein, mediates cytochrome c release from mitochondria in response toactivation of cell surface death receptors, Cell 94 (4) (1998) 481–490.

[99] E. Bossy-Wetzel, D.R. Green, Caspases induce cytochrome c release frommitochondria by activating cytosolic factors, J. Biol. Chem. 274 (25) (1999)17484–17490.

[100] A. Gross, X.-M. Yin, K. Wang, M.C. Wei, J. Jockel, C. Milliman, H. Erdjument-Bromage, P. Tempst, S.J. Korsmeyer, Caspase cleaved BID targetsmitochondria and is required for cytochrome c release, while BCL-XLprevents this release but not tumor necrosis factor-R1/Fas death, J. Biol.Chem. 274 (2) (1999) 1156–1163.

[101] R.M. Kluck, M. Degli Esposti, G. Perkins, C. Renken, T. Kuwana, E. Bossy-Wetzel, M. Goldberg, T. Allen, M.J. Barber, D.R. Green, The pro-apoptoticproteins, Bid and Bax, cause a limited permeabilization of the mitochondrialouter membrane that is enhanced by cytosol, J. Cell Biol. 147 (4) (1999) 809–822.

[102] M.G. Vander Heiden, C.B. Thompson, Bcl-2 proteins: regulators of apoptosisor of mitochondrial homeostasis? Nat. Cell Biol. 1 (8) (1999) E209–E216.

[103] R. Eskes, S. Desagher, B. Antonsson, J.-C. Martinou, Bid induces theoligomerization and insertion of Bax into the outer mitochondrialmembrane, Mol. Cell. Biol. 20 (3) (2000) 929–935.

[104] D.R. Green, Apoptotic pathways: paper wraps stone blunts scissors, Cell 102(1) (2000) 1–4.

[105] J. Zha, S. Weiler, K.J. Oh, M.C. Wei, S.J. Korsmeyer, Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria andapoptosis, Science 290 (5497) (2000) 1761–1765.

[106] Y. Tsujimoto, S. Shimizu, Role of the mitochondrial membrane permeabilitytransition in cell death, Apoptosis 12 (5) (2007) 835–840.

[107] J. Yang, X. Liu, K. Bhalla, C.N. Kim, A.M. Ibrado, J. Cai, T.-I. Peng, D.P. Jones, X.Wang, Prevention of apoptosis by Bcl-2: release of cytochrome c frommitochondria blocked, Science 275 (5303) (1997) 1129–1132.

[108] F. De Giorgi, L. Lartigue, M.K. Bauer, A. Schubert, S. Grimm, G.T. Hanson, S.J.Remington, R.J. Youle, F. Ichas, The permeability transition pore signalsapoptosis by directing Bax translocation and multimerization, FASEB J. 16 (6)(2002) 607–609.

[109] P.-L. Kuo, Y.-L. Hsu, C.-H. Chang, C.-C. Lin, The mechanism of ellipticine-induced apoptosis and cell cycle arrest in human breast MCF-7 cancer cells,Cancer Lett. 223 (2) (2005) 293–301.

[110] B.E. Cham, Drug Therapy Solamargine and Other Solasodine RhamnosylGlycosides as Anticancer Agents, (2013) .

[111] J. Blankemeyer, M. McWilliams, J. Rayburn, M. Weissenberg, M. Friedman,Developmental toxicology of solamargine and solasonine glycoalkaloids infrog embryos, Food Chem. Toxicol. 36 (5) (1998) 383–389.

[112] A.M. Fewell, J.G. Roddick, M. Weissenberg, Interactions between theglycoalkaloids solasonine and solamargine in relation to inhibition offungal growth, Phytochemistry 37 (4) (1994) 1007–1011.

[113] A. Esteves-Souza, T.M. Silva, C.C.F. Alves, M.G. d. Carvalho, R. Braz-Filho, A.Echevarria, Cytotoxic activities against Ehrlich carcinoma and human K562leukaemia of alkaloids and flavonoid from two Solanum species, J. Braz.Chem. Soc. 13 (6) (2002) 838–842.

[114] B.E. Cham, Cancer intralesion chemotherapy with solasodine rhamnosylglycosides, Res. J. Biol. Sci 3 (9) (2008) 1008–1017.

[115] S. Punjabi, L. Cook, P. Kersey, R. Marks, R. Cerio, Solasodine glycoalkaloids: anovel topical therapy for basal cell carcinoma. A double-blind, randomized,placebo-controlled, parallel group, multicenter study, Int. J. Dermatol. 47 (1)(2008) 78–82.

[116] B.E. Cham, Topical solasodine rhamnosyl glycosides derived from theeggplant treats large skin cancers: two case reports, Int. J. Clin. Med. 2(2011) 473–477.

[117] J. MAder, H. Rawel, L.W. Kroh, Composition of phenolic compounds andglycoalkaloids a-solanine and a-chaconine during commercial potatoprocessing, J. Agric. Food Chem. 57 (14) (2009) 6292–6297.

[118] E. Allen, J. Feldmesser, Nematicidal activity of a-chaconine: effect ofhydrogen-ion concentration, J. Nematol. 3 (1) (1971) 58.

[119] H. Ripperger, Steroidal alkaloid glycosides from Solanum uporo,Phytochemistry 44 (4) (1997) 731–734.

http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0480http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0480http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0480http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0485http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0485http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0490http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0490http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0490http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0495http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0495http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0495http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0500http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0500http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0500http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0500http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0500http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0505http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0505http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0505http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0505http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0505http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0510http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0510http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0515http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0515http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0515http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0520http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0520http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0525http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0525http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0525http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0530http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0530http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0535http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0535http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0535http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0540http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0540http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0540http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0540http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0545http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0545http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0545http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0550http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0550http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0555http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0555http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0555http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0560http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0560http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0560http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0565http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0565http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0565http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0565http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0570http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0570http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0575http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0575http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0575http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0575http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0580http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0580http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0580http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0585http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0585http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0585http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0590http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0590http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0595http://refhub.elsevier.com/S0753-3322(17)32732-4/sbref0595

Aglycone solanidine and solasodine derivatives: A natural approach towards cancer1 Introduction2 Steroidal alkaloids/Glycoalkaloids3 Aglycone solanidine alkaloids3.1 Solanine3.1.1 Toxic effects of solanine3.1.2 Antitumor effects of solanine

3.2 Chaconine3.2.1 Anticancer activity of chaconine3.2.2 Antimetastasis of chaconine

4 Aglycone solasodine alkaloids4.1 Solamargine4.1.1 Anticancer effect of solamargine4.1.2 Cytotoxicity in human hepatic cell line4.1.3 The activity of solamargine against breast cell carcinoma

4.2 Solasonine

5 Solasodine rhamnose glycoside (SRGs)6 Conclusion7 Future directionsAuthors contributionConflict of interestAcknowledgementReferences

aglycone solanidine and solasodine derivatives: a natural ... 2017 - aglyco… · review aglycone...

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