Targeting DNA repair pathways: A novel approach to reduce cancer therapeutic resistance

doi:10.1016/j.ctrv.2009.06.005

Cancer Treatment Reviews

Volume 35, Issue 7, November 2009, Pages 590-596

https://doi.org/10.1016/j.ctrv.2009.06.005 Get rights and content

Summary

Increased chemo-resistance and radio-resistance of cancer cells is a major obstacle in the treatment and management of malignant cancers. An important mechanism that underlies the development of such therapeutic resistance is that cancer cells recognize DNA lesions induced by DNA-damaging agents and by ionizing radiation, and repair these lesions by activating various DNA repair pathways. Therefore, Use of pharmacological agents that can inhibit certain DNA repair pathways in cancer cells has the potential for enhancing the targeted cytotoxicity of anticancer treatments and reversing the associated therapeutic resistance associated with DNA repair; such agents, offering a promising opportunity to achieve better therapeutic efficacy. Here we review the major DNA repair pathways and discuss recent advances in the development of novel inhibitors of DNA repair pathways; many of these agents are under preclinical/clinical investigation.

Introduction

Chemotherapeutic agents and ionizing radiation (IR) are widely used in the treatment of cancer because of their ability to directly or indirectly damage DNA, the notion being that formation of DNA breaks, and/or interference with various DNA-associated proteins, might disrupt normal processes such as replication, transcription and/or recombination, and thus result in cell death.¹ The outcome of such treatment, i.e., whether the cell will survive or die, depends on how the cell responds to the cytotoxic DNA lesions by cell cycle arrest or by initiating DNA repair.² Normal cells are proficient in reversing the DNA lesions induced by various chemotherapeutic drugs and IR by activating appropriate repair mechanisms. A similar capacity for cancer cells to effectively recognize DNA damage and initiate DNA repair pathways, however, leads to the phenomenon of therapeutic resistance to many anticancer agents³; on the other hand, owing to inherited or somatic mutations in certain DNA repair genes, cancer cells would rely much more than normal cells on the unaffected and functioning DNA repair mechanisms.⁴ Therefore, pharmacological agents that can manipulate the DNA repair system have the potential for enhancing the cytotoxic effects of chemotherapeutic agents and IR in cancer cells. Indeed, there are reports that the enhancement of DNA repair is one of the crucial mechanisms governing the chemoresistance of tumor cells to DNA-damaging agents, and defects in DNA repair pathways result in hypersensitivity to these agents.[5], [6] In this review, we briefly summarize the major DNA repair pathways, then focus on recent progress in manipulating DNA repair pathways to achieve better therapeutic outcomes with use of current anticancer agents, and to develop novel anti-tumor drugs (Fig. 1).

Section snippets

Double strand breaks (DSBs) and single strand breaks (SSBs)

DSBs are extremely toxic DNA lesions that can lead to cell death or deleterious mutations if left unrepaired.⁷ DSBs may be induced directly or indirectly by many common anticancer agents/treatment. Direct DSBs are also referred to as replication-independent DSBs, since they can be induced by ionizing radiation, UV light (photodynamic therapy), free radicals, and radiomimetic agents such as bleomycin, which are capable of killing non-replicating cells⁸; direct DSBs mediate the specific killing

Direct repair (DR) pathway

DNA direct repair pathway is mainly mediated by the DNA repair protein O6-alkylguanine DNA alkyltransferase (AGT) encoded by the O6-methylguanine-DNA-methyltransferase (MGMT) gene, which transfers the methyl/alkyl adducts from the O6 position of guanine, O4-methyl thymine, O6-ethylguanine and O6-chloroethylguanine to the cysteine residue within its active site, independently from other proteins and without causing DNA strand breaks.¹⁹ AGT repairs with a stechiometric and auto-inactivating

Targeting the direct repair pathway

It has long been known that MGMT contributes to resistance to anticancer drugs[36], [37], [38] such as methylating agents like temozolomide, dacarbazine and procarbazine, and chloroethylating agents such as chloroethylnitrosoureas like BCNU, CCNU or fotemustine, by irreversibly transferring the “toxic” adducts to its own cysteine residue.[39], [40], [41] Significant preclinical data indicates an inverse correlation between the amount of MGMT and the sensitivity to methylating and

Conclusions

The problem of tumor resistance presents a major obstacle to the efficacy of most non-surgical anticancer strategies. Understand the cellular and molecular basis for innate and/or acquired resistance of cancer cells to chemotherapeutic agents and radiotherapy is thus a prerequisite for overcoming this difficulty. In the past decade, great strides have been made in discovering and analyzing a number of DNA repair pathways, and recent developments suggest that specific components of these

Conflict of interest statement

The authors declare no competing conflict of interest.

