Inhibition of glycolysis in cancer cells: A novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia

Rui Hua Xu, Helene Pelicano, Yan Zhou, Jennifer S. Carew, Li Feng, Kapil N. Bhalla, Michael J. Keating, Peng Huang

Research output: Contribution to journalArticle

636 Scopus citations

Abstract

Cancer cells generally exhibit increased glycolysis for ATP generation (the Warburg effect) due in part to mitochondrial respiration injury and hypoxia, which are frequently associated with resistance to therapeutic agents. Here, we report that inhibition of glycolysis severely depletes ATP in cancer cells, especially in clones of cancer cells with mitochondrial respiration defects, and leads to rapid dephosphorylation of the glycolysis-apoptosis integrating molecule BAD at Ser112, relocalization of BAX to mitochondria, and massive cell death. Importantly, inhibition of glycolysis effectively kills colon cancer cells and lymphoma cells in a hypoxic environment in which the cancer cells exhibit high glycolytic activity and decreased sensitivity to common anticancer agents. Depletion of ATP by glycolytic inhibition also potently induced apoptosis in multidrug-resistant cells, suggesting that deprivation of cellular energy supply may be an effective way to overcome multidrug resistance. Our study shows a promising therapeutic strategy to effectively kill cancer cells and overcome drug resistance. Because the Warhurg effect and hypoxia are frequently seen in human cancers, these findings may have broad clinical implications.

Original languageEnglish (US)
Pages (from-to)613-621
Number of pages9
JournalCancer research
Volume65
Issue number2
StatePublished - Jan 15 2005
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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