Sabutoclax, a Mcl-1 Antagonist, Inhibits Tumorigenesis in Transgenic Mouse and Human Xenograft Models of Prostate Cancer
Resistance to available therapeutic agents has been a common problem thwarting progress in treatment of castrate-resistant and metastatic prostate cancer (PCa). Overexpression of the Bcl-2 family members, including Mcl-1, in PCa cells is known to inhibit intracellular mitochondrial-dependent apoptos...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2012-07-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558612800996 |
| _version_ | 1819086736261644288 |
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| author | Roger S. Jackson, II William Placzek Ana Fernandez Shabnam Ziaee Chia-Yi Chu Jun Wei John Stebbins Shinichi Kitada Gloria Fritz John C. Reed Leland W. Chung Maurizio Pellecchia Neil A. Bhowmick |
| author_facet | Roger S. Jackson, II William Placzek Ana Fernandez Shabnam Ziaee Chia-Yi Chu Jun Wei John Stebbins Shinichi Kitada Gloria Fritz John C. Reed Leland W. Chung Maurizio Pellecchia Neil A. Bhowmick |
| author_sort | Roger S. Jackson, II |
| collection | DOAJ |
| description | Resistance to available therapeutic agents has been a common problem thwarting progress in treatment of castrate-resistant and metastatic prostate cancer (PCa). Overexpression of the Bcl-2 family members, including Mcl-1, in PCa cells is known to inhibit intracellular mitochondrial-dependent apoptosis. Here we report the development of a novel transgenic mouse model that spontaneously develops prostatic intraepithelial neoplasia and adenocarcinoma by the inducible, conditional knockout of transforming growth factor β receptor type II in stromal fibroblastic cells (Tgfbr2ColTKO). The Tgfbr2ColTKO prostate epithelia demonstrated down-regulation of luminal and basal differentiation markers, as well as Pten expression and up-regulation of Mcl-1. However, unlike in men, Tgfbr2ColTKO prostates exhibited no regression acutely after castration. The administration of Sabutoclax (BI-97C1), a pan-active Bcl-2 protein family antagonist mediated apoptosis in castrate-resistant PCa cells of Tgfbr2ColTKO mice and human subcutaneous, orthotopic, and intratibial xenograft PCa models. Interestingly, Sabutoclax had little apoptotic effect on benign prostate tissue in Tgfbr2ColTKO and wild-type mice. Sabutoclax was able to block c-Met activation, a critical axis in PCa metastatic progression. Further, Sabutoclax synergistically sensitized PC-3 cells to the cytotoxic effects of docetaxel (Taxotere). Together, these data suggest that Sabutoclax inhibits castrate-resistant PCa alone at the primary and bone metastatic site as well as support sensitivity to docetaxel treatment. |
| first_indexed | 2024-12-21T21:24:59Z |
| format | Article |
| id | doaj.art-988a0c7acbd2499aaaafad293df8e8b7 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-21T21:24:59Z |
| publishDate | 2012-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-988a0c7acbd2499aaaafad293df8e8b72022-12-21T18:49:48ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022012-07-0114765666510.1593/neo.12640Sabutoclax, a Mcl-1 Antagonist, Inhibits Tumorigenesis in Transgenic Mouse and Human Xenograft Models of Prostate CancerRoger S. Jackson, II0William Placzek1Ana Fernandez2Shabnam Ziaee3Chia-Yi Chu4Jun Wei5John Stebbins6Shinichi Kitada7Gloria Fritz8John C. Reed9Leland W. Chung10Maurizio Pellecchia11Neil A. Bhowmick12Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TNSanford-Burnham Medical Research Institute, La Jolla, CADepartment of Medicine, Cedars-Sinai Medical Center, Los Angeles, CADepartment of Medicine, Cedars-Sinai Medical Center, Los Angeles, CADepartment of Medicine, Cedars-Sinai Medical Center, Los Angeles, CASanford-Burnham Medical Research Institute, La Jolla, CASanford-Burnham Medical Research Institute, La Jolla, CASanford-Burnham Medical Research Institute, La Jolla, CADepartment of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TNSanford-Burnham Medical Research Institute, La Jolla, CADepartment of Medicine, Cedars-Sinai Medical Center, Los Angeles, CASanford-Burnham Medical Research Institute, La Jolla, CADepartment of Medicine, Cedars-Sinai Medical Center, Los Angeles, CAResistance to available therapeutic agents has been a common problem thwarting progress in treatment of castrate-resistant and metastatic prostate cancer (PCa). Overexpression of the Bcl-2 family members, including Mcl-1, in PCa cells is known to inhibit intracellular mitochondrial-dependent apoptosis. Here we report the development of a novel transgenic mouse model that spontaneously develops prostatic intraepithelial neoplasia and adenocarcinoma by the inducible, conditional knockout of transforming growth factor β receptor type II in stromal fibroblastic cells (Tgfbr2ColTKO). The Tgfbr2ColTKO prostate epithelia demonstrated down-regulation of luminal and basal differentiation markers, as well as Pten expression and up-regulation of Mcl-1. However, unlike in men, Tgfbr2ColTKO prostates exhibited no regression acutely after castration. The administration of Sabutoclax (BI-97C1), a pan-active Bcl-2 protein family antagonist mediated apoptosis in castrate-resistant PCa cells of Tgfbr2ColTKO mice and human subcutaneous, orthotopic, and intratibial xenograft PCa models. Interestingly, Sabutoclax had little apoptotic effect on benign prostate tissue in Tgfbr2ColTKO and wild-type mice. Sabutoclax was able to block c-Met activation, a critical axis in PCa metastatic progression. Further, Sabutoclax synergistically sensitized PC-3 cells to the cytotoxic effects of docetaxel (Taxotere). Together, these data suggest that Sabutoclax inhibits castrate-resistant PCa alone at the primary and bone metastatic site as well as support sensitivity to docetaxel treatment.http://www.sciencedirect.com/science/article/pii/S1476558612800996 |
| spellingShingle | Roger S. Jackson, II William Placzek Ana Fernandez Shabnam Ziaee Chia-Yi Chu Jun Wei John Stebbins Shinichi Kitada Gloria Fritz John C. Reed Leland W. Chung Maurizio Pellecchia Neil A. Bhowmick Sabutoclax, a Mcl-1 Antagonist, Inhibits Tumorigenesis in Transgenic Mouse and Human Xenograft Models of Prostate Cancer Neoplasia: An International Journal for Oncology Research |
| title | Sabutoclax, a Mcl-1 Antagonist, Inhibits Tumorigenesis in Transgenic Mouse and Human Xenograft Models of Prostate Cancer |
| title_full | Sabutoclax, a Mcl-1 Antagonist, Inhibits Tumorigenesis in Transgenic Mouse and Human Xenograft Models of Prostate Cancer |
| title_fullStr | Sabutoclax, a Mcl-1 Antagonist, Inhibits Tumorigenesis in Transgenic Mouse and Human Xenograft Models of Prostate Cancer |
| title_full_unstemmed | Sabutoclax, a Mcl-1 Antagonist, Inhibits Tumorigenesis in Transgenic Mouse and Human Xenograft Models of Prostate Cancer |
| title_short | Sabutoclax, a Mcl-1 Antagonist, Inhibits Tumorigenesis in Transgenic Mouse and Human Xenograft Models of Prostate Cancer |
| title_sort | sabutoclax a mcl 1 antagonist inhibits tumorigenesis in transgenic mouse and human xenograft models of prostate cancer |
| url | http://www.sciencedirect.com/science/article/pii/S1476558612800996 |
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