Acknowledgements

We would like to thank Dr. Sonal Jhaveri for her comments on the manuscript. This work is supported in part by grant from the Zhejiang Provincial Administration of Traditional Chinese Medicine to J.H. (Grant 2009CA044).

References (89)

P.D. Lawley et al.
DNA adducts from chemotherapeutic agents
Mutat Res
(1996)
A.R. Kinsella et al.
Tumor resistance to antimetabolites
Gen Pharmacol
(1998)
U. Kellner et al.
Culprit and victim – DNA topoisomerase II
Lancet Oncol
(2002)
M. D’Incalci et al.
Importance of the DNA repair enzyme O6-alkyl guanine alkyltransferase (AT) in cancer chemotherapy
Cancer Treat Rev
(1988)
M.R. Middleton et al.
Improvement of chemotherapy efficacy by inactivation of a DNA-repair pathway
Lancet Oncol
(2003)
A. Sabharwal et al.
Exploiting the role of O6-methylguanine-DNA-methyltransferase (MGMT) in cancer therapy
Curr Opin Pharmacol
(2006)
M. Bignami et al.
Mismatch repair and response to DNA-damaging antitumour therapies
Eur J Cancer
(2003)
M.L. Hefferin et al.
Mechanism of DNA double-strand break repair by non-homologous end joining
DNA Repair (Amst)
(2005)
C.H. Bassing et al.
The cellular response to general and programmed DNA double strand breaks
DNA Repair (Amst)
(2004)
E.M. Duguid et al.
The structure of the human AGT protein bound to DNA and its implications for damage detection
J Mol Biol
(2005)

M. Gander et al.

Sequential administration of temozolomide and fotemustine: depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes and in tumours

Ann Oncol

(1999)

B. Gerard et al.

Activity and unexpected lung toxicity of the sequential administration of two alkylating agents – dacarbazine and fotemustine – in patients with melanoma

Eur J Cancer

(1993)

Y. Maki et al.

Role of O6-methylguanine-DNA methyltransferase and effect of O6-benzylguanine on the anti-tumor activity of cis-diaminedichloroplatinum(II) in oral cancer cell lines

Oral Oncol

(2005)

T. Izumi et al.

Mammalian DNA base excision repair proteins: their interactions and role in repair of oxidative DNA damage

Toxicology

(2003)

P. Taverna et al.

Methoxyamine potentiates DNA single strand breaks and double strand breaks induced by temozolomide in colon cancer cells

Mutat Res

(2001)

M.L. Fishel et al.

The DNA base excision repair protein Ape1/Ref-1 as a therapeutic and chemopreventive target

Mol Aspects Med

(2007)

H.Y. Hu et al.

Identification of small molecule synthetic inhibitors of DNA polymerase beta by NMR chemical shift mapping

J Biol Chem

(2004)

J.F. Haince et al.

Targeting poly(ADP-ribosyl)ation: a promising approach in cancer therapy

Trends Mol Med

(2005)

P.A. Nguewa et al.

Poly(ADP-ribose) polymerases: homology, structural domains and functions. Novel therapeutical applications

Prog Biophys Mol Biol

(2005)

C.J. Bakkenist et al.

Initiating cellular stress responses

Cell

(2004)

E. Willmore et al.

A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia

Blood

(2004)

G. Brownlee

Chemotherapeutic drugs; a review

Ann R Coll Surg Engl

(1949)

H. Vermund et al.

Mechanisms of action of radiotherapy and chemotherapeutic adjuvants. A review

Cancer

(1968)

G. Lehne et al.

Challenging drug resistance in cancer therapy – review of the first Nordic conference on chemoresistance in cancer treatment, October 9th and 10th, 1997

Acta Oncol

(1998)

M. Berwick et al.

Markers of DNA repair and susceptibility to cancer in humans: an epidemiologic review

J Natl Cancer Inst

(2000)

D.B. Longley et al.

Molecular mechanisms of drug resistance

J Pathol

(2005)

B.B. Zhou et al.

Targeting the checkpoint kinases: chemosensitization versus chemoprotection

Nat Rev Cancer

(2004)

K.K. Khanna et al.

DNA double-strand breaks: signaling, repair and the cancer connection

Nat Genet

(2001)

R.B. Painter et al.

