Spontaneous development of drug resistance: mismatch repair and p53 defects in resistance to cisplatin in human tumor cells

Branch, Pauline; Masson, Maryse; Aquilina, Gabriele; Bignami, Margherita; Karran, Peter

doi:10.1038/sj.onc.1203668

Cited by 101 publications

(65 citation statements)

References 29 publications

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“…The presence of wt MLH1 (OVCAR3) or a re-expression in an MLH1-defective A2780 variant did not significantly alter the proliferation rate in cisplatin response, but significantly increased sensitivity to 6-TG, a chemotherapeutic purine nucleoside analogue, the primary mechanism of action of which is dependent on the presence of a functional DNA MMR system (Hawn et al, 1995;Buermeyer et al, 1999;Yan et al, 2003) consistent with earlier reports Branch et al, 2000). However, both 6-TG and cisplatin induced an MLH1-dependent apoptosis and arrest in the G2/M phase of cell cycle (our unpublished observations), consistent with earlier reports in OVCAR3 Kolfschoten et al, 2002) (O'Brien andBrown, 2006).…”

Section: Discussionsupporting

confidence: 79%

“…A relationship between MMR status and sensitivity to cisplatin and platinum analogues has been widely reported (Aebi et al, 1996;Drummond et al, 1996;Brown et al, 1997;Fink et al, 1998b;Moreland et al, 1999;Massey et al, 2003;Helleman et al, 2006). Earlier studies using repair-defective variants of the A2780 (MLH1 proficient, wtp53) ovarian cell line have shown that MLH1 restoration sensitises cells to DNA-damaging agents, although sensitivity to cisplatin remained significantly dependent on p53 function Branch et al, 2000). Consistent with this, cisplatin-resistant ovarian cell lines have been observed to acquire an MSI phenotype and are defective in strand-specific MMR (Watanabe et al, 2001).…”

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confidence: 99%

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MLH1 expression sensitises ovarian cancer cells to cell death mediated by XIAP inhibition

et al. 2009

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BACKGROUND: The X-linked inhibitor of apoptosis protein (XIAP), an endogenous apoptosis suppressor, can determine the level of caspase accumulation and the resultant response to apoptosis-inducing agents such as cisplatin in epithelial ovarian cancer (EOC). In addition, the mismatch repair protein, hMLH1, has been linked to DNA damage-induced apoptosis by cisplatin by both p53-dependent and -independent mechanisms. METHODS: In this study, hMLH1 expression was correlated with clinical response to platinum drugs and survival in advanced stage (III -IV) EOC patients. We then investigated whether MLH1 loss was a determinant in anti-apoptosis response to cisplatin mediated by XIAP in isogenic and established EOC cell lines with differential p53 status. RESULTS: The percentage of cells undergoing cisplatin-induced cell killing was higher in MLH1-proficient cells than in MLH1-defective cells. In addition, the presence of wild-type hMLH1 or hMLH1 re-expression significantly increased sensitivity to 6-thioguanine, a MMR-dependent agent. Cell-death response to 6-thioguanine and cisplatin was associated with significant proteolysis of MLH1, with XIAP destabilisation and increased caspase-3 activity. The siRNA-mediated inhibition of XIAP increased MLH1 proteolysis and cell death in MLH1-proficient cells but not in MLH1-defective cells. CONCLUSION: These data suggest that XIAP inhibitors may prove to be an effective means of sensitising EOC to MLH1-dependent apoptosis.

