Abstract | PURPOSE: 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. EXPERIMENTAL DESIGN: 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.
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Authors | Robert D Loberg, Natalie McGregor, Chi Ying, Erin Sargent, Kenneth J Pienta |
Journal | Neoplasia (New York, N.Y.)
(Neoplasia)
Vol. 9
Issue 12
Pg. 1030-7
(Dec 2007)
ISSN: 1476-5586 [Electronic] United States |
PMID | 18084610
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents, Phytogenic
- Mcl1 protein, mouse
- Myeloid Cell Leukemia Sequence 1 Protein
- Neoplasm Proteins
- Proto-Oncogene Proteins c-bcl-2
- RNA, Messenger
- RNA, Neoplasm
- Caspases
- Gossypol
- gossypol acetic acid
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Topics |
- Adenocarcinoma
(drug therapy, surgery)
- Animals
- Antineoplastic Agents, Phytogenic
(therapeutic use)
- Apoptosis
(drug effects)
- Caspases
(physiology)
- Combined Modality Therapy
- Down-Regulation
(drug effects)
- Gene Expression Regulation, Neoplastic
(drug effects)
- Genes, bcl-2
- Gossypol
(analogs & derivatives, therapeutic use)
- Humans
- Male
- Mice
- Mice, SCID
- Myeloid Cell Leukemia Sequence 1 Protein
- Neoplasm Proteins
(biosynthesis, genetics, physiology)
- Orchiectomy
- Prostatic Neoplasms
(drug therapy, surgery)
- Proto-Oncogene Proteins c-bcl-2
(biosynthesis, genetics)
- RNA, Messenger
(biosynthesis)
- RNA, Neoplasm
(biosynthesis)
- Xenograft Model Antitumor Assays
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