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Inhibition of hedgehog signaling improves the anti-carcinogenic effects of docetaxel in prostate cancer
The establishment of docetaxel-based chemotherapeutic treatments has improved the survival of castration-resistant prostate cancer (CRPC) patients. However, most patients develop resistance supporting the development of therapy. The current study was undertaken to establish the therapeutic benefit t...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414161/ https://www.ncbi.nlm.nih.gov/pubmed/25682877 |
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author | Mimeault, Murielle Rachagani, Satyanarayana Muniyan, Sakthivel Seshacharyulu, Parthasarathy Johansson, Sonny L. Datta, Kaustubh Lin, Ming-Fong Batra, Surinder K. |
author_facet | Mimeault, Murielle Rachagani, Satyanarayana Muniyan, Sakthivel Seshacharyulu, Parthasarathy Johansson, Sonny L. Datta, Kaustubh Lin, Ming-Fong Batra, Surinder K. |
author_sort | Mimeault, Murielle |
collection | PubMed |
description | The establishment of docetaxel-based chemotherapeutic treatments has improved the survival of castration-resistant prostate cancer (CRPC) patients. However, most patients develop resistance supporting the development of therapy. The current study was undertaken to establish the therapeutic benefit to target hedgehog signaling cascade using GDC-0449 to improve the efficacy of chemotherapeutic drug, docetaxel. Here, we show that the combination of GDC-0449 plus docetaxel inhibited the proliferation of WPE1-NB26 cells and PC3 cells via a blockade of G1 and G2M phases. The combined treatment significantly inhibited PC cell migration in vitro. Moreover, the apoptotic effect induced by GDC-0449 plus docetaxel on PC3 cells was mediated, at least partly, via the mitochondrial membrane depolarization, H(2)O(2) production and caspase cascade activation. Interestingly, GDC-0449 was effective at inhibiting the prostasphere formation, inducing the prostasphere disintegration and apoptotic death of side population (SP) from PC3 cells and reversing the resistance of SP cells to docetaxel. In addition, GDC-0449 plus docetaxel also have shown a greater anti-tumoral growth inhibitory effect on PC3 cell xenografts. These findings support the use of the hedgehog inhibitor GDC-0449, which is currently in clinical trials, for improving the anticarcinogenic efficacy of docetaxel-based chemotherapeutic treatments against locally advanced, AI and metastatic PC. |
format | Online Article Text |
id | pubmed-4414161 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-44141612015-05-08 Inhibition of hedgehog signaling improves the anti-carcinogenic effects of docetaxel in prostate cancer Mimeault, Murielle Rachagani, Satyanarayana Muniyan, Sakthivel Seshacharyulu, Parthasarathy Johansson, Sonny L. Datta, Kaustubh Lin, Ming-Fong Batra, Surinder K. Oncotarget Research Paper The establishment of docetaxel-based chemotherapeutic treatments has improved the survival of castration-resistant prostate cancer (CRPC) patients. However, most patients develop resistance supporting the development of therapy. The current study was undertaken to establish the therapeutic benefit to target hedgehog signaling cascade using GDC-0449 to improve the efficacy of chemotherapeutic drug, docetaxel. Here, we show that the combination of GDC-0449 plus docetaxel inhibited the proliferation of WPE1-NB26 cells and PC3 cells via a blockade of G1 and G2M phases. The combined treatment significantly inhibited PC cell migration in vitro. Moreover, the apoptotic effect induced by GDC-0449 plus docetaxel on PC3 cells was mediated, at least partly, via the mitochondrial membrane depolarization, H(2)O(2) production and caspase cascade activation. Interestingly, GDC-0449 was effective at inhibiting the prostasphere formation, inducing the prostasphere disintegration and apoptotic death of side population (SP) from PC3 cells and reversing the resistance of SP cells to docetaxel. In addition, GDC-0449 plus docetaxel also have shown a greater anti-tumoral growth inhibitory effect on PC3 cell xenografts. These findings support the use of the hedgehog inhibitor GDC-0449, which is currently in clinical trials, for improving the anticarcinogenic efficacy of docetaxel-based chemotherapeutic treatments against locally advanced, AI and metastatic PC. Impact Journals LLC 2015-02-17 /pmc/articles/PMC4414161/ /pubmed/25682877 Text en Copyright: © 2015 Mimeault et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Mimeault, Murielle Rachagani, Satyanarayana Muniyan, Sakthivel Seshacharyulu, Parthasarathy Johansson, Sonny L. Datta, Kaustubh Lin, Ming-Fong Batra, Surinder K. Inhibition of hedgehog signaling improves the anti-carcinogenic effects of docetaxel in prostate cancer |
title | Inhibition of hedgehog signaling improves the anti-carcinogenic effects of docetaxel in prostate cancer |
title_full | Inhibition of hedgehog signaling improves the anti-carcinogenic effects of docetaxel in prostate cancer |
title_fullStr | Inhibition of hedgehog signaling improves the anti-carcinogenic effects of docetaxel in prostate cancer |
title_full_unstemmed | Inhibition of hedgehog signaling improves the anti-carcinogenic effects of docetaxel in prostate cancer |
title_short | Inhibition of hedgehog signaling improves the anti-carcinogenic effects of docetaxel in prostate cancer |
title_sort | inhibition of hedgehog signaling improves the anti-carcinogenic effects of docetaxel in prostate cancer |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414161/ https://www.ncbi.nlm.nih.gov/pubmed/25682877 |
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