Nicotinamide Blocks Proliferation and Induces Apoptosis of Chronic Lymphocytic Leukemia Cells through Activation of the p53/miR-34a/SIRT1 Tumor Suppressor Network

Abstract

Because of its relatively indolent clinical course, chronic lymphocytic leukemia (CLL) offers a versatile model for testing novel therapeutic regimens and drug combinations. Nicotinamide is the main NAD þ precursor and a direct inhibitor of four classes of enzymes, including the sirtuins. SIRT1, the main member of the sirtuin family, inactivates p53 by deacetylating a critical lysine residue. In this study, we showed that CLL cells express high levels of functional SIRT1, which is inhibited by exogenous nicotinamide. This agent blocks proliferation and promotes apoptosis selectively in leukemic cells that express wild-type (wt) p53. Nicotinamide modulates the p53-dependent genes p21, NOXA, BAX, and Mcl-1, indicating an activation of the p53 pathway and of caspase-3. DNA-damaging chemotherapeutics, such as etoposide, activate a functional loop linking SIRT1 and p53 through the induction of miR-34a. When leukemic cells are simultaneously exposed to nicotinamide and etoposide, we observe a significant increase in miR-34a levels with a concomitant inhibition of SIRT1. Furthermore, p53 acetylation levels are higher than with either agent used alone. Overall, treatment with both nicotinamde and etoposide shows strongly synergistic effects in the induction of apoptosis. We therefore concluded that nicotinamide has the dual property of inhibiting SIRT1 through a noncompetitive enzymatic block (p53 independent) and at the same time through miR-34a induction (p53 dependent). These observations suggested the therapeutic potential of nicotinamide, a novel, safe, and inexpensive drug, to be used in addition to chemotherapy for CLL patients with wt p53. Cancer Res; 71(13); 4473-83. Ó2011 AACR.

Nicotinamide sensitizes human breast cancer cells to the cytotoxic effects of radiation and cisplatin

“…Similarly, AzD2281, another PARP inhibitor, in combination with cisplatin synergistically induced cell growth inhibition of breast cancer cells deficient in BRCA2 (24). In agreement with findings of that report, our results demonstrate that the combination of NAM with cis platin significantly decreased cell viability in the three breast cancer cell lines regardless of the BRCA1 status.…”

miR-34a inhibits cell proliferation in prostate cancer by downregulation of SIRT1 expression

“…Chapman et al (28) proposed that SIRT1 is involved in metabolism and tolerance to oxidative stress, promoting the growth of human urothelial cancer cell. Moreover, inhibition of SIRT1 expression reduced cell proliferation even in p53 mutated cells (29). The present study demonstrated that overexpression of miR-34a significantly reduced SIRT1 mRNA and protein expression levels.…”

Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease

“…Nicotinamide is a known inhibitor of SIRT1, and nicotinamide alters SIRT1-mediated downstream signaling pathways (14,33). However, nicotinamide may inhibit the activity of other sirtuin proteins, including SIRT2-SIRT4 (14,34,35).…”