Proteasomal degradation of Mcl-1 by maritoclax induces apoptosis and enhances the efficacy of ABT-737 in melanoma cells.
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 sever...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3817219?pdf=render |
| _version_ | 1818486643733037056 |
|---|---|
| author | Manoj K Pandey Krishne Gowda Kenichiro Doi Arun K Sharma Hong-Gang Wang Shantu Amin |
| author_facet | Manoj K Pandey Krishne Gowda Kenichiro Doi Arun K Sharma Hong-Gang Wang Shantu Amin |
| author_sort | Manoj K Pandey |
| collection | DOAJ |
| description | 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.For cell viability assessment we performed MTT assay. Apoptosis was determined using western blot and flow cytometric analysis.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.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. |
| first_indexed | 2024-12-10T16:25:51Z |
| format | Article |
| id | doaj.art-70e7312f943945d79c52292b37ec7d7d |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T16:25:51Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-70e7312f943945d79c52292b37ec7d7d2022-12-22T01:41:40ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01811e7857010.1371/journal.pone.0078570Proteasomal degradation of Mcl-1 by maritoclax induces apoptosis and enhances the efficacy of ABT-737 in melanoma cells.Manoj K PandeyKrishne GowdaKenichiro DoiArun K SharmaHong-Gang WangShantu AminMetastatic 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.For cell viability assessment we performed MTT assay. Apoptosis was determined using western blot and flow cytometric analysis.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.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.http://europepmc.org/articles/PMC3817219?pdf=render |
| spellingShingle | Manoj K Pandey Krishne Gowda Kenichiro Doi Arun K Sharma Hong-Gang Wang Shantu Amin Proteasomal degradation of Mcl-1 by maritoclax induces apoptosis and enhances the efficacy of ABT-737 in melanoma cells. PLoS ONE |
| title | Proteasomal degradation of Mcl-1 by maritoclax induces apoptosis and enhances the efficacy of ABT-737 in melanoma cells. |
| title_full | Proteasomal degradation of Mcl-1 by maritoclax induces apoptosis and enhances the efficacy of ABT-737 in melanoma cells. |
| title_fullStr | Proteasomal degradation of Mcl-1 by maritoclax induces apoptosis and enhances the efficacy of ABT-737 in melanoma cells. |
| title_full_unstemmed | Proteasomal degradation of Mcl-1 by maritoclax induces apoptosis and enhances the efficacy of ABT-737 in melanoma cells. |
| title_short | Proteasomal degradation of Mcl-1 by maritoclax induces apoptosis and enhances the efficacy of ABT-737 in melanoma cells. |
| title_sort | proteasomal degradation of mcl 1 by maritoclax induces apoptosis and enhances the efficacy of abt 737 in melanoma cells |
| url | http://europepmc.org/articles/PMC3817219?pdf=render |
| work_keys_str_mv | AT manojkpandey proteasomaldegradationofmcl1bymaritoclaxinducesapoptosisandenhancestheefficacyofabt737inmelanomacells AT krishnegowda proteasomaldegradationofmcl1bymaritoclaxinducesapoptosisandenhancestheefficacyofabt737inmelanomacells AT kenichirodoi proteasomaldegradationofmcl1bymaritoclaxinducesapoptosisandenhancestheefficacyofabt737inmelanomacells AT arunksharma proteasomaldegradationofmcl1bymaritoclaxinducesapoptosisandenhancestheefficacyofabt737inmelanomacells AT honggangwang proteasomaldegradationofmcl1bymaritoclaxinducesapoptosisandenhancestheefficacyofabt737inmelanomacells AT shantuamin proteasomaldegradationofmcl1bymaritoclaxinducesapoptosisandenhancestheefficacyofabt737inmelanomacells |