Blocking Glycolysis Helps Antimitotic Chemotherapeutic Drugs to Work Better

Blocking the attempts of tumor cells to establish glycolysis as their primary means of generating energy was found to significantly augment the chemotherapeutic benefits of drugs that prevent the cells from dividing.

Cancer researchers have long wondered how tumor cells survived when their ability to divide was disrupted by treatment with antimitotic drugs such as the toxanes (paclitaxel and docetaxel) or alkaloids derived from Vinca (Catharanthus roseus), such as vinblastine, vincristine, and vinorelbine.

Investigators at the Spanish National Cancer Research Center (Madrid, Spain) were among groups looking into this question. They reported in the August 31, 2015, online edition of the journal Nature Cell Biology that survival during mitotic arrest was affected by the special energetic requirements of mitotic cells. Prolonged mitotic arrest resulted in mitophagy-dependent loss of mitochondria, accompanied by reduced ATP levels and the activation of AMPK (5' adenosine monophosphate-activated protein kinase).

Oxidative respiration in cells undergoing mitotic arrest was replaced by glycolysis owing to AMPK-dependent phosphorylation of PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3) and increased production of this protein as a consequence of mitotic-specific translational activation of its mRNA. Induction of autophagy or inhibition of AMPK or PFKFB3 resulted in enhanced cell death in mitosis and improved the anticancer efficiency of chemotherapeutic agents (microtubule poisons) in breast cancer cells.

"The therapeutic value of inhibiting PFKFB3 has often been discussed; however, no appropriate cell-based scenario had been proposed for its clinical use. Our results suggest that PFKFB3 inhibitors can be extremely efficient in combination with antimitotic drugs," said senior author Dr. Marcos Malumbres, head of the cell division and cancer group at the Spanish National Cancer Research Center.

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Spanish National Cancer Research Center