Novel strategies for reversing platinum resistance

Shahzad, Mian M.K.; López-Berestein, Gabriel; Sood, Anil K.

doi:10.1016/j.drup.2009.09.001

Cited by 59 publications

(43 citation statements)

References 71 publications

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“…Melanoma shows intrinsic resistance to cisplatin. A number of mechanisms of cisplatin resistance have been recognized in cancer cells: increased reflux, or increased inactivation by sulfhydryl molecules, such as glutathione; altered expression of proteins in signal transduction pathways that control apoptosis; increased DNA repair (Shahzad et al, 2009). An improved understanding of the mechanisms of resistance is needed to increase the utility of cisplatin for the treatment of cancer.…”

Section: Discussionmentioning

confidence: 99%

Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance

Melton

2011

Oncogene

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The incidence of malignant melanoma is growing rapidly worldwide and there is still no effective therapy for metastatic disease. Melanoma is the second most common cancer among young adults in the UK, where incidence rates have more than quadrupled since the 1970s. Increased expression of a number of DNA repair genes has been reported in melanoma and this likely contributes to its extreme resistance to conventional DNA-damaging chemotherapeutics. One such chemotherapeutic that is effective against a range of other cancers, but not melanoma, is cisplatin. The DNA repair proteins ERCC1 and XPF are needed to remove cisplatin-induced DNA damage and we have investigated the response of these proteins to cisplatin in melanoma. The expression of both genes is induced by cisplatin. Use of a MEK inhibitor showed that ERCC1, but not XPF induction was regulated by the mitogen-activated protein kinase (MAPK) pathway, with reduction in expression of DUSP6, the phosphatase that inactivates the extracellular signal-regulated kinase (ERK), being particularly important. DUSP6 overexpression prevented cisplatin induction of both ERCC1 and XPF, resulting in increased sensitivity to cisplatin. A novel ERCC1 mRNA was found that initiated upstream of the normal transcription initiation site, and was strongly regulated by both cisplatin and the MAPK pathway and its role in cisplatin resistance merits further study. The cisplatin induction of ERCC1 and XPF provides important insights into the resistance of melanoma to DNA-damaging chemotherapeutics, which is one of the major obstacles to melanoma treatment.

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Section: Discussionmentioning

confidence: 99%

Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance

Melton

2011

Oncogene

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“…Responses are observed in up to~80% of patients; however, 70-80% of responding patients will relapse, requiring further systemic chemotherapy [2]. Patients who relapse >6-12 months after completing platinum-based chemotherapy may respond again to platinum-based therapy, but repeated use of platinum agents can be limited due to acquired resistance or intolerance [3].…”

Section: Introductionmentioning

confidence: 99%

Phase II study of MLN8237 (alisertib), an investigational Aurora A kinase inhibitor, in patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal carcinoma

Matulonis

Sharma

Ghamande

et al. 2012

Gynecologic Oncology

127

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“…Chemoresistance, a common development in ovarian carcinomas, is a major hurdle that significantly hinders treatment success [5,6]. Recent evidence suggests that the dysregulation of pro-apoptotic genes is a key factor for the onset and maintenance of chemoresistance [5,7].…”

Section: Introductionmentioning

confidence: 99%

Secreted frizzled-related protein 4 expression is positively associated with responsiveness to Cisplatin of ovarian cancer cell lines in vitro and with lower tumour grade in mucinous ovarian cancers

et al. 2012

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BackgroundOvarian cancer is one of the most lethal malignancies in women, as it is frequently detected at an advanced stage, and cancers often become refractory to chemotherapy. Evidence suggests that dysregulation of pro-apoptotic genes plays a key role in the onset of chemoresistance. The secreted Frizzled-Related Protein (sFRP) family is pro-apoptotic and also a negative modulator of the Wnt signalling cascade. Studies have demonstrated that the re-expression of sFRPs, in particular sFRP4, is associated with a better prognosis, and that experimentally induced expression results in cell death.ResultsIn vitro experimental models determined that sFRP4 was differentially expressed in chemosensitive (A2780) and chemoresistant (A2780 ADR and A2780 Cis) ovarian cell lines, with chemosensitive cells expressing significantly higher levels of sFRP4. Transfection of the chemoresistant cell lines with sFRP4 significantly increased their sensitivity to chemotherapy. Conversely, silencing of sFRP4 expression in the chemosensitive cell line resulted in a corresponding increase in chemoresistance. Comparison of sFRP4 expression in tumour biopsies revealed a positive trend between sFRP4 expression and tumour grade, with mucinous cyst adenocarcinomas exhibiting significantly decreased sFRP4 levels compared to mucinous borderline tumours.ConclusionsThis study indicates a role for sFRP4 as a predictive marker of chemosensitivity in ovarian cancer and suggests that this pathway may be worth exploiting for novel therapies.

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Novel strategies for reversing platinum resistance

Cited by 59 publications

References 71 publications

Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance

Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance

Phase II study of MLN8237 (alisertib), an investigational Aurora A kinase inhibitor, in patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal carcinoma

Secreted frizzled-related protein 4 expression is positively associated with responsiveness to Cisplatin of ovarian cancer cell lines in vitro and with lower tumour grade in mucinous ovarian cancers

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