Breast cancer is the most prevalent
cancer and the second leading cause of
cancer death in women.
Cisplatin is a commonly used chemotherapeutic drug for
breast cancer treatment. Owing to serious side effects, the combination of
cisplatin with other drugs is an effective strategy to simultaneously reduce side effects and increase the anticancer efficacy. GLUT1 is an emerging target for
cancer treatment since
cancer cells usually consume more
glucose, a phenomenon called the Warburg effect. In this study, we found that the combination of
cisplatin and a novel GLUT1 inhibitor #43 identified from our previous high-throughput screening exerted a synergistic anticancer effect in MCF-7 and MDA-MB-231
breast cancer cells. Mechanism studies in MCF-7 cells revealed that combination of
cisplatin and #43 significantly induced apoptosis, intracellular
reactive oxygen species, and loss of mitochondrial membrane potential. Furthermore, #43 enhanced the
DNA damaging effect of
cisplatin. Akt/mTOR downstream signaling and the ERK signaling pathway usually involved in cell growth and survival were inhibited by the combination treatment. On the other hand, phosphorylation of p38 and JNK, which may be associated with apoptosis, was induced by the combination treatment. Altogether, our data indicate that oxidative stress, DNA damage, the Akt/mTOR and MAPK signaling pathways, and apoptosis may be involved in the synergism of
cisplatin and #43 in
breast cancer cells.