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.
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.
Tang
D G
DG
Wayne State University, Biomide Laboratories, Detroit, USA. dtang@uc1.ac.uk
Li
L
L
Zhu
Z
Z
Joshi
B
B
Johnson
C R
CR
Marnett
L J
LJ
Honn
K V
KV
Crissman
J D
JD
Krajewski
S
S
Reed
J C
JC
Timar
J
J
Porter
A T
AT
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010881:Piperidones / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology
C117140:1-hydroxy-4-(1-naphthyl)-6-octylpiperidine-2-one; D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D016859:Lipoxygenase Inhibitors; D009363:Neoplasm Proteins; D010881:Piperidones; D017382:Reactive Oxygen Species; D015842:Serine Proteinase Inhibitors; D010450:Endopeptidases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases