ダウンロード数 : ?
ファイル
言語
英語
著者
原嶋 奈々江
内容記述(抄録等)
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.
主題
prostate cancer
docetaxel
apoptosis
Bcl-2
Bcl-xL
掲載誌名
Oncotarget
5
22
開始ページ
11399
終了ページ
11412
ISSN
19492553
発行日
2014-10-15
DOI
PubMed ID
出版者
Impact Journals
資料タイプ
学術雑誌論文
ファイル形式
PDF
権利関係
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
著者版/出版社版
出版社版
業績ID
e25215
e27413
e26870
e27093
部局
医学部 医学科
医学部 附属病院
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