Growth inhibition and induction of apoptosis by 2-deoxy-D-glucose in human squamous carcinoma cell lines

Tumors are generally associated with increased glucose utilization and glycolytic energy (ATP) production, which has been considered as a target for developing primary and adjuvant therapies. The relationship between glucoprivation induced by glucose withdrawal or the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) and growth inhibition as well as cell death has not been completely understood. In the present studies, effects of 2-DG on the proliferation and cell death have been investigated in four human squamous carcinoma cell lines (4451, 4197, OCT-1 and OCT-2) differing in their biological behaviour. Incubation of exponentially growing cells with 2-DG (5 mM; equimolar with glucose) elicited a heterogeneous response among the cell lines with profound growth inhibition and cell death in 4197 (carrying a wild type p53 gene) and OCT-2 cells, while a transient growth delay was observed in OCT-1. No significant effects were observed in 4451 cells (carrying a mutated p53 gene) under these conditions. Further analysis clearly revealed that cell death in 4197 and OCT-2 cells were mainly due to the induction of apoptosis by 2-DG in these cells, but did not correlate either with the endogenous levels of pro and anti-apoptotic proteins Bax and Bcl2 or c-myc as reported earlier. These results support the proposition that inhibition of glucose metabolism could result in both cytostatic as well as cytotoxic effects that could vary among different tumors of similar origin. Further the cytotoxicity induced by 2-DG mainly arise on account of the induction of apoptosis, which may involve multiple mechanisms.