In Vivo Evaluation of AT-101 (R-(—)-Gossypol Acetic Acid) in Androgen-Independent Growth of VCaP Prostate Cancer Cells in Combination with Surgical Castration
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: We have established a prost...
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| Format: | Article |
| Language: | English |
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Elsevier
2007-12-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558607801138 |
| _version_ | 1818277449988833280 |
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| author | Robert D. Loberg Natalie McGregor Chi Ying Erin Sargent Kenneth J. Pienta |
| author_facet | Robert D. Loberg Natalie McGregor Chi Ying Erin Sargent Kenneth J. Pienta |
| author_sort | Robert D. Loberg |
| collection | DOAJ |
| description | 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: 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, BCI-xL, 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. |
| first_indexed | 2024-12-12T23:01:44Z |
| format | Article |
| id | doaj.art-91a0531a296b4974b4837599230b542a |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-12T23:01:44Z |
| publishDate | 2007-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-91a0531a296b4974b4837599230b542a2022-12-22T00:08:48ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022007-12-019121030103710.1593/neo.07778In Vivo Evaluation of AT-101 (R-(—)-Gossypol Acetic Acid) in Androgen-Independent Growth of VCaP Prostate Cancer Cells in Combination with Surgical CastrationRobert D. Loberg0Natalie McGregor1Chi Ying2Erin Sargent3Kenneth J. Pienta4Department of Urology, University of Michigan Urology Center, Ann Arbor, MI, USADepartment of Internal Medicine, University of Michigan, Ann Arbor, MI, USADepartment of Internal Medicine, University of Michigan, Ann Arbor, MI, USADepartment of Internal Medicine, University of Michigan, Ann Arbor, MI, USADepartment of Urology, University of Michigan Urology Center, Ann Arbor, MI, USAPURPOSE: 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: 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, BCI-xL, 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.http://www.sciencedirect.com/science/article/pii/S1476558607801138ApoptosisBcl-2BH3 domainhormone refractoryorchiectomy |
| spellingShingle | Robert D. Loberg Natalie McGregor Chi Ying Erin Sargent Kenneth J. Pienta In Vivo Evaluation of AT-101 (R-(—)-Gossypol Acetic Acid) in Androgen-Independent Growth of VCaP Prostate Cancer Cells in Combination with Surgical Castration Neoplasia: An International Journal for Oncology Research Apoptosis Bcl-2 BH3 domain hormone refractory orchiectomy |
| title | In Vivo Evaluation of AT-101 (R-(—)-Gossypol Acetic Acid) in Androgen-Independent Growth of VCaP Prostate Cancer Cells in Combination with Surgical Castration |
| title_full | In Vivo Evaluation of AT-101 (R-(—)-Gossypol Acetic Acid) in Androgen-Independent Growth of VCaP Prostate Cancer Cells in Combination with Surgical Castration |
| title_fullStr | In Vivo Evaluation of AT-101 (R-(—)-Gossypol Acetic Acid) in Androgen-Independent Growth of VCaP Prostate Cancer Cells in Combination with Surgical Castration |
| title_full_unstemmed | In Vivo Evaluation of AT-101 (R-(—)-Gossypol Acetic Acid) in Androgen-Independent Growth of VCaP Prostate Cancer Cells in Combination with Surgical Castration |
| title_short | In Vivo Evaluation of AT-101 (R-(—)-Gossypol Acetic Acid) in Androgen-Independent Growth of VCaP Prostate Cancer Cells in Combination with Surgical Castration |
| title_sort | in vivo evaluation of at 101 r gossypol acetic acid in androgen independent growth of vcap prostate cancer cells in combination with surgical castration |
| topic | Apoptosis Bcl-2 BH3 domain hormone refractory orchiectomy |
| url | http://www.sciencedirect.com/science/article/pii/S1476558607801138 |
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