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Abstract
Multiple myeloma (MM) is a plasma cell neoplasm that has a low apoptotic index. We
investigated a new class of small molecules that target the terminal apoptosis pathway,
called procaspase activating compounds (PACs), in myeloma cells. PAC agents (PAC-1
and B-PAC-1) convert executioner procaspases (procaspase 3, 6, and 7) to active caspases
3, 6, and 7, which cleave target substrates to induce cellular apoptosis cascade.
We hypothesized that targeting this terminal step could overcome survival and drug-resistance
signals in myeloma cells and induce programmed cell death. Myeloma cells expressed
executioner caspases. Additionally, our studies demonstrated that B-PAC-1 is cytotoxic
to chemotherapy-resistant or sensitive myeloma cell lines (n = 7) and primary patient
cells (n = 11). Exogenous zinc abrogated B-PAC-1-induced cell demise. Apoptosis induced
by B-PAC-1 treatment was similar in the presence or absence of growth-promoting cytokines
such as interleukin 6 and hepatocyte growth factor. Presence or absence of antiapoptotic
proteins such as BCL-2, BCL-XL, or MCL-1 did not impact B-PAC-1-mediated programmed
cell death. Collectively, our data demonstrate the proapoptotic effect of B-PAC-1
in MM and suggest that activating terminal executioner procaspases 3, 6, and 7 bypasses
survival and drug-resistance signals in myeloma cells. This novel strategy has the
potential to become an effective antimyeloma therapy.