Novel inosine monophosphate dehydrogenase inhibitor VX-944 induces apoptosis in multiple myeloma cells primarily via caspase-independent AIF/Endo G pathway.
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.
Ishitsuka
Kenji
K
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Hideshima
Teru
T
Hamasaki
Makoto
M
Raje
Noopur
N
Kumar
Shaji
S
Podar
Klaus
K
Le Gouill
Steven
S
Shiraishi
Norihiko
N
Yasui
Hiroshi
H
Roccaro
Aldo M
AM
Tai
Yu-Zu
YZ
Chauhan
Dharminder
D
Fram
Robert
R
Tamura
Kazuo
K
Jain
Jugnu
J
Anderson
Kenneth C
KC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051033:Apoptosis Inducing Factor; D015153:Blotting, Western; D001854:Bone Marrow Cells; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D004706:Endodeoxyribonucleases / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005420:Flavoproteins / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D009101:Multiple Myeloma / Q000473:pathology*; D009930:Organic Chemicals / Q000494:pharmacology*
C494829:AIFM1 protein, human; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D004791:Enzyme Inhibitors; D005420:Flavoproteins; D015850:Interleukin-6; D008565:Membrane Proteins; D009930:Organic Chemicals; C504340:VX-944; D007334:Insulin-Like Growth Factor I; D007168:IMP Dehydrogenase; C488211:IMPDH1 protein, human; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D020169:Caspases