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Cholesterol depletion by methyl-β-cyclodextrin augments tamoxifen induced cell death by enhancing its uptake in melanoma
BACKGROUND: Despite modern advances in treatment, skin cancer is still one of the most common causes of death in the western countries. Chemotherapy plays an important role in melanoma management. Tamoxifen has been used either alone or in- combination with other chemotherapeutic agents to treat mel...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175626/ https://www.ncbi.nlm.nih.gov/pubmed/25178635 http://dx.doi.org/10.1186/1476-4598-13-204 |
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author | Mohammad, Naoshad Malvi, Parmanand Meena, Avtar Singh Singh, Shivendra Vikram Chaube, Balkrishna Vannuruswamy, Garikapati Kulkarni, Mahesh J Bhat, Manoj Kumar |
author_facet | Mohammad, Naoshad Malvi, Parmanand Meena, Avtar Singh Singh, Shivendra Vikram Chaube, Balkrishna Vannuruswamy, Garikapati Kulkarni, Mahesh J Bhat, Manoj Kumar |
author_sort | Mohammad, Naoshad |
collection | PubMed |
description | BACKGROUND: Despite modern advances in treatment, skin cancer is still one of the most common causes of death in the western countries. Chemotherapy plays an important role in melanoma management. Tamoxifen has been used either alone or in- combination with other chemotherapeutic agents to treat melanoma. However, response rate of tamoxifen as a single agent has been comparatively low. In the present study, we investigated whether treatment with methyl-β-cyclodextrin (MCD), a cholesterol depleting agent, increases the efficacy of tamoxifen in melanoma cells. METHODS: This was a two-part study that incorporated in vitro effects of tamoxifen and MCD combination by analyzing cell survival, apoptosis and cell cycle analysis and in vivo antitumor efficacy on tumor isografts in C57BL/6J mice. RESULTS: MCD potentiated tamoxifen induced anticancer effects by causing cell cycle arrest and induction of apoptosis. Sensitization to tamoxifen was associated with down regulation of antiapoptotic protein Bcl-2(,) up-regulation of proapoptotic protein Bax, reduced caveolin-1 (Cav-1) and decreased pAkt/pERK levels. Co-administration of tamoxifen and MCD caused significant reduction in tumor volume and tumor weight in mice due to enhancement of drug uptake in the tumor. Supplementation with cholesterol abrogated combined effect of tamoxifen and MCD. CONCLUSION: Our results emphasize a potential synergistic effect of tamoxifen with MCD, and therefore, may provide a unique therapeutic window for improvement in melanoma treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1476-4598-13-204) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4175626 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-41756262014-09-27 Cholesterol depletion by methyl-β-cyclodextrin augments tamoxifen induced cell death by enhancing its uptake in melanoma Mohammad, Naoshad Malvi, Parmanand Meena, Avtar Singh Singh, Shivendra Vikram Chaube, Balkrishna Vannuruswamy, Garikapati Kulkarni, Mahesh J Bhat, Manoj Kumar Mol Cancer Research BACKGROUND: Despite modern advances in treatment, skin cancer is still one of the most common causes of death in the western countries. Chemotherapy plays an important role in melanoma management. Tamoxifen has been used either alone or in- combination with other chemotherapeutic agents to treat melanoma. However, response rate of tamoxifen as a single agent has been comparatively low. In the present study, we investigated whether treatment with methyl-β-cyclodextrin (MCD), a cholesterol depleting agent, increases the efficacy of tamoxifen in melanoma cells. METHODS: This was a two-part study that incorporated in vitro effects of tamoxifen and MCD combination by analyzing cell survival, apoptosis and cell cycle analysis and in vivo antitumor efficacy on tumor isografts in C57BL/6J mice. RESULTS: MCD potentiated tamoxifen induced anticancer effects by causing cell cycle arrest and induction of apoptosis. Sensitization to tamoxifen was associated with down regulation of antiapoptotic protein Bcl-2(,) up-regulation of proapoptotic protein Bax, reduced caveolin-1 (Cav-1) and decreased pAkt/pERK levels. Co-administration of tamoxifen and MCD caused significant reduction in tumor volume and tumor weight in mice due to enhancement of drug uptake in the tumor. Supplementation with cholesterol abrogated combined effect of tamoxifen and MCD. CONCLUSION: Our results emphasize a potential synergistic effect of tamoxifen with MCD, and therefore, may provide a unique therapeutic window for improvement in melanoma treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1476-4598-13-204) contains supplementary material, which is available to authorized users. BioMed Central 2014-09-01 /pmc/articles/PMC4175626/ /pubmed/25178635 http://dx.doi.org/10.1186/1476-4598-13-204 Text en © Mohammad et al.; licensee BioMed Central Ltd. 2014 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Mohammad, Naoshad Malvi, Parmanand Meena, Avtar Singh Singh, Shivendra Vikram Chaube, Balkrishna Vannuruswamy, Garikapati Kulkarni, Mahesh J Bhat, Manoj Kumar Cholesterol depletion by methyl-β-cyclodextrin augments tamoxifen induced cell death by enhancing its uptake in melanoma |
title | Cholesterol depletion by methyl-β-cyclodextrin augments tamoxifen induced cell death by enhancing its uptake in melanoma |
title_full | Cholesterol depletion by methyl-β-cyclodextrin augments tamoxifen induced cell death by enhancing its uptake in melanoma |
title_fullStr | Cholesterol depletion by methyl-β-cyclodextrin augments tamoxifen induced cell death by enhancing its uptake in melanoma |
title_full_unstemmed | Cholesterol depletion by methyl-β-cyclodextrin augments tamoxifen induced cell death by enhancing its uptake in melanoma |
title_short | Cholesterol depletion by methyl-β-cyclodextrin augments tamoxifen induced cell death by enhancing its uptake in melanoma |
title_sort | cholesterol depletion by methyl-β-cyclodextrin augments tamoxifen induced cell death by enhancing its uptake in melanoma |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175626/ https://www.ncbi.nlm.nih.gov/pubmed/25178635 http://dx.doi.org/10.1186/1476-4598-13-204 |
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