Therapeutic Effect of Sodium Glucose Co-Transporter 2 Inhibitor Dapagliflozin on Renal Cell Carcinoma

Abstract

BackgroundPatients with type 2 diabetes mellitus (T2DM) have a high incidence of renal cell carcinoma (RCC) and high sodium glucose co-transporters 2 (SGLT2) expressions. The purpose of this study was to evaluate the anticancer activity of dapagliflozin as an SGLT2 inhibitor on RCC cell lines in vitro and in vivo.Material/MethodsqRT-PCR and Western blot were used to detect SGLT2 expression on different human renal cells. Then, flow cytometry and immunofluorescence were used to investigate the effects of dapagliflozin on cell cycle, apoptosis, and SGLT2 expression of CaKi-1 cells. Finally, a xenograft model and immunohistochemical staining were used to investigate the function of dapagliflozin in nude mice.ResultsWe proved that SGLT2 is highly expressed in RCC cell lines. We found that dapagliflozin exerts a higher cytotoxic effect on human RCC than on normal human renal cells, regulates the cell cycle and apoptosis, and reduces the glucose uptake and SGLT2 expression of CaKi-1 cells. Moreover, dapagliflozin inhibits tumor growth and reduces SGLT2 expression in vivo.ConclusionsOur results indicate that dapagliflozin has high efficiency and low toxicity and could be a new therapeutic target for RCC.

Clinical response to sodium glucose co‐transporter 2 inhibitor ipragliflozin in a patient with metastatic renal cell carcinoma

“…2 A recent study reported that dapagliflozin, an SGLT2 inhibitor, reduces the viability of renal cell carcinoma cell lines, thus regulating the cell cycle and apoptosis in vitro and in vivo. 3 In liver cancer cells, canaglifrozin inhibits cell growth by not only inhibiting glucose uptake but also by affecting intratumor angiogenesis. 5 It is possible that ipragliflozin affects both glucose uptake and tumor angiogenesis.…”

“…SGLT2 inhibitors are a new class of therapeutic agents indicating type 2 diabetes mellitus, reducing glucose reabsorption in the renal proximal tubule, and plasma glucose levels . A recent study reported that SGLT2 inhibitors have anticancer effects and reduce tumor growth in renal cell carcinoma in vitro and in vivo . However, it has been unclear whether SGLT2 inhibitors clinically exert anticancer effects in mRCC.…”

“…2 A recent study reported that SGLT2 inhibitors have anticancer effects and reduce tumor growth in renal cell carcinoma in vitro and in vivo. 3 However, it has been unclear whether SGLT2 inhibitors clinically exert anticancer effects in mRCC.…”

Is cancer incidence modified by SGLT2 inhibitors?

“…В немалом числе работ, опубликованных главным образом в 2016-2018 гг., представлены результаты изучения влияния ингибиторов SGLT2 (в первую очередь дапаглифлозина и канаглифлозина) в экспериментах in vitro, проводившихся на культивируемых линиях опухолевых клеток [18][19][20][21]. В частности, исследовались линии рака толстой кишки [18], почечно-клеточной карциномы [19], рака печени [20], а также бронхокарциномы и рака предстательной железы [21].…”

“…В немалом числе работ, опубликованных главным образом в 2016-2018 гг., представлены результаты изучения влияния ингибиторов SGLT2 (в первую очередь дапаглифлозина и канаглифлозина) в экспериментах in vitro, проводившихся на культивируемых линиях опухолевых клеток [18][19][20][21]. В частности, исследовались линии рака толстой кишки [18], почечно-клеточной карциномы [19], рака печени [20], а также бронхокарциномы и рака предстательной железы [21]. Практически все эти исследования продемонстрировали ингибирование роста трансформированных клеток при добавлении в культуру упомянутых глифлозинов на основе, среди прочего, таких механизмов, как торможение клеточного цикла и усиление апоптоза [19], угнетение гликолиза, ангиогенеза [20], липогенеза и -подобно метформину -процессов клеточного дыхания, регулируемых митохондриальным комплексом I [21].…”