Novel inosine monophosphate dehydrogenase inhibitor VX-944 induces apoptosis in multiple myeloma cells primarily via caspase-independent AIF/Endo G pathway

Kenji Ishitsuka, Teru Hideshima, Makoto Hamasaki, Noopur Raje, Shaji K Kumar, Klaus Podar, Steven Le Gouill, Norihiko Shiraishi, Hiroshi Yasui, Aldo M. Roccaro, Yu Zu Tai, Dharminder Chauhan, Robert Fram, Kazuo Tamura, Jugnu Jain, Kenneth C. Anderson

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51 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5888-5896
Number of pages9
JournalOncogene
Volume24
Issue number38
DOIs
StatePublished - Sep 1 2005
Externally publishedYes

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Keywords

  • AIF/Endo G pathway
  • Apoptosis
  • IMPDH inhibitor
  • Multiple myeloma
  • VX-944

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Ishitsuka, K., Hideshima, T., Hamasaki, M., Raje, N., Kumar, S. K., Podar, K., Le Gouill, S., Shiraishi, N., Yasui, H., Roccaro, A. M., Tai, Y. Z., Chauhan, D., Fram, R., Tamura, K., Jain, J., & Anderson, K. C. (2005). Novel inosine monophosphate dehydrogenase inhibitor VX-944 induces apoptosis in multiple myeloma cells primarily via caspase-independent AIF/Endo G pathway. Oncogene, 24(38), 5888-5896. https://doi.org/10.1038/sj.onc.1208739