BMD188, a novel hydroxamic acid compound, demonstrates potent anti- prostate cancer effects in vitro and in vivo by inducing apoptosis: Requirements for mitochondria, reactive oxygen species, and proteases

Dean G. Tang, Li Li, Zhenyu Zhu, Bindu Joshi, Carl R. Johnson, Lawrence J. Marnett, Kenneth V. Honn, John D. Crissman, Stanislaw Krajewski, John C. Reed, József Timar, Arthur T. Porter

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22 Citations (Scopus)

Abstract

A newly synthesized cyclic hydroxamic acid compound, BMD188 [cis-1- hydroxy-4-(1-naphthyl)-6-octylpiperidine-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 (Du145) 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.

Original languageEnglish
Pages (from-to)179-190
Number of pages12
JournalPathology and Oncology Research
Volume4
Issue number3
Publication statusPublished - Dec 17 1998

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Keywords

  • Apoptosis
  • Chemotherapy
  • Free radical
  • Hydroxamic acid
  • Mitochondria
  • Prostate cancer

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Oncology
  • Cancer Research

Cite this

Tang, D. G., Li, L., Zhu, Z., Joshi, B., Johnson, C. R., Marnett, L. J., Honn, K. V., Crissman, J. D., Krajewski, S., Reed, J. C., Timar, J., & Porter, A. T. (1998). BMD188, a novel hydroxamic acid compound, demonstrates potent anti- prostate cancer effects in vitro and in vivo by inducing apoptosis: Requirements for mitochondria, reactive oxygen species, and proteases. Pathology and Oncology Research, 4(3), 179-190.