The Pharmacology of CD38/NADase: An Emerging Target in Cancer and Diseases of Aging

Abstract

Recent reports indicate that intracellular NAD levels decline in tissues during chronological aging, and that therapies aimed 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 in the pathogenesis of multiple conditions including aging, obesity, diabetes, heart disease, asthma, and inflammation. Interestingly, many of these functions are mediated by 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 aimed at CD38, and explores how these agents may represent a novel approach for treating human conditions including cancer, metabolic disease, and diseases of aging.

The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD+ decline

“…Furthermore, we have also demonstrated that CD38 plays a key role in the age-related NAD + decline [2, 9]. However, to date several aspects of the biology of this enzyme remain to be elucidated [26–27]. For instance, what drives CD38 expression in the biology of aging is an open question [27–30].…”

“…However, to date several aspects of the biology of this enzyme remain to be elucidated [26–27]. For instance, what drives CD38 expression in the biology of aging is an open question [27–30]. Surprisingly, the possible link between CD38 expression and the cellular senescence phenotype has not been explored.…”

Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia

“…17,18 Several NAD 1 consumer proteins, such as CD38, poly (ADP-ribose) polymerase, and sirtuins, have been shown to manage DNA repair mechanisms and mediate cancer disease progression by protecting cells during nutrient-deficient events. [19][20][21][22][23][24] In the absence of NAD 1 , both classes of proteins lose their cytotoxic protective features, making NAD 1 reduction a potential target for cancer therapeutic agents.…”

Aging-related inflammation driven by cellular senescence enhances NAD consumption via activation of CD38+pro-inflammatory macrophages

“…Loss of CD38 activity in Cd38 KO mice or in mice treated with a CD38-specific inhibitor, 78c, are protected from age-related NAD decline and show improved metabolic health 14,41 . Therefore, blocking CD38 NADase activity is emerging as a promising therapeutic target to suppress NAD loss associated with aging 73 . In this study, we identified macrophages as a key cell type showing increased expression of CD38 during aging and the mechanisms responsible for this enhanced CD38 expression.…”