TY - JOUR
T1 - -(-)Gossypol promotes the apoptosis of bladder cancer cells in vitro
AU - Macoska, Jill A.
AU - Adsule, Shreelekha
AU - Tantivejkul, Kwanchanit
AU - Wang, Shaomeng
AU - Pienta, Kenneth J.
AU - Lee, Cheryl T.
N1 - Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2008/11
Y1 - 2008/11
N2 - Dysregulation of Bcl2 family member proteins has been associated with poor chemotherapeutic response in bladder cancer, suggesting that agents targeting these crucial proteins may provide an interventional strategy to slow or halt bladder cancer progression and metastasis. In this study, we investigated whether the cottonseed polyphenol, -(-)gossypol, a BH3 mimetic, can reduce the expression of pro-survival, or increase the expression of pro-apoptotic, Bcl2 family proteins and thereby effectively sensitize otherwise resistant bladder cancer cells to the standard chemotherapeutic drugs gemcitabine, paclitaxel and carboplatin. These studies show that gossypol induced apoptosis in both chemosensitive UM-UC2 and chemoresistant resistant UM-UC9 bladder cancer cells in vitro in a dose and time dependent manner via a caspase mediated death signaling pathway. Moreover, in combined treatments, gossypol synergized with gemcitabine and carboplatin to induce apoptosis in chemoresistant bladder cancer cells. This effect was associated with the down-regulation the Bcl-xl and Mcl-1 pro-survival Bcl2 family proteins and up-regulation of the Bim and Puma BH3-only Bcl2 family proteins. Overall, these studies show that gossypol sensitizes bladder cancer cells to standard chemotherapeutic drugs and may provide a promising new strategy for bladder cancer treatment.
AB - Dysregulation of Bcl2 family member proteins has been associated with poor chemotherapeutic response in bladder cancer, suggesting that agents targeting these crucial proteins may provide an interventional strategy to slow or halt bladder cancer progression and metastasis. In this study, we investigated whether the cottonseed polyphenol, -(-)gossypol, a BH3 mimetic, can reduce the expression of pro-survival, or increase the expression of pro-apoptotic, Bcl2 family proteins and thereby effectively sensitize otherwise resistant bladder cancer cells to the standard chemotherapeutic drugs gemcitabine, paclitaxel and carboplatin. These studies show that gossypol induced apoptosis in both chemosensitive UM-UC2 and chemoresistant resistant UM-UC9 bladder cancer cells in vitro in a dose and time dependent manner via a caspase mediated death signaling pathway. Moreover, in combined treatments, gossypol synergized with gemcitabine and carboplatin to induce apoptosis in chemoresistant bladder cancer cells. This effect was associated with the down-regulation the Bcl-xl and Mcl-1 pro-survival Bcl2 family proteins and up-regulation of the Bim and Puma BH3-only Bcl2 family proteins. Overall, these studies show that gossypol sensitizes bladder cancer cells to standard chemotherapeutic drugs and may provide a promising new strategy for bladder cancer treatment.
KW - -(-)Gossypol
KW - Apoptosis
KW - Bladder cancer
KW - Chemotherapy
UR - http://www.scopus.com/inward/record.url?scp=56649095807&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=56649095807&partnerID=8YFLogxK
U2 - 10.1016/j.phrs.2008.09.005
DO - 10.1016/j.phrs.2008.09.005
M3 - Article
C2 - 18840529
AN - SCOPUS:56649095807
SN - 1043-6618
VL - 58
SP - 323
EP - 331
JO - Pharmacological Research
JF - Pharmacological Research
IS - 5-6
ER -