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Simvastatin enhances irinotecan-induced apoptosis in prostate cancer via inhibition of MCL-1

Prostate cancer is one of the most common malignant tumors around the world. Hyperlipidemia is considered as one of the most important risk factors for the development of prostate cancer. Simvastatin is widely used for the treatment of hyperlipidemia and was previously shown to induce apoptosis in s...

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Autores principales: Alqudah, Mohammad A.Y., Mansour, Hebah T., Mhaidat, Nizar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6111232/
https://www.ncbi.nlm.nih.gov/pubmed/30166915
http://dx.doi.org/10.1016/j.jsps.2017.12.012
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author Alqudah, Mohammad A.Y.
Mansour, Hebah T.
Mhaidat, Nizar
author_facet Alqudah, Mohammad A.Y.
Mansour, Hebah T.
Mhaidat, Nizar
author_sort Alqudah, Mohammad A.Y.
collection PubMed
description Prostate cancer is one of the most common malignant tumors around the world. Hyperlipidemia is considered as one of the most important risk factors for the development of prostate cancer. Simvastatin is widely used for the treatment of hyperlipidemia and was previously shown to induce apoptosis in several cancer types including lung, colon, pancreas, breast, and prostate cancer. In this study we aimed to explore the potential role of simvastatin in enhancing irinotecan-induced apoptosis in prostate cancer cells. In addition, the underlying molecular mechanisms driving this potential effect of simvastatin were also explored. PC3 cells were treated with simvastatin, irinotecan or combination. Cell viability was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) colorimetric assay. Flow cytometry technique was used to analyze apoptosis and cell cycle progression. Western blot was used for detection of protein expression. Results showed that simvastatin has a significant anti-proliferative activity on PC3 cells. Combined treatment of simvastatin with irinotecan exhibited a significant inhibition of PC3 cell growth compared to each treatment alone. Flow cytometry analysis showed that PC3 cell treatment with simvastatin and irinotecan combination demonstrated a remarkable increase in the percentage of apoptotic cells and those accumulated at G0/G1 phase when compared to each treatment alone. Moreover, induction of apoptosis was caspase-independent. Western blot showed that apoptosis was accompanied by upregulation of GRP-78 level and downregulation of Mcl-1 levels in a time-dependent manner. The results of this study demonstrated that combined treatment of simvastatin with chemotherapeutic agents such as irinotecan resulted in enhancement of growth inhibition and induction of prostate cancer cell apoptosis.
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spelling pubmed-61112322018-08-30 Simvastatin enhances irinotecan-induced apoptosis in prostate cancer via inhibition of MCL-1 Alqudah, Mohammad A.Y. Mansour, Hebah T. Mhaidat, Nizar Saudi Pharm J Article Prostate cancer is one of the most common malignant tumors around the world. Hyperlipidemia is considered as one of the most important risk factors for the development of prostate cancer. Simvastatin is widely used for the treatment of hyperlipidemia and was previously shown to induce apoptosis in several cancer types including lung, colon, pancreas, breast, and prostate cancer. In this study we aimed to explore the potential role of simvastatin in enhancing irinotecan-induced apoptosis in prostate cancer cells. In addition, the underlying molecular mechanisms driving this potential effect of simvastatin were also explored. PC3 cells were treated with simvastatin, irinotecan or combination. Cell viability was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) colorimetric assay. Flow cytometry technique was used to analyze apoptosis and cell cycle progression. Western blot was used for detection of protein expression. Results showed that simvastatin has a significant anti-proliferative activity on PC3 cells. Combined treatment of simvastatin with irinotecan exhibited a significant inhibition of PC3 cell growth compared to each treatment alone. Flow cytometry analysis showed that PC3 cell treatment with simvastatin and irinotecan combination demonstrated a remarkable increase in the percentage of apoptotic cells and those accumulated at G0/G1 phase when compared to each treatment alone. Moreover, induction of apoptosis was caspase-independent. Western blot showed that apoptosis was accompanied by upregulation of GRP-78 level and downregulation of Mcl-1 levels in a time-dependent manner. The results of this study demonstrated that combined treatment of simvastatin with chemotherapeutic agents such as irinotecan resulted in enhancement of growth inhibition and induction of prostate cancer cell apoptosis. Elsevier 2018-02 2017-12-13 /pmc/articles/PMC6111232/ /pubmed/30166915 http://dx.doi.org/10.1016/j.jsps.2017.12.012 Text en © 2017 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Alqudah, Mohammad A.Y.
Mansour, Hebah T.
Mhaidat, Nizar
Simvastatin enhances irinotecan-induced apoptosis in prostate cancer via inhibition of MCL-1
title Simvastatin enhances irinotecan-induced apoptosis in prostate cancer via inhibition of MCL-1
title_full Simvastatin enhances irinotecan-induced apoptosis in prostate cancer via inhibition of MCL-1
title_fullStr Simvastatin enhances irinotecan-induced apoptosis in prostate cancer via inhibition of MCL-1
title_full_unstemmed Simvastatin enhances irinotecan-induced apoptosis in prostate cancer via inhibition of MCL-1
title_short Simvastatin enhances irinotecan-induced apoptosis in prostate cancer via inhibition of MCL-1
title_sort simvastatin enhances irinotecan-induced apoptosis in prostate cancer via inhibition of mcl-1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6111232/
https://www.ncbi.nlm.nih.gov/pubmed/30166915
http://dx.doi.org/10.1016/j.jsps.2017.12.012
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