In vivo evaluation of AT-101 (R-(-)-gossypol acetic acid) in androgen-independent growth of VCaP prostate cancer cells in combination with surgical castration.
OBJECTIVE
Upregulation of Bcl-2 family members is a well-established mechanism in the development of androgen-independent prostate cancer. Inhibition of the antiapoptotic proteins Bcl-2 and Mcl-1 may delay the transition to androgen-independent growth.


METHODS
We have established a prostate cancer model with VCaP prostate cancer cells in vivo to study the transition to androgen independence. Here, we investigated the efficacy of AT-101 (R-(-)-gossypol acetic acid; a pan small molecule inhibitor of Bcl-2, Bcl-x(L), and Mcl-1) in combination with surgical castration to delay the onset of androgen-independent growth in vivo.


RESULTS
AT-101 (15 mg/kg, per os (p.o.) 5 days/week) in combination with surgical castration delayed the onset of androgen-independent prostate cancer growth in vivo. In addition, we demonstrate the induction of caspase-9-and caspase-3-dependent induction of apoptosis following AT-101 treatment in vitro which was accompanied by an AT-101-induced downregulation of Bcl-2 and Mcl-1 mRNA and protein expression.


CONCLUSIONS
We conclude that AT-101 in combination with surgical castration delays the onset of androgen-independent prostate cancer in vivo by disrupting the antiapoptotic activity of Bcl-2 upregulation during the transition to androgen independence. Further studies are needed to define the mechanism of action by which AT-101 attenuates the expression of Bcl-2 and Mcl-1 and to characterize the potential for AT-101 in combination with hormone therapy.
Loberg
Robert D
RD
Department of Urology, University of Michigan Urology Center, Ann Arbor, MI, USA. rloberg@umich.edu
McGregor
Natalie
N
Ying
Chi
C
Sargent
Erin
E
Pienta
Kenneth J
KJ
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000601:surgery; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000502:physiology; D003131:Combined Modality Therapy; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019254:Genes, bcl-2; D006072:Gossypol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000601:surgery; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D020169:Caspases; D006072:Gossypol; C028178:gossypol acetic acid