Potentiation of paclitaxel antitumor activity by galloflavin or oxamate as lactate dehydrogenase inhibitors

Abstract

Increased aerobic glycolysis in cancer, a phenomenon known as the Warburg effect, has been observed in various tumors and represents a major biochemical alteration associated with malignant transformation. Several cancers display an elevated expression of lactate dehydrogenase-A (LDHA), which is involved in tumor initiation, maintenance, and progression. Significantly, inhibition of LDH-A has been reported to have an antiproliferative effect on breast cancer and inhibited tumor progression. Accordingly, several LDH-A inhibitors are being tested for their anticancer activity, such as oxamate and galloflavin. In the current study, the anti-tumor activity of oxamate and galloflavin was tested in vitro using MCF7 and OVCAR-3 human carcinoma cell lines. Furthermore, both drugs were examined in combination with paclitaxel (Taxol). Additionally, the potential anti-tumor effect of oxamate in the solid Ehrlich carcinoma (SEC) mouse model was examined alone and in combination with paclitaxel. Oxamate and galloflavin significantly reduced cell survival of MCF7 and OVCAR3 cell lines. They also caused significant reductions in LDH enzyme activity and ATP cellular content in addition to a significant increase in MDA content. Both oxamate and galloflavin potentiated the anticancer effect of paclitaxel both in vivo and in vitro. Moreover, potentiation of apoptosis and the anti-angiogenic effect of paclitaxel by oxamate were found in vivo. In conclusion, LDH inhibitor may represent a promising agent that enhances the anti-tumor activity of paclitaxel chemotherapy.