The Pharmacology of CD38/NADase: An emerging target for cancer and aging diseases

Recent reports indicate that intracellular levels of NAD decline in tissues during chronological aging, and that therapies aim at increasing cellular NAD levels could have beneficial effects in many age-related diseases. The protein CD38 (CLUSTER OF DIFFERENTIATION 38) is a multifunctional enzyme that degrades NAD and modulates cellular NAD homeostasis. At the physiological level, CD38 has been implicated in the regulation of metabolism, and the pathogenesis of multiple conditions including: aging, obesity, diabetes, heart disease, asthma and inflammation. Interestingly, many of these functions are mediated by the CD38 enzymatic activity. In addition, CD38 has also been identified as a cell surface marker in hematologic cancers such as multiple myeloma, and a cytotoxic anti-CD38 antibody has been approved by the FDA for use in this disease. Although this is a remarkable development, killing CD38-positive tumor cells with cytotoxic anti-CD38 antibodies is only one of the potential pharmacological uses of targeting CD38. The present review discusses the biology of the CD38 enzyme and the current state of development of pharmacological tools aim at CD38 and explores how these agents may represent a novel approach to treat human conditions including cancer, metabolic diseases and diseases of aging.