Under the dysfunction of mitochondria,
cancer cells preferentially utilize both glycolytic and pentose phosphate pathways rather than electron transport chains to desperately generate
adenosine triphosphate (
ATP) and
nicotinamide adenine dinucleotide phosphate (reduced form) (
NADPH), classically recognized as the Warburg effect. Based on this background, the present study tested the hypothesis that anti-diabetic
sodium-glucose cotransporter 2 (
SGLT2) inhibitors would exert a
tumor-suppressive impact on intractable human
hematological malignancies via the modulation of
glucose metabolism within cells and cell cycles. The level of
mRNA for SGLT2 was remarkably elevated in leukemic cells from patients with
adult T-cell leukemia (ATL), one of the most intractable
blood cancers in humans, and as well as in two kinds of ATL cell lines (MT-1 and MT-2). Two kinds of
SGLT2 inhibitors,
Luseogliflozin and
Tofogliflozin substantially suppressed the proliferation of MT-1 and MT-2 cells in both adherent and anchorage-independent culture conditions. Such a suppressive effect on
tumor cell growth was reproduced by
Luseogliflozin in leukemic cells in peripheral blood from patients with ATL. In MT-2 cells, both of
SGLT2 inhibitors considerably attenuated
glucose uptake, intracellular
ATP levels, and
NADPH production, resultantly enhancing cell cycle arrest at the G0/G1 phase. From the standpoint of metabolic oncology, the present study suggests that
SGLT2 inhibitors would be a promising adjunctive option for the treatment of the most intractable human
hematological malignancies like ATL.