Mechanisms of Resistance to Camptothecins

Saleem, Ahamed; Edwards, Troy K.; Rasheed, Zeshaan A.; Rubin, Eric H.

doi:10.1111/j.1749-6632.2000.tb07024.x

Cited by 49 publications

(23 citation statements)

References 30 publications

(40 reference statements)

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“…This drug is approved for treatment of colon and lung cancers and shows promising activity against a number of other cancers including cervical, ovarian carcinomas, and also neuroblastoma (16). However, the clinical response rates for irinotecan for some cancers have been lower than expected from xenograft models, for reasons that are largely unknown (17). The finding that MRP4 confers resistance to irinotecan in vitro suggests that its expression may be one factor that impinges on the efficacy of Irinotecan in specific tumors.…”

Section: Discussionmentioning

confidence: 83%

Expression of multidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro

Norris

Smith

Tanabe

et al. 2005

Molecular Cancer Therapeutics

127

105

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Members of the multidrug resistance -associated protein (MRP) family of transporters are believed to contribute to cytotoxic drug resistance and chemotherapy failure. We observed frequent MRP4 overexpression in aggressive primary neuroblastoma, a disease for which we have previously shown MRP1 to be a prognostic indicator. High MRP4 expression correlated with MYCN oncogene amplification and was significantly associated with poor clinical outcome. Although MRP4 is known to transport some nucleoside analogues, it has not previously been associated with resistance to drugs used to treat solid tumors. We now show that it mediates substantial resistance in vitro to the topoisomerase I poison irinotecan/CPT-11 and its active metabolite SN-38. These results suggest that MRP4 will be a useful prognostic marker for neuroblastoma and that clinical trials of irinotecan as a neuroblastoma treatment should monitor MRP4 expression. The same may be true for other tumor types expressing high levels of the transporter. [Mol Cancer Ther 2005;4(4):547 -53]

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Section: Discussionmentioning

confidence: 83%

Expression of multidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro

Norris

Smith

Tanabe

et al. 2005

Molecular Cancer Therapeutics

127

105

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“…Top1 plays an essential role in cell metabolism and survival and it is a primary target of camptothecins [10,12,24]. The conventional role of human Top1 comprises of the relaxation of DNA supercoiling and relief of torsional strain during DNA processing, including replication, transcription and repair.…”

Section: Discussionmentioning

confidence: 99%

NSC606985, a novel camptothecin analog, induces apoptosis and growth arrest in prostate tumor cells

Tan

Cai

et al. 2008

Cancer Chemother Pharmacol

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Purpose-Prostate cancer is a major cause of cancer mortality in American males. Once prostate cancer has metastasized, there is currently no curative therapy available. The development of effective agents is therefore a continuing effort to combat this disease. In the present study, the effects and potential mechanisms of NSC606985 (NSC), a water-soluble camptothecin analog, in prostate cancer cells were investigated.Methods-Prostatic tumor cells, DU-145, LNCaP and PC-3, were used for the study. Cell proliferation, cell cycle, cell apoptosis and caspase 3/7 activity were determined in the presence or absence of NSC. The levels of Bax and Bak, and the release of cytochrome c from mitochondria were analyzed by Western blot. Results-Treatment NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript produced a time-and dose-dependent induction of cell apoptosis and cell cycle arrest as evidenced by cell morphological changes, increases in S-phase and sub-G1 cell fractions, an elevation of caspase 3/7 activity, DNA fragmentation and apoptotic cells. NSC increased the levels of apoptotic proteins, Bax and Bak, and induced a release of cytochrome c from mitochondria to cytosol in DU-145 cells. Co-administration of Z-VAD-FMK, a pan-caspase inhibitor, blocked NSC-induced caspase 3/7 activity and cell apoptosis without affecting NSC-induced cell cycle arrest. In contrast, co-administration of a PKCδ inhibitor, rottlerin, had no significant effect on NSC induction of caspase activity, and slightly potentiated NSC-induced cell death. Furthermore, like camptothecin, a mutation of topoi-somerase 1 that prevents the binding of camptothecin to the enzyme completely abolished the NSC effect in DU-145 cells. Conclusion-The data obtained suggest that NSC is able to decrease cell growth, induce cell apoptosis and cause growth arrest in prostatic tumor cells, which may involve an interaction with topoisomerase 1 and an activation of mitochondrial apoptotic pathway.

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“…Reduced intracellular drug accumulation (5) and alterations in CPT-11 and SN38 metabolism play important role in the development of resistance (6). In addition, quantitative and qualitative alterations of TopoI have been extensively reported in cell lines (7)(8)(9)(10)27). Finally, alterations in the cellular responses to ternary complex formation that ultimately lead either to repair of DNA damage or to cell death (11,12) can induce resistance to camptothecins.…”

Section: Introductionmentioning

confidence: 99%

Targeting the p38 MAPK Pathway Inhibits Irinotecan Resistance in Colon Adenocarcinoma

et al. 2011

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Despite recent advances in the treatment of colon cancer, tumor resistance is a frequent cause of chemotherapy failure. To better elucidate the molecular mechanisms involved in resistance to irinotecan (and its active metabolite SN38), we established SN38-resistant clones derived from HCT-116 and SW48 cell lines. These clones show various levels (6-to 60-fold) of resistance to SN-38 and display enhanced levels of activated MAPK p38 as compared with the corresponding parental cells. Because four different isoforms of p38 have been described, we then studied the effect of p38 overexpression or downregulation of each isoform on cell sensivity to SN38 and found that both a and b isoforms are involved in the development of resistance to SN38. In this line, we show that cell treatment with SB202190, which inhibits p38a and p38b, enhanced the cytotoxic activity of SN38. Moreover, p38 inhibition sensitized tumor cells derived from both SN38-sensitive and -resistant HCT116 cells to irinotecan treatment in xenograft models. Finally, we detected less phosphorylated p38 in primary colon cancer of patients sensitive to irinotecan-based treatment, compared with nonresponder patients. This indicates that enhanced level of phosphorylated p38 could predict the absence of clinical response to irinotecan. Altogether, our results show that the p38 MAPK pathway is involved in irinotecan sensitivity and suggest that phosphorylated p38 expression level could be used as a marker of clinical resistance to irinotecan. They further suggest that targeting the p38 pathway may be a potential strategy to overcome resistance to irinotecan-based chemotherapies in colorectal cancer.

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Mechanisms of Resistance to Camptothecins

Cited by 49 publications

References 30 publications

Expression of multidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro

Expression of multidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro

NSC606985, a novel camptothecin analog, induces apoptosis and growth arrest in prostate tumor cells

Targeting the p38 MAPK Pathway Inhibits Irinotecan Resistance in Colon Adenocarcinoma

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