Platinum–DNA Interactions and Subsequent Cellular Processes Controlling Sensitivity to Anticancer Platinum Complexes

Ahmad, Saeed

doi:10.1002/cbdv.200800340

Cited by 190 publications

(194 citation statements)

References 185 publications

(218 reference statements)

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“…First, conventional chemotherapeutics can be highly mutagenic (3). In fact, considerable work has gone into highlighting the mutagenic properties of platinum-based and other DNA adduct-forming chemotherapeutics as well as the genes that act in the cellular response to these toxins (4)(5)(6). Second, patients treated with conventional chemotherapies show significantly increased incidence of secondary malignancies, a phenomenon specifically tied to the mutagenic potential of genotoxic agents (7).…”

mentioning

confidence: 99%

Error-prone translesion synthesis mediates acquired chemoresistance

Xie¹,

Doles

Hemann

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

193

207

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The development of cancer drug resistance is a persistent clinical problem limiting the successful treatment of disseminated malignancies. However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. Error-prone translesional DNA synthesis (TLS) is known to underlie the mutagenic effects of numerous anticancer agents, but little is known as to whether mutation induced by this process is ultimately relevant to tumor drug resistance. Here, we use a tractable mouse model of B-cell lymphoma to interrogate the role of error-prone translesional DNA synthesis in chemotherapyinduced mutation and resistance to front-line chemotherapy. We find that suppression of Rev1, an essential TLS scaffold protein and dCMP transferase, inhibits both cisplatin-and cyclophosphamideinduced mutagenesis. Additionally, by performing repeated cycles of tumor engraftment and treatment, we show that Rev1 plays a critical role in the development of acquired cyclophosphamide resistance. Thus, chemotherapy not only selects for drug-resistant tumor population but also directly promotes the TLS-mediated acquisition of resistance-causing mutations. These data provide an example of an alteration that prevents the acquisition of drug resistance in tumors in vivo. Because TLS also represents a critical mechanism of DNA synthesis in tumor cells following chemotherapy, these data suggest that TLS inhibition may have dual anticancer effects, sensitizing tumors to therapy as well as preventing the emergence of tumor chemoresistance.DNA polymerase | cancer | chemotherapy | relapse T he development of acquired chemoresistance is a persistent clinical problem limiting the successful treatment of disseminated malignancies. Tumors that relapse following initial treatment frequently are refractory to subsequent administration of the initial drug regimen as well as to distinct sets of chemotherapeutics. Although a number of key pathways have been implicated in resistance to conventional chemotherapeutics, including enhanced drug efflux, increased drug metabolism, drug inactivation, enhanced DNA repair, and defects in apoptosis programs (1, 2), the mechanisms by which tumors develop drug resistance-causing mutations remains unclear.At its core, acquired chemoresistance represents the emergence of subpopulations of drug-resistant tumor cells, a phenomenon rooted in the inherent genetic heterogeneity of the tumor itself. This heterogeneity may occur as a consequence of tumor genetic instability, a process known to underlie tumor development in numerous malignancies. Alternatively, cancer therapy itself may promote mutation and subsequent chemoresistance in relapsed tumors. Support for the latter hypothesis comes from several observations. First, conventional chemotherapeutics can be highly mutagenic (3). In fact, considerable work has gone into highlighting the mutagenic properties of platinum-based and other DNA adduct-forming chemotherapeutics as well as the genes that act in the cellular res...

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mentioning

confidence: 99%

Error-prone translesion synthesis mediates acquired chemoresistance

Xie¹,

Doles

Hemann

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

193

207

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confidence: 99%

“…Although only 5 to 10% of covalently bound cisplatin is bound to DNA, it is this DNA damage that is largely responsible for its cytotoxic properties (4)(5)(6). The predominant forms of cisplatin-induced damage are intrastrand crosslinks: 1,2-(GpG) (65%), 1,2 (ApG) (25%), and 1,3 (GpNpG) (5-10%), with interstrand crosslinks and monoadducts accounting for 1 to 3% (4). Binding of HMGB proteins to 1,2-intrastrand crosslinks can contribute to cytotoxicity by shielding them from DNA repair (4,5), although interstrand crosslinks are a particularly cytotoxic form of DNA damage (7,8).…”

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confidence: 99%

“…The predominant forms of cisplatin-induced damage are intrastrand crosslinks: 1,2-(GpG) (65%), 1,2 (ApG) (25%), and 1,3 (GpNpG) (5-10%), with interstrand crosslinks and monoadducts accounting for 1 to 3% (4). Binding of HMGB proteins to 1,2-intrastrand crosslinks can contribute to cytotoxicity by shielding them from DNA repair (4,5), although interstrand crosslinks are a particularly cytotoxic form of DNA damage (7,8). Numerous mechanisms of cisplatin resistance have been identified, including decreasing drug uptake (e.g., by down-regulation of the copper transporter CTR1), increased efflux, and increased glutathione-based detoxification (6,9).…”

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confidence: 99%

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Suppression of Rev3, the catalytic subunit of Polζ, sensitizes drug-resistant lung tumors to chemotherapy

Doles¹,

Oliver²,

Cameron³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

164

148

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Platinum-based chemotherapeutic drugs are front-line therapies for the treatment of non-small cell lung cancer. However, intrinsic drug resistance limits the clinical efficacy of these agents. Recent evidence suggests that loss of the translesion polymerase, Polζ, can sensitize tumor cell lines to cisplatin, although the relevance of these findings to the treatment of chemoresistant tumors in vivo has remained unclear. Here, we describe a tumor transplantation approach that enables the rapid introduction of defined genetic lesions into a preclinical model of lung adenocarcinoma. Using this approach, we examined the effect of impaired translesion DNA synthesis on cisplatin response in aggressive late-stage lung cancers. In the presence of reduced levels of Rev3, an essential component of Polζ, tumors exhibited pronounced sensitivity to cisplatin, leading to a significant extension in overall survival of treated recipient mice. Additionally, treated Rev3-deficient cells exhibited reduced cisplatin-induced mutation, a process that has been implicated in the induction of secondary malignancies following chemotherapy. Taken together, our data illustrate the potential of Rev3 inhibition as an adjuvant therapy for the treatment of chemoresistant malignancies, and highlight the utility of rapid transplantation methodologies for evaluating mechanisms of chemotherapeutic resistance in preclinical settings.

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“…2). The DNA adducts interfere with DNA replication and transcription, and ultimately lead to cell death by cancer (Ahmad, 2010;Wang & Lippard, 2005). The predominant adducts formed by cisplatin in vitro are 1,2-intrastrand crosslinks.…”

Section: Cisplatin-dna Adductsmentioning

confidence: 99%

A DNA Repair Protein BRCA1 as a Potentially Molecular Target for the Anticancer Platinum Drug Cisplatin

Ratanaphan¹

2011

DNA Repair

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Platinum–DNA Interactions and Subsequent Cellular Processes Controlling Sensitivity to Anticancer Platinum Complexes

Cited by 190 publications

References 185 publications

Error-prone translesion synthesis mediates acquired chemoresistance

Error-prone translesion synthesis mediates acquired chemoresistance

Suppression of Rev3, the catalytic subunit of Polζ, sensitizes drug-resistant lung tumors to chemotherapy

A DNA Repair Protein BRCA1 as a Potentially Molecular Target for the Anticancer Platinum Drug Cisplatin

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