Modulation of G6PD affects bladder cancer via ROS accumulation and the AKT pathway in vitro.

Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme of the pentose phosphate pathway. Multiple studies have previously revealed that elevated G6PD levels promote cancer progression in numerous tumor types; however, the underlying mechanism remains unclear. In the present study, it was demonstrated that high G6PD expression is a poor prognostic factor in bladder cancer, and the levels of G6PD expression increase with increasing tumor stage. Patients with bladder cancer with high G6PD expression had worse survival rates compared with those with lower G6PD expression in resected tumors. In vitro experiments revealed that knockdown of G6PD suppressed cell viability and growth in Cell Counting Kit-8 and colony formation assays, and increased apoptosis in bladder cancer cell lines compared with normal cells. Further experiments indicated that the weakening of the survival ability in G6PD-knockdown bladder cancer cells may be explained by intracellular reactive oxygen species accumulation and protein kinase B pathway suppression. Furthermore, it was additionally revealed that 6-aminonicotinamide (6-AN), a competitive G6PD inhibitor, may be a potential therapy for bladder cancer, particularly in cases with high G6PD expression, and that the combination of cisplatin and 6-AN may optimize the clinical dose or minimize the side effects of cisplatin.

Design, synthesis, and evaluation of 4,6-diaminonicotinamide derivatives as novel and potent immunomodulators targeting JAK3.

In organ transplantation, T cell-mediated immune responses play a key role in the rejection of allografts. Janus kinase 3 (JAK3) is specifically expressed in hematopoietic cells and associated with regulation of T cell development via interleukin-2 signaling pathway. Here, we designed novel 4,6-diaminonicotinamide derivatives as immunomodulators targeting JAK3 for prevention of transplant rejection. Our optimization of C4- and C6-substituents and docking calculations to JAK3 protein confirmed that the 4,6-diaminonicotinamide scaffold resulted in potent inhibition of JAK3. We also investigated avoidance of human ether-a-go-go related gene (hERG) inhibitory activity. Selected compound 28 in combination with tacrolimus prevented allograft rejection in a rat heterotopic cardiac transplantation model.

Treatment of experimental acute corneal inflammation with inhibitors of the oxidative metabolism.

The authors studied the effect of topical 2% 6-aminonicotinamide and 0.1% adenosine on an experimental model of acute corneal inflammation. Luminol-enhanced chemiluminescence (LAC), as an indirect measurement of free-radical release, and computer-assisted planimetry of the corneal ulcer and its infiltrate were performed both ex vivo and in vivo on the fifth day following the induction of experimental alkali burn keratitis. The authors proved that both drugs significantly inhibited LAC both ex vivo and in vivo and that such treatments had also a significant beneficial effect on the evolution of the corneal ulcer and its infiltrate. To the best of the authors' knowledge, this finding had not been previously reported in experimental corneal inflammation and may indicate that treatment with inhibitors of the oxidative metabolism could offer a new approach in the pharmacological modulation of acute corneal inflammation.

Cerebral endogenous substrate utilization during the recovery period after profound hypoglycemia.

Markedly decreased levels of energy-rich phosphates were seen in cerebral cortex after severe hypoglycemia, followed by their partial restitution during the recovery period. During hypoglycemia the nonglucose endogenous substrates were provided by glycolytic intermediates, by Krebs cycle intermediates, and by related amino acids. Other potential substrates for brain oxidation were provided by the breakdown of phospholipids and fatty acids. After a 20-min period of posthypoglycemic recovery, partial restoration of carbohydrates and amino acids occurred, although the amino acid pool size was still reduced. The alterations in phospholipids and fatty acids persisted, while there was a tendency toward normalization of the free fatty acid content. During the posthypoglycemic recovery, treatment with some specific metabolic modulators (6-aminonicotinamide, hopantenate, uridine, L-acetylcarnitine) suggested the possibility of an alternative cerebral substrate utilization owing to modulation of the cerebral biochemical machinery. Thus, increased carbohydrate utilization by hopantenate was consistent with decreased lipid breakdown, while increased carbohydrate utilization by uridine was concomitant with decreased amino acid degradation. In this way, decreased cerebral carbohydrate utilization by 6-amino-nicotinamide was associated with increased lipid and amino acid breakdown. Furthermore, the increased loss of cerebral phospholipids and phospholipid-bound fatty acids by L-acetylcarnitine occurred in the presence of a large glucose availability and was associated with an extensive reduction of cerebral glycolytic flux.

Synergistic antileukemic effect of 6-aminonicotinamide and 1,3-bis(2-chloroethyl)-1-nitrosourea on L1210 cells in vitro and in vivo.

A series of nicotinamide analogs were evaluated for their ability to inhibit L1210 cell poly(adenosine diphosphoribose) polymerase, and also for their ability to potentiate the cytocidal effects of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), nitrogen mustard, and gamma-irradiation. In L1210 cells growing in culture and in vivo. In vitro, nicotinamide, 5-methylnicotinamide, 6-aminonicotinamide, and benzamide effectively inhibited L1210 cell poly(adenosine diphosphoribose) polymerase; 1-methylnicotinamide, nicotinic acid, and benzoic acid did not. In culture, 6-aminonicotinamide potentiated the cytocidal effect of BCNU; however, it did not significantly potentiate the effects of nitrogen mustard or gamma-irradiation in vivo, both 6-aminonicotinamide and nicotinamide potentiated the cytocidal effect of BCNU; however, the concentrations of nicotinamide required for this effect were 10- to 20-fold higher than those of 6-aminonicotinamide. None of the analogs significantly potentiated the in vivo effect of nitrogen mustard or gamma-irradiation. Treatment of L1210-bearing mice with varying combinations of BCNU and 6-aminonicotinamide produced a synergistic increase in life span; in some cases, the combination led to the production of long term disease-free survivors.

Topical 6-aminonicotinamide plus oral niacinamide therapy for psoriasis.

Ninety-nine patients with psoriasis were treated topically with 6-aminonicotinamide (6-AN) in four years. In a double-blind study, 1% 6-AN gel was superior to 0.1% triamcinolone acetonide in 29 comparisons, equal in three, and inferior in one when applied without occlusion for four weeks. In an open study, 1% 6-AN was better than four "potent" steroid creams in 34 comparisons, equal in four, and inferior in one. Substantial improvement or complete clearing of plaques occurred in 85 of 99 patients. Tachyphylaxis occurred in ten, but was not permanent. Mucocutaneous toxicity appeared in 25% but was usually easily controlled. Tinnitus occurred in four, but none had deterioration of audiogram readings. The combination of topical 6-AN and oral niacinamide therapy gives promise of an effective and safe treatment for psoriasis. One of three patients with pityriasis rubra pilaris improved considerably with 6-AN.

Pityriasis rubra pilaris responding to aminonicotinamide.

A 32-year-old man with pityriasis rubra pilaris diagnosed by clinical appearance and histologic examination was treated with 1% aminonicotinamide cream applied once daily. Improvement was noted within four days, and almost complete clearing occurred after two weeks of therapy. No side-effects were noted.