Dual inhibition of glycolysis and autophagy as a therapeutic strategy in the treatment of Ehrlich ascites carcinoma
Dual inhibition of glycolysis and autophagy as a therapeutic strategy in the treatment of Ehrlich ascites carcinoma
Cancer cells have extra biosynthetic demands to sustain cell growth and redox homeostasis. Glycolysis and autophagy are crucial to fuel and recycle these biosynthetic demands. This plasticity of cancer cell metabolism participates in therapy resistances. The current study was designed to assess the therapeutic efficacy of dual targeting of glycolysis and autophagy in cancer. Using 3‐bromopyruvate (3‐BP; antiglycolytic inhibitor) and hydroxychloroquine (HCQ; autophagy inhibitor), we demonstrate their antitumor activity in Ehrlich ascites carcinoma (EAC)‐bearing mice. A combination of 3‐BP and HCQ significantly decreases tumor ascitic volume and cell count as compared with the EAC group and individual treatment groups. The enhanced antitumor activity is accompanied by hexokinase inactivation, inhibition of cellular protective autophagy, elevated antioxidant activity, and reduced oxidative stress levels. Together, these results suggest targeting both pathways in cancer as an effective therapeutic strategy. Further studies are required to validate this strategy in different cancer models and preclinical trials.
3-bromopyruvate, autophagy, glycolysis, hexokinase 2, hydroxychloroquine
Mansour, Mohammed A.
03d901e1-959e-4c7d-acc6-33c6a4b129f7
Ibrahim, Wafaa M.
f2a9cf99-bb77-4517-b32a-159ea3850f57
Salama, Mona M.
4c93e891-298e-42fa-ac63-34c3d246b016
Salama, Afrah F.
5558e250-308a-4e94-9efd-0ece23c88e01
1 July 2020
Mansour, Mohammed A.
03d901e1-959e-4c7d-acc6-33c6a4b129f7
Ibrahim, Wafaa M.
f2a9cf99-bb77-4517-b32a-159ea3850f57
Salama, Mona M.
4c93e891-298e-42fa-ac63-34c3d246b016
Salama, Afrah F.
5558e250-308a-4e94-9efd-0ece23c88e01
Mansour, Mohammed A., Ibrahim, Wafaa M., Salama, Mona M. and Salama, Afrah F.
(2020)
Dual inhibition of glycolysis and autophagy as a therapeutic strategy in the treatment of Ehrlich ascites carcinoma.
Journal of Biochemical and Molecular Toxicology, 34 (7), [e22498].
(doi:10.1002/jbt.22498).
Abstract
Cancer cells have extra biosynthetic demands to sustain cell growth and redox homeostasis. Glycolysis and autophagy are crucial to fuel and recycle these biosynthetic demands. This plasticity of cancer cell metabolism participates in therapy resistances. The current study was designed to assess the therapeutic efficacy of dual targeting of glycolysis and autophagy in cancer. Using 3‐bromopyruvate (3‐BP; antiglycolytic inhibitor) and hydroxychloroquine (HCQ; autophagy inhibitor), we demonstrate their antitumor activity in Ehrlich ascites carcinoma (EAC)‐bearing mice. A combination of 3‐BP and HCQ significantly decreases tumor ascitic volume and cell count as compared with the EAC group and individual treatment groups. The enhanced antitumor activity is accompanied by hexokinase inactivation, inhibition of cellular protective autophagy, elevated antioxidant activity, and reduced oxidative stress levels. Together, these results suggest targeting both pathways in cancer as an effective therapeutic strategy. Further studies are required to validate this strategy in different cancer models and preclinical trials.
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Accepted/In Press date: 13 March 2020
e-pub ahead of print date: 20 March 2020
Published date: 1 July 2020
Additional Information:
Funding Information:
The authors would like to thank colleagues from the Biochemistry department at faculties of Science and Medicine, the University of Tanta for their critical discussions and recommendations.
Publisher Copyright:
© 2020 Wiley Periodicals, Inc.
Keywords:
3-bromopyruvate, autophagy, glycolysis, hexokinase 2, hydroxychloroquine
Identifiers
Local EPrints ID: 441883
URI: http://eprints.soton.ac.uk/id/eprint/441883
ISSN: 1095-6670
PURE UUID: 79092660-3cec-4616-887d-817d6ccb6def
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Date deposited: 01 Jul 2020 16:31
Last modified: 16 Mar 2024 07:39
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Contributors
Author:
Mohammed A. Mansour
Author:
Wafaa M. Ibrahim
Author:
Mona M. Salama
Author:
Afrah F. Salama
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