DNA Repair in Cancer TherapyDNA Repair in Cancer TherapyDNA Repair in Cancer TherapyDNA Repair in Cancer Therapy

Cancer therapyCancer therapy

Cancer treatments have traditionally been divided into three categories

1. Chemotherapy

2. Radiation therapy

3. Surgery

Reviewed in:

Raffoul, J.J., Heydari, S.R. and Hillman, G.G., Journal of Oncology , 2012

Chemotherapy is based on targeting rapidly proliferating cells (cancer) by damaging their DNA with one or more cytotoxic drugs.

Radiation therapy also targets rapidly proliferating cells and damage their DNA.

Cancer therapyCancer therapy

Chemotherapy is not localized to a specific tissue or area of the body

Chemotherapy can also be used together with radiation or surgical methods toeradicate the primary tumor and circulating cancer cells.

Reviewed in:

Raffoul, J.J., Heydari, S.R. and Hillman, G.G., Journal of Oncology , 2012

Cancers continually evolve to develop drug resistance, making them difficult to completely destroy. When a cancer reaches the point of multi-drug resistance, there are limited treatment options.

In contrast, radiation and surgical techniques are targeted treatments.

One important mechanism by which cancer cells can develop multi-drug resistance is to increase their DNA repair capacity.

Drugs or radiation kill cancer cells in tumors; however, rapidly growing tumors accumulate mutations that may lead to overexpression of DNA repair genes

Such tumors may be favored by natural selection to become capable of surviving and thus develop greater DNA repair capacity than normal tissues.

Cancer therapyCancer therapy

Reviewed in:

Raffoul, J.J., Heydari, S.R. and Hillman, G.G., Journal of Oncology , 2012

Inhibition of DNA repairInhibition of DNA repair

thus develop greater DNA repair capacity than normal tissues.

The toxicity of chemotherapy drugs can be reduced in cancer cells by DNA repairthat remove DNA lesions before they become toxic. The efficacy of cancer therapycan thus be influenced by DNA repair capacity.

Therefore, DNA repair pathways are promising targets for novel cancer treatments

Inhibition of DNA repair in cancer therapyInhibition of DNA repair in cancer therapy

Sensitizing cells to DNA damaging agents by targeting DNA repair pathways isan emerging concept that is receiving much attention.

Altering the ability of a cancer cell to respond to DNA damaging agents shouldrender a cell more susceptible to death.

Reviewed in:

Raffoul, J.J., Heydari, S.R. and Hillman, G.G., Journal of Oncology , 2012

It is therefore worth pursuing new strategies of cancer therapy that target DNA repair.

Inhibition of DNA repair in cancer therapyInhibition of DNA repair in cancer therapy

DNA repair inhibitors may be used to selectively kill cancer cells.

DNA repair inhibitors can be used in combination with DNA damage-basedchemotherapeutic drugs.

These inhibitors will prevent the removal of toxic DNA lesions by DNA repair,and thus increase the efficacy of the therapy.

Reviewed in:

Raffoul, J.J., Heydari, S.R. and Hillman, G.G., Journal of Oncology , 2012

Inhibiting DNA repair enzymes is of great interest in new drug development for cancer therapy

and thus increase the efficacy of the therapy.

“A through understanding of DNA repair pathways dysregulated during carcinogenesis andneoplastic progression, as well as types of DNA damage induced during cancer development,may hold the key to the breakthrough in improving therapy in the fight against cancer.”

Aziz, K., Nowsheen, S. and Georgakilas, A.G., Curr. Mol. Med. 10, 626-639, 2010

DNA repair and cancer therapy DNA repair and cancer therapy

“A knowledge of DNA repair proteins’ overexpression or underexpression in cancers will helppredict and guide development of treatments, and yield the greatest therapeutic response.”

Kelley, M. R., DNA Repair in Cancer Therapy, Elsevier, 2012

Cancer treatments and their effectsCancer treatments and their effects

Various anticancer treatments, the types of DNA damage they causeand the DNA repair pathways that are activated to generate repairs

Reviewed in:

Kelley, M., DNA Repair in Cancer Therapy, Elsevier, 2012

DNA repair pathways that repair DNA lesions formed by cancer therapyDNA repair pathways that repair DNA lesions formed by cancer therapy

NHEJ: non-homologous end joining

BER: base excision repair

NER: nucleotide excision repair

SSBR: ss-DNA break repair

ENDO: endonuclease-mediated repair

HR: homologous recombination

FA: Fanconie anamia repair

Reviewed in:

Helleday, T., Petermann, E., Lunding, C., Hodgson, B. and Sharma, R.A., Nature Reviews Cancer 8, 193-204, 2008

