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language
eng
Author
Harashima, Nanako
Description
Docetaxel (DTX) is a useful chemotherapeutic drug for the treatment of hormone-refractory prostate cancer. However, emergence of DTX resistance has been a therapeutic hurdle. In this study, we investigated the effect of combining DTX with Bcl-2 family inhibitors using human prostate cancer cell lines (PC3, LNCaP, and DU145 cells). PC3 cells were less sensitive to DTX than were the other two cell lines. In contrast to ABT-199, which inhibits Bcl-2 and Bcl-w, both ABT-263 and ABT-737, which inhibit Bcl-2, Bcl-xL, and Bcl-w, significantly augmented the antitumor effect of DTX on PC3 cells. ABT-263 also enhanced the antitumor effect of DTX on a DTX-resistant PC3 variant cell line. The antitumor effect of ABT-263 was due mainly to its inhibitory effect on Bcl-xL. In a xenograft mouse model, DTX and ABT-737 combination therapy significantly inhibited PC3 tumor growth. Interestingly, although ABT-263 activated caspase-9 in PC3 cells, inhibition of caspase-9 unexpectedly promoted ABT-263-induced apoptosis in a caspase-8-dependent manner. This augmented apoptosis was also observed in LNCaP cells. These findings indicate that Bcl-xL inhibition can sensitize DTX-resistant prostate cancer cells to DTX, and they reveal a unique apoptotic pathway in which antagonism of Bcl-2 family members in caspase-9-inhibited prostate cancer cells triggers caspase-8-dependent apoptosis.
Subject
prostate cancer
docetaxel
apoptosis
Bcl-2
Bcl-xL
Journal Title
Oncotarget
Volume
5
Issue
22
Start Page
11399
End Page
11412
ISSN
19492553
Published Date
2014-10-15
DOI
PubMed ID
Publisher
Impact Journals
NII Type
Journal Article
Format
PDF
Rights
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
Text Version
出版社版
Gyoseki ID
e25215
e27413
e26870
e27093
OAI-PMH Set
School of Medicine, Faculty of Medicine
University Hospital, Faculty of Medicine
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