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

Oncogene volume 24, pages 5888–5896 (2005)Cite this article

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.

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Acknowledgements

We acknowledge K Lin, R Hoover, Y Yao, M Harding, J Thomson, M Partridge and C Sorensen at Vertex for critical reading of the manuscript or advice during the course of these studies. This study is supported by National Institutes of Health Grants Specialized Programs of Research Excellence (SPORE) IP50 CA10070-01, PO-1 78378, and RO-1 CA 50947; the Doris Duke Distinguished Clinical Research Scientist Award (KCA); the Multiple Myeloma Research Foundation (TH); and the Cure for Myeloma Research Fund (KCA).

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Authors and Affiliations

  1. Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, 02115, MA, USA

    Kenji Ishitsuka, Teru Hideshima, Makoto Hamasaki, Noopur Raje, Shaji Kumar, Klaus Podar, Steven Le Gouill, Norihiko Shiraishi, Hiroshi Yasui, Aldo M Roccaro, Yu-Zu Tai, Dharminder Chauhan & Kenneth C Anderson

  2. Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, 02139, MA, USA

    Robert Fram & Jugnu Jain

  3. 1st Department of Internal Medicine, Fukuoka University, 7-45-1 Nanakuma Jonan Fukuoka 814-0180, Japan

    Kazuo Tamura

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Ishitsuka, K., Hideshima, T., Hamasaki, M. et al. Novel inosine monophosphate dehydrogenase inhibitor VX-944 induces apoptosis in multiple myeloma cells primarily via caspase-independent AIF/Endo G pathway. Oncogene 24, 5888–5896 (2005). https://doi.org/10.1038/sj.onc.1208739

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