Repair replication in HeLa cells after large doses of x-irradiation

Nature

(1967)

A. Kuzminov

Single-strand interruptions in replicating chromosomes cause double-strand breaks

Proc Natl Acad Sci USA

(2001)

N. Saleh-Gohari et al.

Spontaneous homologous recombination is induced by collapsed replication forks that are caused by endogenous DNA single-strand breaks

Mol Cell Biol

(2005)

X. Li et al.

Homologous recombination in DNA repair and DNA damage tolerance

Cell Res

(2008)

L.H. Hurley

DNA and its associated processes as targets for cancer therapy

Nat Rev Cancer

(2002)

M. Bouziane et al.

Repair of DNA alkylation damage

Acta Biochim Pol

(1998)

J.C. Wang

Cellular roles of DNA topoisomerases: a molecular perspective

Nat Rev Mol Cell Biol

(2002)

Y. Pommier

Topoisomerase I inhibitors: camptothecins and beyond

Nat Rev Cancer

(2006)

S.L. Gerson

MGMT: its role in cancer aetiology and cancer therapeutics

Nat Rev Cancer

(2004)

T. Duncan et al.

Reversal of DNA alkylation damage by two human dioxygenases

Proc Natl Acad Sci USA

(2002)

K.K. Chan et al.

Base excision repair fidelity in normal and cancer cells

Mutagenesis

(2006)

A. Sancar et al.

Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints

Annu Rev Biochem

(2004)

P.C. Hanawalt

Subpathways of nucleotide excision repair and their regulation

Oncogene

(2002)

J.E. Cleaver

Cancer in xeroderma pigmentosum and related disorders of DNA repair

Nat Rev Cancer

(2005)

M.J. Schofield et al.

DNA mismatch repair: molecular mechanisms and biological function

Annu Rev Microbiol

(2003)

S.P. Scott et al.

The cellular control of DNA double-strand breaks

J Cell Biochem

(2006)

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ANTI-TUMOUR TREATMENTTargeting DNA repair pathways: A novel approach to reduce cancer therapeutic resistance

Summary

Introduction

Section snippets

Double strand breaks (DSBs) and single strand breaks (SSBs)

Direct repair (DR) pathway

Targeting the direct repair pathway

Conclusions

Conflict of interest statement

Acknowledgements

Mutat Res

Gen Pharmacol

Lancet Oncol

Cancer Treat Rev

Lancet Oncol

Curr Opin Pharmacol

Eur J Cancer

DNA Repair (Amst)

DNA Repair (Amst)

J Mol Biol

Ann Oncol

Eur J Cancer

Oral Oncol

Toxicology

Mutat Res

Mol Aspects Med

J Biol Chem

Trends Mol Med

Prog Biophys Mol Biol

Cell

Blood

Chemotherapeutic drugs; a review

Ann R Coll Surg Engl

Mechanisms of action of radiotherapy and chemotherapeutic adjuvants. A review

Cancer

Challenging drug resistance in cancer therapy – review of the first Nordic conference on chemoresistance in cancer treatment, October 9th and 10th, 1997

Acta Oncol

Markers of DNA repair and susceptibility to cancer in humans: an epidemiologic review

J Natl Cancer Inst

Molecular mechanisms of drug resistance

J Pathol

Targeting the checkpoint kinases: chemosensitization versus chemoprotection

Nat Rev Cancer

DNA double-strand breaks: signaling, repair and the cancer connection

Nat Genet

Repair replication in HeLa cells after large doses of x-irradiation

Nature

Single-strand interruptions in replicating chromosomes cause double-strand breaks

Proc Natl Acad Sci USA

Spontaneous homologous recombination is induced by collapsed replication forks that are caused by endogenous DNA single-strand breaks

Mol Cell Biol

Homologous recombination in DNA repair and DNA damage tolerance

Cell Res

DNA and its associated processes as targets for cancer therapy

Nat Rev Cancer

Repair of DNA alkylation damage

Acta Biochim Pol

Cellular roles of DNA topoisomerases: a molecular perspective

Nat Rev Mol Cell Biol

Topoisomerase I inhibitors: camptothecins and beyond

Nat Rev Cancer

MGMT: its role in cancer aetiology and cancer therapeutics

Nat Rev Cancer

Reversal of DNA alkylation damage by two human dioxygenases

Proc Natl Acad Sci USA

Base excision repair fidelity in normal and cancer cells

Mutagenesis

Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints

Annu Rev Biochem

Subpathways of nucleotide excision repair and their regulation

Oncogene

Cancer in xeroderma pigmentosum and related disorders of DNA repair

Nat Rev Cancer

DNA mismatch repair: molecular mechanisms and biological function

Annu Rev Microbiol

The cellular control of DNA double-strand breaks

J Cell Biochem

ANTI-TUMOUR TREATMENT
Targeting DNA repair pathways: A novel approach to reduce cancer therapeutic resistance