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Section: Discussionsupporting

confidence: 79%

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confidence: 99%

MLH1 expression sensitises ovarian cancer cells to cell death mediated by XIAP inhibition

et al. 2009

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“…These results therefore fail to demonstrate a role for Msh2 in mutation surveillance following cisplatin treatment and question the signi®cance of mismatch repair in the clearance of cisplatin-induced DNA damage in normal cells. Our ®ndings complement recent studies by Branch et al (2000), who demonstrated that loss of MMR was only a minor contributor to cisplatin resistance in ovarian tumour cell lines.…”

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confidence: 78%

Msh-2 suppresses in vivo mutation in a gene dose and lesion dependent manner

et al. 2001

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Mice de®cient for the mismatch repair (MMR) gene Msh2 show accelerated tumourigenesis and a reduced apoptotic response to DNA damage of methylation type. Here we examine the e ect of mutation for Msh2 on in vivo mutation frequencies in the intestine as determined by loss of function at the Dolichos bi¯orus (Dlb-1) locus. Spontaneous mutation frequencies were scored in cohorts of ageing mice either wild type or mutant for Msh2. In mice less than 1 year old, mutation frequencies were only elevated in Msh2 null mice. However, beyond this age heterozygous Msh2 mice showed signi®cantly higher mutation frequencies than controls. These ®ndings implicate a gene dose dependent requirement for Msh2 in mutation suppression and prompted an analysis of young Msh2 mutants following exposure to DNA damage. Following exposure to N-methyl-N'-nitro-Nnitrosoguanidine (MNNG), Msh2 de®cient mice show a reduced apoptotic response and an increase in mutation frequency. Heterozygotes did not di er from controls. Following exposure to cisplatin, no signi®cant elevation was seen in mutation frequencies, even within homozygotes. This is particularly surprising given the association between cisplatin resistance and MMR de®ciency. These ®ndings therefore demonstrate a complex reliance upon functional Msh2 in mutation surveillance. We have identi®ed three separate scenarios. First, where retention of both Msh2 alleles over an extended period of time appears critical to the suppression of spontaneous mutation; second, 3 weeks following exposure to MNNG, where only complete loss of Msh2 results in elevated mutation; and ®nally following cisplatin exposure, where induced levels of mutation are independent of Msh2 status. Oncogene

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“…This has been documented in vitro, by comparing the sensitivity to cisplatin of a wide panel of TP53-proficient and -deficient tumor cell lines (O'Connor et al, 1997;Branch et al, 2000), and also in vivo, in the clinical setting (Hengstler et al, 2001). Thus, ovarian cancer patients harboring wild-type TP53 reportedly have a higher probability to benefit from cisplatin-based chemotherapy than patients with TP53 mutations (Gadducci et al, 2002;Feldman et al, 2008).…”

Section: Mechanism Of Post-target Resistancementioning

confidence: 99%

Molecular mechanisms of cisplatin resistance

et al. 2011

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Platinum-based drugs, and in particular cis-diamminedichloroplatinum(II) (best known as cisplatin), are employed for the treatment of a wide array of solid malignancies, including testicular, ovarian, head and neck, colorectal, bladder and lung cancers. Cisplatin exerts anticancer effects via multiple mechanisms, yet its most prominent (and best understood) mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of mitochondrial apoptosis. Despite a consistent rate of initial responses, cisplatin treatment often results in the development of chemoresistance, leading to therapeutic failure. An intense research has been conducted during the past 30 years and several mechanisms that account for the cisplatin-resistant phenotype of tumor cells have been described. Here, we provide a systematic discussion of these mechanism by classifying them in alterations (1) that involve steps preceding the binding of cisplatin to DNA (pre-target resistance), (2) that directly relate to DNAcisplatin adducts (on-target resistance), (3) concerning the lethal signaling pathway(s) elicited by cisplatin-mediated DNA damage (post-target resistance) and (4) affecting molecular circuitries that do not present obvious links with cisplatin-elicited signals (off-target resistance). As in some clinical settings cisplatin constitutes the major therapeutic option, the development of chemosensitization strategies constitute a goal with important clinical implications.

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Spontaneous development of drug resistance: mismatch repair and p53 defects in resistance to cisplatin in human tumor cells

Cited by 101 publications

References 29 publications

MLH1 expression sensitises ovarian cancer cells to cell death mediated by XIAP inhibition

MLH1 expression sensitises ovarian cancer cells to cell death mediated by XIAP inhibition

Msh-2 suppresses in vivo mutation in a gene dose and lesion dependent manner

Molecular mechanisms of cisplatin resistance

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