Das, Deepika SharmaRay, ArghyaDas, AbhishekSong, YanOronsky, BryanRichardson, PaulScicinski, JanChauhan, DharminderAnderson, Kenneth2016-12-022016Das, Deepika Sharma, Arghya Ray, Abhishek Das, Yan Song, Bryan Oronsky, Paul Richardson, Jan Scicinski, Dharminder Chauhan, and Kenneth C. Anderson. 2016. “A Novel Hypoxia-Selective Epigenetic Agent RRx-001 Triggers Apoptosis and Overcomes Drug Resistance in Multiple Myeloma Cells.” Leukemia 30 (11): 2187-2197. doi:10.1038/leu.2016.96. http://dx.doi.org/10.1038/leu.2016.96.0887-6924http://nrs.harvard.edu/urn-3:HUL.InstRepos:29625960The hypoxic bone-marrow (BM) microenvironment confers growth/survival and drug-resistance in multiple myeloma (MM) cells. Novel therapies targeting the MM cell in its hypoxic-BM milieu may overcome drug resistance. Recent studies led to the development of a novel molecule RRx-001 with hypoxia-selective epigenetic and Nitric Oxide-donating properties. Here we demonstrate that RRx-001 decreases the viability of MM cell lines and primary patient cells, as well as overcomes drug-resistance. RRx-001 inhibits MM cell growth in the presence of BM stromal cells. RRx-001 induced apoptosis is associated with: 1) activation of caspases; 2) release of ROS and nitrogen-species; 3) induction of DNA damage via ATM/γ-H2AX; and 4) decrease in DNA methytransferase (DNMT) and global methylation. RNA interference study shows a predominant role of DNMT1 in MM cell survival versus DNMT3a or DNMT3b. Deubiquitylating enzyme USP7 stimulates DNMT1 activity; and conversely, USP7-siRNA reduced DNMT1 activity and decreased MM cell viability. RRx-001 plus USP7 inhibitor P5091 triggered synergistic anti-MM activity. MM xenograft studies show that RRx-001 is well tolerated, inhibits tumor growth, and enhances survival. Combining RRx-001 with pomalidomide, bortezomib or SAHA induces synergistic anti-MM activity. Our results provide the rationale for translation of RRx-001, either alone or in combination, to clinical evaluation in MM.en-USJournal Article2016-12-0210.1038/leu.2016.96