The Chemopreventive Effect of the Dietary Compound Kaempferol on the MCF-7 Human Breast Cancer Cell Line Is Dependent on Inhibition of Glucose Cellular Uptake

Abstract

Our aim was to investigate the effect of several dietary polyphenols on glucose uptake by breast cancer cells. Uptake of (3)H-deoxy-D-glucose ((3)H-DG) by MCF-7 cells was time-dependent, saturable, and inhibited by cytochalasin B plus phloridzin. In the short-term (26 min), myricetin, chrysin, genistein, resveratrol, kaempferol, and xanthohumol (10-100 µM) inhibited (3)H-DG uptake. Kaempferol was found to be the most potent inhibitor of (3)H-DG uptake [IC50 of 4 µM (1.6-9.8)], behaving as a mixed-type inhibitor. In the long-term (24 h), kaempferol (30 µM) was also able to inhibit (3)H-DG uptake, associated with a 40% decrease in GLUT1 mRNA levels. Interestingly enough, kaempferol (100 µM) revealed antiproliferative (sulforhodamine B and (3)H-thymidine incorporation assays) and cytotoxic (extracellular lactate dehydrogenase activity determination) properties, which were mimicked by low extracellular (1 mM) glucose conditions and reversed by high extracellular (20 mM) glucose conditions. Finally, exposure of cells to kaempferol (30 µM) induced an increase in extracellular lactate levels over time (to 731 ± 32% of control after a 24 h exposure), due to inhibition of MCT1-mediated lactate cellular uptake. In conclusion, kaempferol potently inhibits glucose uptake by MCF-7 cells, apparently by decreasing GLUT1-mediated glucose uptake. The antiproliferative and cytotoxic effect of kaempferol in these cells appears to be dependent on this effect.

Kaempferol – A dietary anticancer molecule with multiple mechanisms of action: Recent trends and advancements

“…4). Furthermore, results of these studies demonstrate that KMFdependent arrest of G0/G1 or G2/M transition is possibly due to inhibition of epidermal growth factor receptor (EGFR) activity, hexokinase-2 expression (Yao et al, 2016), inhibition of the activity of estrogen (Kim et al, 2016) or uptake of glucose (Azevedo et al, 2015). Of note, growth factors, hormones, glucose and hexokinases are positive regulators of cell cycle.…”

“…Recent in vitro and in vivo studies have shown the antiproliferative and proapoptotic activities of KMF against various types of cancers including breast (Azevedo et al, 2015;Kim, Hwang, & Choi, 2016;Liao et al, 2016), ovarian (Luo, Rankin, Li, Depriest, & Chen, 2011), lung (Kuo et al, 2015), pancreas (Zhang, Chen, Li, Chen, & Yao, 2008), esophagus (Yao et al, 2016), stomach , colon , prostate (Halimah et al, 2015), bladder (Dang et al, 2015), kidney (Song et al, 2014) and others. Most of these studies demonstrate that the mechanism of KMF is dependent on the inhibition of proliferation of various cancer cells either via cell cycle arrest or induction of apoptosis (Kuo et al, 2015;Liao et al, 2016).…”

Natural Polyphenols for Prevention and Treatment of Cancer

“…Kaempferol induced apoptosis in MCF-7 breast cancer cells [111]. In the same cell line, treatment of kaempferol (100 μM) also significantly suppressed glucose uptake mediated by GLUT1, which might be another mechanism underlying its anti-proliferative effects [112]. Besides, both in vitro and in vivo study revealed that kaempferol could prevent breast cancer induced by 17β-estradiol or triclosn, an exogenous estrogen [113].…”

Anticancer agents interacting with membrane glucose transporters

“…The same effects were mimicked by low glucose conditions and were reversed by high concentrations of glucose, suggesting that the cytotoxic effects are provoked by the block of glucose uptake. 26 …”