Proteasomal degradation of Mcl-1 by maritoclax induces apoptosis and enhances the efficacy of ABT-737 in melanoma cells

Manoj K. Pandey, Krishne Gowda, Kenichiro Doi, Arun Sharma, Hong-Gang Wang, Shantu Amin

Research output: Contribution to journalArticle

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Abstract

Background and purpose: Metastatic melanoma remains one of the most invasive and highly drug resistant cancers. The over expression of anti-apoptotic protein Mcl-1 has been associated with inferior survival, poor prognosis and chemoresistance of malignant melanoma. A BH3 mimetic, ABT-737, has demonstrated efficacy in several forms of cancers. However, the efficacy of ABT-737 depends on Mcl-1. Because the over expression of Mcl-1 is frequently observed in melanoma, specifically targeting of Mcl-1 may overcome the resistance of ABT-737. In this study, we investigated the effects of Maritoclax, a novel Mcl-1-selective inhibitor, alone and in combination with ABT-737, on the survival of human melanoma cells. Experimental approach: For cell viability assessment we performed MTT assay. Apoptosis was determined using western blot and flow cytometric analysis. Key results: The treatment of Maritoclax reduced the cell viability of melanoma cells with an IC50 of between 2.2-5.0 μM. Further, treatment of melanoma cells with Maritoclax showed significant decrease in Mcl-1 expression. We found that Maritoclax was able to induce apoptosis in melanoma cells in a caspase-dependent manner. Moreover, Maritoclax induced Mcl-1 degradation via the proteasome system, which was associated with its pro-apoptotic activity. We also found that Maritoclax treatment increased mitochondrial translocation of Bim and Bmf. Importantly, Maritoclax markedly enhanced the efficacy of ABT-737 against melanoma cells in both two- and three-dimensional spheroids. Conclusions and implications: Taken together, these results suggest that targeting of Mcl-1 by Maritoclax may represent a new therapeutic strategy for melanoma treatment that warrants further investigation as a single therapy or in combination with other agents such as Bcl-2 inhibitors.

Original languageEnglish (US)
Article numbere78570
JournalPloS one
Volume8
Issue number11
DOIs
StatePublished - Nov 4 2013

Fingerprint

melanoma
Melanoma
apoptosis
Apoptosis
Degradation
degradation
cells
cell viability
Cell Survival
Cells
Apoptosis Regulatory Proteins
marinopyrrole A
ABT-737
therapeutics
neoplasms
Proteasome Endopeptidase Complex
Survival
Caspases
caspases
proteasome endopeptidase complex

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

@article{3e73ac683b164431beae735f85da663f,
title = "Proteasomal degradation of Mcl-1 by maritoclax induces apoptosis and enhances the efficacy of ABT-737 in melanoma cells",
abstract = "Background and purpose: Metastatic melanoma remains one of the most invasive and highly drug resistant cancers. The over expression of anti-apoptotic protein Mcl-1 has been associated with inferior survival, poor prognosis and chemoresistance of malignant melanoma. A BH3 mimetic, ABT-737, has demonstrated efficacy in several forms of cancers. However, the efficacy of ABT-737 depends on Mcl-1. Because the over expression of Mcl-1 is frequently observed in melanoma, specifically targeting of Mcl-1 may overcome the resistance of ABT-737. In this study, we investigated the effects of Maritoclax, a novel Mcl-1-selective inhibitor, alone and in combination with ABT-737, on the survival of human melanoma cells. Experimental approach: For cell viability assessment we performed MTT assay. Apoptosis was determined using western blot and flow cytometric analysis. Key results: The treatment of Maritoclax reduced the cell viability of melanoma cells with an IC50 of between 2.2-5.0 μM. Further, treatment of melanoma cells with Maritoclax showed significant decrease in Mcl-1 expression. We found that Maritoclax was able to induce apoptosis in melanoma cells in a caspase-dependent manner. Moreover, Maritoclax induced Mcl-1 degradation via the proteasome system, which was associated with its pro-apoptotic activity. We also found that Maritoclax treatment increased mitochondrial translocation of Bim and Bmf. Importantly, Maritoclax markedly enhanced the efficacy of ABT-737 against melanoma cells in both two- and three-dimensional spheroids. Conclusions and implications: Taken together, these results suggest that targeting of Mcl-1 by Maritoclax may represent a new therapeutic strategy for melanoma treatment that warrants further investigation as a single therapy or in combination with other agents such as Bcl-2 inhibitors.",
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Proteasomal degradation of Mcl-1 by maritoclax induces apoptosis and enhances the efficacy of ABT-737 in melanoma cells. / Pandey, Manoj K.; Gowda, Krishne; Doi, Kenichiro; Sharma, Arun; Wang, Hong-Gang; Amin, Shantu.

