Sulfoquinovosyl acylpropanediol (SQAP): Inhibition of poly(ADP-ribose) metabolism and enhanced cytotoxicity in homologous recombination repair-deficient Chinese hamster-derived cells.

Abstract

Sulfoquinovosyl acylpropanediol (SQAP; a synthetic derivative of the sulfoglycolipid natural product sulfoquinovosyl acylglycerol, SQAG), has anti-tumor and radiosensitizing activities in tumor xenograft mouse models. Here, we have studied the PARP inhibitory activity of SQAP and synthetic lethality in BRCA2-deficient cells. In initial screening studies with DNA repair-deficient Chinese hamster ovary cells, homologous recombination repair-deficient cell lines showed increased sensitivity to SQAP, compared to wild-type cells or other DNA repair-deficient mutants. Chinese hamster lung V79 cells and the derivative cell lines V-C8 (BRCA2-deficient) and V-C8 + BRCA2 gene corrections were used to test the role of BRCA2 in SQAP cytotoxicity. The findings were confirmed in studies of the human colon cancer cell lines DLD-1 and its BRCA2-knockout derivative. SQAP inhibited the enzymes poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG). SQAP pretreatment decreased H2O2induced poly(ADP-ribose) formation in V79 cells. SQAP caused DNA double-strand breaks and chromosome aberrations in V79 BRCA2-mutated cells but did not affect cells in the G2 phase. We have demonstrated that SQAP induces synthetic lethality in BRCA2-deficient Chinese hamster-derived cells via its effects on poly(ADP-ribose) metabolism, motivating further examination of its therapeutic potential, especially against tumors that are deficient in homologous recombination repair due to mutations in BRCA2 or other genes.

• Authors: Junko Maeda, Kaitlyn D Shellenberger, Wataru Kurihara, Tomohiro Haga, Takamitsu A Kato
• Journal: Mutation research. Genetic toxicology and environmental mutagenesis (Mutat Res Genet Toxicol Environ Mutagen) 2023 Nov-Dec Vol. 892 Pg. 503703 ISSN: 1879-3592 [Electronic] Netherlands
• PMID: 37973295 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Elsevier B.V. All rights reserved.

Chemical References

• Poly Adenosine Diphosphate Ribose
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases

Topics

• Cricetinae
• Humans
• Animals
• Mice
• Cricetulus
• Poly Adenosine Diphosphate Ribose
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
• Recombinational DNA Repair
• CHO Cells
• DNA Repair
• Poly(ADP-ribose) Polymerases (metabolism)
• Neoplasms (genetics)
• Homologous Recombination