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

By R. Xu, H. Pelicano, Yan Zhou, J. Carew, Li Feng, K. Bhalla, M. Keating, Peng Huang. Cancer Research, 2005

860 citations recorded by the source corpus.

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 Ser(112), 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 Warburg effect and hypoxia are frequently seen in human cancers, these findings may have broad clinical implications.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/738e7ec17043beb0e639851668c21114730528b3

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. C. V. Dang
2. E. Michelakis
3. John R. Mackey
4. Jung-whan Kim
5. Linda Webster
6. B. Zhivotovsky
7. V. Gogvadze
8. S. Orrenius

In Molecular Biology

1. C. V. Dang
2. S. Orrenius
3. V. Gogvadze
4. B. Zhivotovsky
5. Jung-whan Kim
6. E. Michelakis
7. John R. Mackey
8. Linda Webster

Citations in the corpus

• Cancer's molecular sweet tooth and the Warburg effect. (2006, background): “Inhibition of glycolysis can overcome tumor drug resistance (19).”
• An overview of active and passive targeting strategies to improve the nanocarriers efficiency to tumour sites (2019, background): “In the mid-twentieth century, Otto Warburg([60]) described a switch of the cancerous cellular metabolism into glycolysis with the formation of lactic acid as an endpoint to this glycolytic metabolism.([61]) The lactic acid if accumulated intracellularly would lead to cell death.”
• Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer (2008, background): “Inhibiting GLY (which has previously been tested as a potential treatment for cancer) results in ATP depletion and necrosis, not apoptosis, because apoptosis is an energy-consuming process, requiring active mitochondria (Xu et al, 2005).”
• Mitochondria in cancer cells: what is so special about them? (2008, positive): “Among the effects of the ATP depletion were rapid dephosphorylation of the pro-apoptotic protein Bad, migration of Bax to the mitochondria, and massive cell death[ 72 ].Similartotheeffectsofinhibitingkeystepsinthe glycolytic pathway, suppression of glucose transport might alsosensitizetumorcellstoan”