Impact of anti-diabetic sodium-glucose cotransporter 2 inhibitors on tumor growth of intractable hematological malignancy in humans

• Published in: Biomedicine & pharmacotherapy 2022-05, Vol.149, p.112864-112864, Article 112864
• Main Authors: Nakachi, Sawako, Okamoto, Shiki, Tamaki, Keita, Nomura, Ikumi, Tomihama, Mamiko, Nishi, Yukiko, Fukushima, Takuya, Tanaka, Yuetsu, Morishima, Satoko, Imamura, Minako, Maeda, Shiro, Tsutsui, Masato, Matsushita, Masayuki, Masuzaki, Hiroaki
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate; Adult T cell leukemia (ATL); Hematologic Neoplasms - drug therapy; Hematological malignancy; Humans; Metabolic oncology; NADP - metabolism; Sodium-glucose cotransporter-2 (SGLT2); Sodium-Glucose Transporter 2 - metabolism; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Warburg effect
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2022.112864

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. [Display omitted] •SGLT2 inhibitors attenuate the growth of cell lines of adult T-cell leukemia (ATL).•SGLT2 inhibitors also suppress the growth of malignant cells from patients with ATL.•Such effects are mediated in part by modulating glucose metabolism and cell cycle.•SGLT2 inhibitors are promising adjunctive to treat intractable hematological cancers.