Faculty Collaboration Database

EPR Investigations to Study the Impact of Mito-Metformin on the Mitochondrial Function of Prostate Cancer Cells. Molecules 2022 Sep 10;27(18)

Date

09/24/2022

Pubmed ID

36144606

Pubmed Central ID

PMC9504708

DOI

10.3390/molecules27185872

Scopus ID

2-s2.0-85138362586 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

BACKGROUND: Mito-metformin10 (MM10), synthesized by attaching a triphenylphosphonium cationic moiety via a 10-carbon aliphatic side chain to metformin, is a mitochondria-targeted analog of metformin that was recently demonstrated to alter mitochondrial function and proliferation in pancreatic ductal adenocarcinoma. Here, we hypothesized that this compound may decrease the oxygen consumption rate (OCR) in prostate cancer cells, increase the level of mitochondrial ROS, alleviate tumor hypoxia, and radiosensitize tumors.

METHODS: OCR and mitochondrial superoxide production were assessed by EPR (9 GHz) in vitro in PC-3 and DU-145 prostate cancer cells. Reduced and oxidized glutathione were assessed before and after MM10 exposure. Tumor oxygenation was measured in vivo using 1 GHz EPR oximetry in PC-3 tumor model. Tumors were irradiated at the time of maximal reoxygenation.

RESULTS: 24-hours exposure to MM10 significantly decreased the OCR of PC-3 and DU-145 cancer cells. An increase in mitochondrial superoxide levels was observed in PC-3 but not in DU-145 cancer cells, an observation consistent with the differences observed in glutathione levels in both cancer cell lines. In vivo, the tumor oxygenation significantly increased in the PC-3 model (daily injection of 2 mg/kg MM10) 48 and 72 h after initiation of the treatment. Despite the significant effect on tumor hypoxia, MM10 combined to irradiation did not increase the tumor growth delay compared to the irradiation alone.

CONCLUSIONS: MM10 altered the OCR in prostate cancer cells. The effect of MM10 on the superoxide level was dependent on the antioxidant capacity of cell line. In vivo, MM10 alleviated tumor hypoxia, yet without consequence in terms of response to irradiation.

Author List

d'Hose D, Mathieu B, Mignion L, Hardy M, Ouari O, Jordan BF, Sonveaux P, Gallez B

Author

Micael Joel Hardy PhD Visiting Assistant Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antioxidants
Carbon
Cell Line, Tumor
Glutathione Disulfide
Humans
Male
Metformin
Mitochondria
Pancreatic Neoplasms
Prostatic Neoplasms
Reactive Oxygen Species
Superoxides