Statins Alleviate Tumor Hypoxia in Prostate Cancer Models by Decreasing Oxygen Consumption: An Opportunity for Radiosensitization?

Biomolecules. 2022 Oct 3;12(10):1418. doi: 10.3390/biom12101418.

Abstract

Background: Because statins were found to decrease the oxygen consumption rate (OCR) of a variety of normal cells, our hypothesis was that statins may also decrease the OCR of cancer cells, alleviate tumor hypoxia and radiosensitize tumors.

Methods: OCR was assessed using the Seahorse XF96 technology and EPR respirometry in PC-3 prostate cancer cells. Mitochondrial superoxide production was measured by EPR with mitoTEMPO-H as a sensing probe. Tumor pO2 was measured in vivo using low-frequency EPR oximetry to define the optimal window of reoxygenation, the time at which tumors were irradiated with a single 6 Gy dose with a Cesium-137 irradiator.

Results: 24-h exposure to simvastatin and fluvastatin significantly decreased the OCR of PC-3 cancer cells. An increase in mitochondrial superoxide levels was also observed after fluvastatin exposure. The PC-3 prostate cancer model was found highly hypoxic at the basal level. When mice were treated with simvastatin or fluvastatin (daily injection of 20 mg/kg), tumor oxygenation increased 48 and 72 h after initiation of the treatment. However, despite reoxygenation, simvastatin did not sensitize the PC-3 tumor model to RT.

Conclusions: exposure to statins affect tumor metabolism and tumor oxygenation, however, with limited impact on tumor growth with or without irradiation.

Keywords: EPR; cancer metabolism; irradiation; oxygen; oxygen consumption; statins; superoxide; tumor hypoxia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fluvastatin / pharmacology
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors* / pharmacology
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use
  • Male
  • Mice
  • Oxygen / metabolism
  • Oxygen Consumption
  • Prostatic Neoplasms* / drug therapy
  • Prostatic Neoplasms* / radiotherapy
  • Simvastatin / pharmacology
  • Simvastatin / therapeutic use
  • Superoxides
  • Tumor Hypoxia

Substances

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Fluvastatin
  • Superoxides
  • Simvastatin
  • Oxygen

Grants and funding

This research was funded by the Belgian Fonds National de la Recherche Scientifique (F.R.S.-FNRS, Grant No. J008220F), and the Actions de Recherche Concertées program of the Communauté Française de Belgique (ARC 21-26/118). B.F.J. and P.S. are Research Directors of the F.R.S.-FNRS. This study used the equipment of the Nuclear and Electron Spin Technologies platform.