Abstract 1242: Modulating the cellular redox state by targeting the NAD glycohydrolase CD38: A novel therapeutic approach for chemosensitizing B-cell malignancies

Abstract

Abstract The cellular redox state, which is controlled by the NAD/NADH and NADP/NADPH redox partners, is critical for numerous cellular activities including energy metabolism, signaling and transcription. Hematopoietic tumors have higher levels of intrinsic reactive oxygen species (ROS) due to increased NAD biosynthesis and metabolism required to further stimulate tumorigenesis. To compensate for such toxic levels of ROS, cancer cells rely heavily on their antioxidant defense mechanisms to prevent ROS-induced death/senescence and to promote neoplastic cell behavior. It has been postulated that pairing drugs that block the tumor antioxidant pathways with ROS-inducing chemotherapeutics may kill tumors more effectively. We hypothesized that the modulation of NAD metabolism dramatically alters the cellular redox state, and that drugs affecting NAD metabolism may be effective anti-cancer therapeutics. Using an in vivo model of Streptozotocin (STZ)-induced oxidative stress, we show that the NAD glycohydrolase CD38, which is expressed by many B-cell malignancies, acts as an antioxidant by lowering intrinsic ROS levels and by protecting cells from extrinsic ROS, DNA alkylating chemotherapeutics and ROS-induced senescence. In addition, we show that the overexpression of human CD38 increases the viability of murine Ba/F3 pro-B cells cultured in the absence of the survival factor IL-3. To examine the role of CD38 in tumor cell growth and survival, we reduced CD38 expression in human multiple myeloma KMS-12-PE cells by RNA interference (RNAi) targeting three separate regions of the CD38 coding sequence. The knockdown of CD38 expression resulted in a significant decrease in the number of stable transformants generated, suggesting that CD38 plays a key role in tumor cell survival. Lastly, we show that CD38 antagonists synergize with the chemotherapeutic agent Melphalan to block tumor cell survival in vitro. In summary, this work suggests that CD38 is an antioxidant protein selectively used to maintain a cellular redox balance, and proposes that targeting the enzymatic activity of CD38 may be a novel therapeutic strategy for chemosensitizing B-cell malignancies. We are currently conducting a high-throughput screening (HTS) campaign of over 200 thousand small-molecule compounds to identify inhibitors of CD38 that can be used in combination with standard ROS-inducing chemotherapies to treat CD38+ B-cell malignancies, such as multiple myeloma and chronic lymphocytic leukemia. Citation Format: Davide Botta, Tulin Dadali, Betty Mousseau, Anna Manouvakhova, Melinda I. Sosa, Sara N. MKellip, LaKeisha Woods, Nichole A. Tower, Larry J. Ross, Lynn Rasmussen, E Lucile White, James R. Bostwick, Frances E. Lund. Modulating the cellular redox state by targeting the NAD glycohydrolase CD38: A novel therapeutic approach for chemosensitizing B-cell malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1242. doi:10.1158/1538-7445.AM2015-1242