1. Novel inosine monophosphate dehydrogenase inhibitor VX-944 induces apoptosis in multiple myeloma cells primarily via caspase-independent AIF/Endo G pathway.
- Author
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Ishitsuka, Kenji, Hideshima, Teru, Hamasaki, Makoto, Raje, Noopur, Kumar, Shaji, Podar, Klaus, Le Gouill, Steven, Shiraishi, Norihiko, Yasui, Hiroshi, Roccaro, Aldo M., Yu-Zu Tai, Chauhan, Dharminder, Fram, Robert, Tamura, Kazuo, Jain, Jugnu, and Anderson, Kenneth C.
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APOPTOSIS , *CELL death , *PLASMACYTOMA , *ORGANELLES , *PROINSULIN , *CYTOKINES - Abstract
Inosine monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme required for the de novo synthesis of guanine nucleotides from IMP. VX-944 (Vertex Pharmaceuticals, Cambridge, MA, USA) is a small-molecule, selective, noncompetitive inhibitor directed against human IMPDH. In this report, we show that VX-944 inhibits in vitro growth of human multiple myeloma (MM) cell lines via induction of apoptosis. Interleukin-6, insulin-like growth factor-1, or co-culture with bone marrow stromal cells (BMSCs) do not protect against VX-944-induced MM cell growth inhibition. VX-944 induced apoptosis in MM cell lines with only modest activation of caspases 3, 8, and 9. Furthermore, the pan-caspase inhibitor z-VAD-fmk did not inhibit VX-944-induced apoptosis and cell death. During VX-944-induced apoptosis, expressions of Bax and Bak were enhanced, and both apoptosis-inducing factor (AIF) and endonuclease G (Endo G) were released from the mitochondria to cytosol, suggesting that VX-944 triggers apoptosis in MM cells primarily via a caspase-independent, Bax/AIF/Endo G pathway. Importantly, VX-944 augments the cytotoxicity of doxorubicin and melphalan even in the presence of BMSCs. Taken together, our data demonstrate a primarily non-caspase-dependent apoptotic pathway triggered by VX-944, thereby providing a rationale to enhance MM cell cytotoxicity by combining this agent with conventional agents which trigger caspase activation.Oncogene (2005) 24, 5888–5896. doi:10.1038/sj.onc.1208739; published online 6 June 2005 [ABSTRACT FROM AUTHOR]
- Published
- 2005
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