Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy.

Most solid tumor cells adapt to their heterogeneous microenvironment by depending largely on aerobic glycolysis for energy production, a phenomenon called the Warburg effect, which is a hallmark of cancer. The altered energy metabolism not only provides cancer cell with ATP for cellular energy, but also generate essential metabolic intermediates that play a pivotal role in the biosynthesis of macromolecules, to support cell proliferation, invasiveness, and chemoresistance. The cellular metabolic reprogramming in cancer is regulated by several oncogenic proteins and tumor suppressors such as hypoxia-inducible factor (HIF-1), Myc, p53, and PI3K/Akt/mTOR pathway. A better understanding of the mechanisms involved in the regulation of aerobic glycolysis can help in developing glycolytic inhibitors as anticancer agents. These metabolic antiglycolytic agents could be more effective if used in drug combinations to combat cancer. Several preclinical and early clinical studies have shown the effectiveness of targeting the glycolytic pathway as a therapeutic approach to suppress cancer progression. This review aimed to present the most recent data on the emerging drug candidate targeting enzymes and intermediates involved in glucose metabolism to provide therapeutic opportunities and challenges for antiglycolytic cancer therapy.

Renal protective effect of SGLT2 inhibitor dapagliflozin alone and in combination with irbesartan in a rat model of diabetic nephropathy.

Considering the complementary mechanisms of SGLT2 inhibitors and angiotensin inhibitors on kidney, it is postulated that combination of both agents could afford greater protection against diabetic renal injury. So, we investigated renal protective effects of SGLT2 inhibitor, dapagliflozin, alone and in combination with irbesartan in a rat model of diabetic nephropathy. Diabetic rats, injected with nicotinamide-streptozotocin, were treated orally for 12 weeks with either vehicle, dapagliflozin 2 mg/kg/day, irbesartan 30 mg/kg/day, or combination of both drugs; respectively. Biochemical analysis included blood glucose, HbA1c, urinary albumin excretion, creatinine clearance, TGF-ß1, sRAGE, oxidative markers, and histopathological examination of kidneys. Treatment with dapagliflozin, irbesartan, and especially their combination, produced significant reduction in albuminuria, improved renal function parameters, increased sRAGE level and improved inflammatory and oxidative markers, together with amelioration of renal histopathological changes. Beside glycemic control, dapagliflozin produced higher sRAGE levels than irbesartan, suggesting that inhibition of AGE-RAGE axis is important in its renoprotective action. Combination of dapagliflozin and irbesartan produced more remarkable protective effects on renal function and structure, than use of either agent alone. It is concluded that, combination of SGLT2 inhibitor, dapagliflozin and ARB, irbesartan could offer more effective renal protection and represent a promising therapeutic option for management of diabetic nephropathy.