No abstract

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that does not express the estrogen receptor, progesterone receptor, and the HER2 receptor. Since it does not express these receptors, TNBC does not respond to many of the standard therapies for breast cancer. To decrease the number of deaths associated with breast cancer, we must identify therapeutic strategies that effectively prevent the growth and progression of TNBC. Recent studies from our laboratory and others show that the sodium glucose transporter 2 (SGLT2) inhibitor canagliflozin reduces proliferation of human prostate cancer cell lines. To determine whether SGLT2 inhibitors can also suppress TNBC growth, we tested the effect of canagliflozin and other SGLT2 inhibitors on proliferation and protein expression within the BT‐549 human breast cancer cells. Presto Blue assays revealed that two SGLT2 inhibitors, canagliflozin and ipragliflozin, significantly inhibited BT‐549 cell proliferation. However, the SGLT2 inhibitor empagliflozin produced little to no change in cell proliferation. We next examined the effect of SGLT2 inhibitors on Akt and Erk ½ MAP kinase, two proteins that promote TNBC growth. Western blot analysis revealed that canagliflozin reduced phosphorylation of Akt and Erk ½ within BT‐549 cells. Therefore, the ability of canagliflozin to block BT‐549 proliferation may be due in part to canagliflozin‐mediated decreases in Akt and Erk activity. The epidermal growth factor receptor (EGFR) activates both Akt and Erk ½ signaling in BT‐549 cells. To determine whether inhibition of EGFR signaling would alter the response to canagliflozin, we tested the combined effect of canagliflozin and EGFR inhibitors on BT‐549 cell proliferation. Canagliflozin alone was more effective at reducing BT‐549 cell proliferation than the EGFR inhibitors gefitinib and lapatinib. However, the combined effect of canagliflozin and gefitinib as well as the combined effect of canagliflozin and lapatinib was greater than that produced by either compound alone. These data suggest that combination treatments involving canagliflozin and EGFR inhibitors may serve as an effective therapy for patients with TNBC.Support or Funding InformationNIH grant 5T34GM007663This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

BackgroundThere is still a need to identify effective treatments for castration‐resistant prostate cancers. Recent studies have shown that two drugs used to treat type 2 diabetes, metformin and canagliflozin, may be effective treatments for castration‐resistant prostate cancer. Both drugs have individually been shown to inhibit proliferation of 22Rv1 and PC3 prostate cancer cell lines. However, it is not known if combined treatment with metformin and canagliflozin suppresses the growth of prostate cancer cells better than each drug alone. The goal of this study was to determine the effectiveness of the combination of canagliflozin and metformin as an alternative treatment for prostate cancer.MethodsPresto Blue Assays were used to assess the effect of metformin and canagliflozin on proliferation of the 22Rv1 and PC3 prostate cancer cell lines. Western blot analysis was also performed to determine the effect of metformin and canagliflozin (both individually and combined) on androgen receptor (AR) protein levels. Western blots were stripped and re‐probed for the protein actin to confirm that gels were evenly loaded.ResultsCanagliflozin at a concentration of 30 uM produced a significant decrease in the proliferation of PC3 and 22Rv1 cells. While metformin showed no significant decrease in proliferation of PC3 cells, metformin (5 mM) did significantly decrease 22Rv1 cell proliferation. The combination of canagliflozin and metformin showed a significant decrease in both PC3 and 22Rv1 cells. However, the effect of the combination was no greater than canagliflozin alone. AR protein levels were reduced by canagliflozin, metformin, and the combination of both drugs. Moreover, the combination of metformin and canagliflozin was the most effective in reducing AR protein levels.ConclusionThe combination of canagliflozin and metformin was equally effective as canagliflozin alone at reducing prostate cancer cell proliferation. However, this drug combination was more effective at suppressing AR protein levels within castration‐resistant prostate cancer cells. Taken together, these data suggest that combination treatments involving metformin and canagliflozin could be used to decrease tumor growth and AR expression in prostate cancer patients who have developed castration‐resistant prostate cancer.Support or Funding InformationSupported by NIH grants MD007593 and T34GM007663This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.