Drug-resistance in human melanoma

Helmbach, Heike; Rossmann, Evelyn; Kern, Manfred; Schadendorf, Dirk

doi:10.1002/ijc.1378

Cited by 164 publications

(141 citation statements)

References 56 publications

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“…27,30 Defects at multiple levels of major apoptotic pathways have been described in melanoma. 4 Our findings provide a novel information on the pro-apoptotic action of cyclosporine A and NIM811 on 5 melanoma cell lines. It may be clinically valuable to develop a new therapeutic approach with CsA derivative as an anti-tumor agent.…”

Section: Therapeutic Potential Of Non-immunosuppressive Analog Of Csamentioning

confidence: 78%

“…1,2 Advanced malignant melanoma has a poor prognosis because chemotherapy is ineffective mostly in part due to the intrinsic or extrinsic resistance of melanoma cells to systemic treatment with anti-cancer agents. 3,4 Mechanisms of the chemoresistant phenotype are still to be determined. Because many anticancer drugs kill susceptible cells through induction of apoptosis, 5,6 alterations of the apoptotic pathways may account for the ability of some tumor cells to resist drug therapy.…”

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confidence: 99%

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Cyclosporine A and its non-immunosuppressive derivative NIM811 induce apoptosis of malignant melanoma cells inin vitro andin vivo studies

et al. 2005

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Advanced melanoma is a highly malignant tumor with an increasing incidence that has a poor prognosis due to resistance to common therapeutic strategies. We have demonstrated previously that cyclosporine A (CsA) induces apoptosis of rat glioma cells, reactive astrocytes, and fibroblasts. In our present study, we investigated effects of CsA and its nonimmunosuppressive derivative NIM811 on survival of human and murine melanoma cells. We demonstrated that CsA and NIM811 affect survival of human and murine melanoma cells and induce morphological changes, alterations in nuclear morphology and an internucleosomal DNA fragmentation, consistent with an apoptotic type of death. Western blot analysis showed an activation of caspases 9, 7, 3 and PARP cleavage detectable at 24 hr after exposure of human melanoma cells to the drugs. CsA and NIM811 induced a significant increase in subG1 population of murine B16F10 melanoma cells indicative of apoptotic DNA fragmentation. Studies in murine model of melanoma showed that NIM811, but not CsA, retards tumor progression and significantly decreases tumor volume after intratumoral application. Our findings indicate that CsA and its derivatives may be new candidates for the treatment of melanoma patients. ' 2005 Wiley-Liss, Inc.

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Section: Therapeutic Potential Of Non-immunosuppressive Analog Of Csamentioning

confidence: 78%

mentioning

confidence: 99%

Cyclosporine A and its non-immunosuppressive derivative NIM811 induce apoptosis of malignant melanoma cells inin vitro andin vivo studies

et al. 2005

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“…Although most cancers selectively acquire drug resistance following drug treatment, drug resistance in melanoma is thought to be largely due to intrinsic survival factors (1). In this regard, several lines of evidence suggest that defects in apoptotic signaling cascades may represent a critical event in melanoma progression (2). Consistent with this notion are reports of modified expression of proapoptotic and antiapoptotic factors such as Bcl-2, Bcl-XL, and Mcl-1 in melanoma (3,4).…”

Section: Introductionmentioning

confidence: 96%

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Doudican¹,

Rodriguez²,

Osman

et al. 2008

Molecular Cancer Research

128

114

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Most metastatic melanoma patients fail to respond to available therapy, underscoring the need for novel approaches to identify new effective treatments. In this study, we screened 2,000 compounds from the Spectrum Library at a concentration of 1 Mmol/L using two chemoresistant melanoma cell lines ) and a spontaneously immortalized, nontumorigenic melanocyte cell line (melan-a). We identified 10 compounds that inhibited the growth of the melanoma cells yet were largely nontoxic to melanocytes. Strikingly, 4 of the 10 compounds (mebendazole, albendazole, fenbendazole, and oxybendazole) are benzimidazoles, a class of structurally related, tubulin-disrupting drugs. Mebendazole was prioritized to further characterize its mechanism of melanoma growth inhibition based on its favorable pharmacokinetic profile. Our data reveal that mebendazole inhibits melanoma growth with an average IC 50 of 0.32 Mmol/L and preferentially induces apoptosis in melanoma cells compared with melanocytes. The intrinsic apoptotic response is mediated through phosphorylation of Bcl-2, which occurs rapidly after treatment with mebendazole in melanoma cells but not in melanocytes. Phosphorylation of Bcl-2 in melanoma cells prevents its interaction with proapoptotic Bax, thereby promoting apoptosis. We further show that mebendazole-resistant melanocytes can be sensitized through reduction of Bcl-2 protein levels, showing the essential role of Bcl-2 in the cellular response to mebendazole-mediated tubulin disruption. Our results suggest that this screening approach is useful for identifying agents that show promise in the treatment of even chemoresistant melanoma and identifies mebendazole as a potent, melanoma-specific cytotoxic agent. (Mol Cancer Res 2008;6(8):1308 -15)

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“…Melanoma, the most aggressive form of skin cancer, is notoriously resistant to all current modalities of cancer therapy (Helmbach et al, 2001). A large set of genetic, functional and biochemical studies suggest that melanoma cells become insensitive to a variety of chemotherapeutic drugs by exploiting their intrinsic resistance to apoptosis and by reprogramming their proliferation and survival pathways during melanoma progression.…”

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confidence: 99%

Combined effects of GSTP1 and MRP1 in melanoma drug resistance

Depeille¹,

Cuq²,

Passagne³

et al. 2005

Br J Cancer

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Glutathione-S-transferase Pi1 (GSTP1) and multidrug resistance protein 1 (MRP1) are overexpressed in melanoma, a skin cancer notoriously resistant to all current modalities of cancer therapy. To investigate the involvement of these detoxifying enzymes in the drug resistance of melanoma, an inducible (Tet-Ont system) antisense (AS) RNA strategy was used to specifically inhibit GSTP1 expression in A375 cells, a human melanoma cell line expressing high levels of GSTP1 and MRP1. Stable transfectant clones were established and analysed for GSTP1 inhibition by AS RNA. The clone A375-ASPi1, presenting a specific 40% inhibition of GSTP1 expression in the presence of doxycycline, was selected. Lowering the GSTP1 level significantly increased (about 3.3-fold) the sensitivity of A375-ASPi1 cells to etoposide. Inhibitors of glutathione synthesis (BSO), GSTs (curcumin, ethacrynic acid), and also of MRPs (MK571, sulphinpyrazone) improved the sensitising effect of GSTP1 AS RNA. All these inhibitors had stronger sensitising effects in control cells expressing high GSTP1 level (A375-ASPi1 cells in the absence of doxycycline). In conclusion, GSTP1 can act in a combined fashion with MRP1 to protect melanoma cells from toxic effects of etoposide.

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Drug-resistance in human melanoma

Cited by 164 publications

References 56 publications

Cyclosporine A and its non-immunosuppressive derivative NIM811 induce apoptosis of malignant melanoma cells inin vitro andin vivo studies

Cyclosporine A and its non-immunosuppressive derivative NIM811 induce apoptosis of malignant melanoma cells inin vitro andin vivo studies

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Combined effects of GSTP1 and MRP1 in melanoma drug resistance

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