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BMD188, A novel hydroxamic acid compound, demonstrates potent anti-prostate cancer effectsin vitro andin vivo by inducing apoptosis: requirements for mitochondria, reactive oxygen species, and proteases

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Pathology & Oncology Research

Abstract

A newly synthesized cyclic hydroxamic acid compound, BMD188 [cis-l-hydroxy-4-(l-naphthyl)-6-oc-tylpiperidine-2-one], was found to induce the apoptotic death of cultured prostate cancer cells by activating caspase-3. Orally administered BMD188 significantly inhibited the primary growth of prostate cancer cells (Dul45) orthotopically implanted into SCID mice. Mechanistic studies indicated that BMD188 did not alter the protein levels of several Bcl-2 family members. In contrast, the BMD188 effect required three essential factors: reactive oxygen species (ROS), the mitochondrial respiratory chain function, and proteases. First, the apoptosis-inducing effect of BMD188 could be blocked by ROS scavengers such as Desferal. Second, both BMD188-induced PARP cleavage as well as PC3 cell apoptosis could be dramatically inhibited by several complex-specific mitochondrial respiration blockers. The involvement of mitochondria was also supported by the observations that BMD188 dramatically altered the mitochondrial distribution and morphology without affecting the cellular ATP levels. Finally, the apoptosis-inducing effect of BMD188 in PC3 cells could be significantly inhibited by serine protease inhibitors (TPCK and TLCK) as well as by caspase inhibitors (zVAD-fmk and DEVD-CHO). Collectively, the present study suggests that BMD188 and its analogs may find clinical applications in the treatment of prostate cancer patients by inducing apoptotic death of prostate cancer cells.

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Authors and Affiliations

  1. Biomide Laboratories, Wayne State University, Detroit

    Dean G Tang, Li Li, Zhenyu Zhu & Bindu Joshi

  2. Departments of Radiation Oncology, Wayne State University, Detroit

    Kenneth V Honn & Arthur T. Porter

  3. Karmanos Cancer Insitute, Detroit

    Dean G Tang, Kenneth V Honn, John D Crissman & Arthur T. Porter

  4. Departments of Chemistry, Wayne State University, Detroit

    Carl R Johnson

  5. Department of Biochemistry, Vanderbilt University Medical Center, Nashville

    Lawrence J Marnett

  6. Departments of Pathology, Wayne State University, Detroit

    John D Crissman

  7. Apoptosis & Cell Death Program, The Burham Institute, La Jolla

    Stanislaw Krajewski & John C Reed

  8. lst Institute of Pathology and Experimental Cancer Research, Semmelweis University of Medicine, Budapest, Hungary

    József Timar

Authors
  1. Dean G Tang
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  2. Li Li
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  3. Zhenyu Zhu
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  4. Bindu Joshi
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  5. Carl R Johnson
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  7. Kenneth V Honn
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  9. Stanislaw Krajewski
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  11. József Timar
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  12. Arthur T. Porter
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Correspondence to Dean G Tang.

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G Tang, D., Li, L., Zhu, Z. et al. BMD188, A novel hydroxamic acid compound, demonstrates potent anti-prostate cancer effectsin vitro andin vivo by inducing apoptosis: requirements for mitochondria, reactive oxygen species, and proteases. Pathol. Oncol. Res. 4, 179–190 (1998). https://doi.org/10.1007/BF02905247

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  • DOI: https://doi.org/10.1007/BF02905247

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