Nicotinamide, the amide derivative of vitamin B3
, is a precursor used by cells for the synthesis of nicotinamide adenine dinucleotide, which is known to play a major role as a co-enzyme in numerous oxidation-reduction reactions [1
]. Studies by Ogata et al. [2
] suggest that nicotinamide acts as an inducer of apoptosis in HL-60 cells. More interestingly, some studies show that nicotinamide represents a pharmacological agent, and has been reported to exert inhibitory effects on poly(ADP-ribose) polymerase (PARP) [3
]. PARPs have been involved in DNA repair and replication [4
], cell viability, apoptosis and regulation of numerous cellular functions [6
]. Szabo [8
] indicated that PARP inhibition not only prevents the development of diabetic endothelial dysfunction, but also restores normal vascular function in established diabetes. Thus, as a PARP inhibitor, nicotinamide may be useful in the therapy of diseases, where PARP is thought to play a role.
Nicotinamide has been used in a broad spectrum of diseases, such as preventing streptozotocin-induced diabetes in rats [9
] or exerting protective effects on acute lung injury caused by ischemia-reperfusion [10
]. Therefore, new functions of nicotinamide, such as use as anticancer tools, are of interest. It was shown that several niacin-related compounds including nicotinamide had an effect on the differentiation of leukemia cells [11
]. Studies by Munshi et al. [12
] showed that nicotinamide inhibited retinoic acid (RA)-induced CD38 expression and differentiation. Niacin-related compounds such as isonicotinamide or vitamin B3
had histone deacetylase(HDAC) inhibitory activity, like phenyl butyrate, and affected leukemic cell differentiation [11
]. Merzvinskyte et al. [13
] showed that treating HL-60 cells with both sodium phenyl butyrate plus vitamin B3
, prior to RA treatment caused enhanced CD11b expression, inducible oxidative metabolism, and cell cycle arrest, suggesting that niacin-related compounds may regulate cell differentiation. Nicotinamide may thus affect a variety of processes that regulate proliferation and differentiation [11
], including cellular response to RA or 1,25-dihydroxyvitamin D3
(D3), two well-known inducers of differentiation.
RA or D3 are known to induce HL-60 myeloblastic leukemia cells to undergo G0 cell cycle arrest and myeloid or monocytic differentiation [15
]. Our previous studies have indicated that in HL-60 cells RA and D3 cause ERK phosphorylation and activation of MAPK signaling leading to myeloid or monocytic differentiation and G0 cell cycle arrest [16
]. In this process RA or D3 induces the early expression of CD38, which is associated with lipid rafts upon receptor stimulation, and signals through MAPK to promote cell differentiation [17
]. These considerations motivate the anticipation that nicotinamide may cooperate with RA or D3 to regulate cell differentiation and proliferation.
In this study, we investigated whether nicotinamide affects processes involved in control of proliferation and differentiation that regulate RA- or D3-induced differentiation and cell cycle arrest. This would contribute to understanding the mechanism of differentiation and cell arrest for inducers used in the treatment of leukemia [19
]. This study also showed interesting evidence that nicotinamide worked together with RA or D3 to regulate functional cell differentiation and cell cycle arrest. Nicotinamide has already been used in the clinic to treat various diseases [20
]; the finding thus has interesting clinical relevance. Nicotinamide also induced ERK activation and further enhanced the ERK activation induced by RA, but diminished the D3-induced enhanced ERK activation, suggesting that nicotinamide differentially affects HL-60 cell myeloid or monocytic differentiation. Our study provides a comprehensive scientific evaluation of the differential roles of nicotinamide in RA- or D3-induced differentiation and cell cycle arrest. The data suggest the potential advantage of combined RA/nicotinamide therapy.