In: PloS one, Vol. 8, No. 11, e78570, 04.11.2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Proteasomal degradation of Mcl-1 by maritoclax induces apoptosis and enhances the efficacy of ABT-737 in melanoma cells

AU - Pandey, Manoj K.

AU - Gowda, Krishne

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AU - Sharma, Arun

AU - Wang, Hong-Gang

AU - Amin, Shantu

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N2 - Background and purpose: Metastatic melanoma remains one of the most invasive and highly drug resistant cancers. The over expression of anti-apoptotic protein Mcl-1 has been associated with inferior survival, poor prognosis and chemoresistance of malignant melanoma. A BH3 mimetic, ABT-737, has demonstrated efficacy in several forms of cancers. However, the efficacy of ABT-737 depends on Mcl-1. Because the over expression of Mcl-1 is frequently observed in melanoma, specifically targeting of Mcl-1 may overcome the resistance of ABT-737. In this study, we investigated the effects of Maritoclax, a novel Mcl-1-selective inhibitor, alone and in combination with ABT-737, on the survival of human melanoma cells. Experimental approach: For cell viability assessment we performed MTT assay. Apoptosis was determined using western blot and flow cytometric analysis. Key results: The treatment of Maritoclax reduced the cell viability of melanoma cells with an IC50 of between 2.2-5.0 μM. Further, treatment of melanoma cells with Maritoclax showed significant decrease in Mcl-1 expression. We found that Maritoclax was able to induce apoptosis in melanoma cells in a caspase-dependent manner. Moreover, Maritoclax induced Mcl-1 degradation via the proteasome system, which was associated with its pro-apoptotic activity. We also found that Maritoclax treatment increased mitochondrial translocation of Bim and Bmf. Importantly, Maritoclax markedly enhanced the efficacy of ABT-737 against melanoma cells in both two- and three-dimensional spheroids. Conclusions and implications: Taken together, these results suggest that targeting of Mcl-1 by Maritoclax may represent a new therapeutic strategy for melanoma treatment that warrants further investigation as a single therapy or in combination with other agents such as Bcl-2 inhibitors.

AB - Background and purpose: Metastatic melanoma remains one of the most invasive and highly drug resistant cancers. The over expression of anti-apoptotic protein Mcl-1 has been associated with inferior survival, poor prognosis and chemoresistance of malignant melanoma. A BH3 mimetic, ABT-737, has demonstrated efficacy in several forms of cancers. However, the efficacy of ABT-737 depends on Mcl-1. Because the over expression of Mcl-1 is frequently observed in melanoma, specifically targeting of Mcl-1 may overcome the resistance of ABT-737. In this study, we investigated the effects of Maritoclax, a novel Mcl-1-selective inhibitor, alone and in combination with ABT-737, on the survival of human melanoma cells. Experimental approach: For cell viability assessment we performed MTT assay. Apoptosis was determined using western blot and flow cytometric analysis. Key results: The treatment of Maritoclax reduced the cell viability of melanoma cells with an IC50 of between 2.2-5.0 μM. Further, treatment of melanoma cells with Maritoclax showed significant decrease in Mcl-1 expression. We found that Maritoclax was able to induce apoptosis in melanoma cells in a caspase-dependent manner. Moreover, Maritoclax induced Mcl-1 degradation via the proteasome system, which was associated with its pro-apoptotic activity. We also found that Maritoclax treatment increased mitochondrial translocation of Bim and Bmf. Importantly, Maritoclax markedly enhanced the efficacy of ABT-737 against melanoma cells in both two- and three-dimensional spheroids. Conclusions and implications: Taken together, these results suggest that targeting of Mcl-1 by Maritoclax may represent a new therapeutic strategy for melanoma treatment that warrants further investigation as a single therapy or in combination with other agents such as Bcl-2 inhibitors.

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