Mechanisms of base excision repairMechanisms of base excision repair

repaired DNA repaired DNA

Reviewed in:

Hoeijmakers, J.H.J., Nature 411, 366-374, 2001

Friedberg, E.C., Walker, G.C., Siede, W., Wood, R.D., Schultz, R.A. and Ellenberger, T., DNA Repair and Mutagenesis, 2006

Mechanisms of nucleotide excision repairMechanisms of nucleotide excision repair

Reviewed in:

Sancar, A., Science 266, 1954–1956, 1994

Friedberg, E.C., Walker, G.C., Siede, W., Wood, R.D., Schultz, R.A. and Ellenberger, T., DNA Repair and Mutagenesis, 2006

Poly (ADP-ribose) polymerase 1 (PARP1)

PARP1 is required for the efficient repair of apurinic/apyrimidic sites and single-stranded DNA breaks.

It also interacts with BRCA1 and BRCA2.

Cells deficient in BRCA1 or BRCA2 are highly sensitive to PARP1 inhibition.

Targeted DNA repair enzymesTargeted DNA repair enzymes

Apurinic/apyrimidic endonuclease 1 (APE1)

O6-methylguanine-DNA methyl transferase (MGMT)

MGMT is an alkyl transferase that removes alkylations on the O6-position of guanine produced by anticancer agents.

Reviewed in:

Helleday, T., Petermann, E., Lunding, C., Hodgson, B. and Sharma, R.A., Nature Reviews Cancer 8, 193-204, 2008

Kelley, M., DNA Repair in Cancer Therapy, Elsevier, 2012

APE1 hydrolyzes the phosphate bond at 5' to the apurinic/apyrimidic site (AP site or abasic site), causing a strand breaks and leaving a 3'-OH group and a 5‘-deoxyribose-phosphate terminus.

Clinical trials of DNA repair inhibitorsClinical trials of DNA repair inhibitors

Reviewed in:

Helleday, T., Petermann, E., Lunding, C., Hodgson, B. and Sharma, R.A., Nature Reviews Cancer 8, 193-204, 2008

PARP: poly (ADP-ribose) polymerase

BER: base excision repair

MGMT: O-6-methylguanine-DNA methyl transferase

Inhibition of APE1 in cancer therapyInhibition of APE1 in cancer therapy

TMZ, temozolomideIR, ionizing radiation

Reviewed in:

Kelley, M., DNA Repair in Cancer Therapy, Elsevier, 2012

Potential biomarkers and DNA repair inhibitors in developmentPotential biomarkers and DNA repair inhibitors in development

Reviewed in:

Kelley, M., DNA Repair in Cancer Therapy, Elsevier, 2012

Substrates of NEIL1 proteinSubstrates of NEIL1 protein

Repair inhibitors of human NEIL1 proteinRepair inhibitors of human NEIL1 protein

enzyme amount (µµµµg)

excise

d leve

l(lesion

s/106DNA b

ase

s)

FapyGua

FapyAde

8-OH-Gua

Hazra, T.K., Izumi, T., Boldogh, I., Imhoff, B., Kow, Y.W., Pawel Jaruga, P., Dizdaroglu, M. and Mitra, S., Proc. Natl. Acad. Sci., USA 99, 3523-3528, 2002

Jaruga, P., Birincioglu, M., Rosenquist, T. A., and Dizdaroglu, M., Biochemistry 43, 15909-15914, 2004

Roy, L., Jaruga, P., Wood, T.G., McCullough, A.K., Dizdaroglu, M. and Lloyd, R.S., J. Biol. Chem. 282, 15790-15798, 2007

Liu, M., Bandaru, V., Bond, J. P., Jaruga, P., Zhao, X., Christov, P. P., Burrows, C. J., Rizzo, C. J., Dizdaroglu, M. and Wallace, S. S., Proc. Natl. Acad. Sci. USA 107, 4925-4930, 2010

Repair inhibitors of human NEIL1 proteinRepair inhibitors of human NEIL1 protein

45

60

75

06D

NA

bases)

120

160

06D

NA

bases)

cont

rol

NEI

L1N

EIL

1 +

#2N

EIL

1 +

#6N

EIL

1 +

#7N

EIL

1 +

#8

NE

IL1

+ #1

1

NE

IL1

+ #1

9

0

15

30

level (lesio

ns/1

0

cont

rol

NEI

L1N

EIL

1 +

#2N

EIL

1 +

#6N

EIL

1 +

#7N

EIL

1 +

#8

NE

IL1

+ #1

1

NE

IL1

+ #1

9

0

40

80

level (lesio

ns/1

0