| Effect of dual inhibition of apoptosis and autophagy in prostate cancer. | |
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MedLine Citation:
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PMID: 22241682 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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PURPOSE: Targeting multiple anti-apoptotic proteins is now possible with the small molecule BH3 domain mimetics such as ABT-737. Given recent studies demonstrating that autophagy is a resistance mechanism to multiple therapeutic agents in the setting of apoptotic inhibition, we hypothesized that hydroxychloroquine (HCQ), an anti-malarial drug that inhibits autophagy, will increase cytotoxicity of ABT-737. EXPERIMENTAL DESIGN: Cytotoxicity of ABT-737 and HCQ was assessed in vitro in PC-3 and LNCaP cells, and in vivo in a xenograft mouse model. The role of autophagy as a resistance mechanism was assessed by siRNA knockdown of the essential autophagy gene beclin1. ROS was measured by flow cytometry, and mitophagy assessed by the mCherry-Parkin reporter. RESULTS: Induction of autophagy by ABT-737 was a mechanism of resistance in prostate cancer cell lines. Therapeutic inhibition of autophagy with HCQ increased cytotoxicity of ABT-737 both in vitro and in vivo. ABT-737 induced LC-3 and decreased p62 expression by immunoblot in cell lines and by immunohistochemistry in tumors in vivo. Assessment of ROS and mitochondria demonstrated that ROS production by ABT-737 and HCQ was a mechanism of cytotoxicity. CONCLUSIONS: We demonstrated that autophagy inhibition with HCQ enhances ABT-737 cytotoxicity in vitro and in vivo, that LC-3 and p62 represent assessable markers in human tissue for future clinical trials, and that ROS induction is a mechanism of cytotoxicity. These results support a new paradigm of dual targeting of apoptosis and autophagy in future clinical studies. Prostate © 2012 Wiley Periodicals, Inc. |
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Authors:
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Ahamed Saleem; Dmitri Dvorzhinski; Urmila Santanam; Robin Mathew; Kevin Bray; Mark Stein; Eileen White; Robert S Dipaola |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-12 |
Journal Detail:
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Title: The Prostate Volume: - ISSN: 1097-0045 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-13 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8101368 Medline TA: Prostate Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 Wiley Periodicals, Inc. |
Affiliation:
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The Cancer Institute of New Jersey, New Brunswick, New Jersey; Presently at Qassim University, Buraidah, Saudi Arabia. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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