A novel radiosensitizer α-sulfoquinovosyl-acylpropanediol (SQAP) inhibits DNA repair pathways and sensitize cells to cancer chemotherapeutic agents

Abstract

Abstract Sulfoglycolipid, α-sulfoquinovosyl-acylpropanediol (SQAP) is a novel veterinary radiosensitizer, which is known to cause angiogenesis alteration and sensitizes hypoxic tumors in the in vivo animal model. We examined the SQAP radio/chemo-sensitization mechanisms from DNA repair with canine cancer cell lines and Chinese hamster cell lines. Previous studies have shown that SQAP radiosensitization was limited to in vivo xenograft models, but we found SQAP sensitized cells to radiation in vitro cell culture system. SQAP sensitized canine osteosarcoma and melanoma cell lines to gamma-ray irradiation in normoxia or hypoxia conditions. This result suggested that SQAP was expected to affect the repair of DNA damage induced by ionizing radiation and enhanced cellular radiosensitivity. To further identify potential mechanisms of radiosensitization, we utilized several assays to determine DNA repair inhibition by SQAP. SQAP treatment inhibited NHEJ and HR activity measured by EJ5-GFP and DR-GFP assays. SQAP treatment reduced the spontaneous sister chromatid exchange formation in CHO wild type and EM9 (XRCC1 mutant). On the other hand, 51D1 (rad51d mutant, homologous recombination (HR) repair deficient) showed no reduction. In vitro topoisomerase assay revealed SQAP disrupted topoisomerase I and II alpha activities. SQAP sensitized series of chemotherapeutic agents including doxorubicin, carboplatin, bleomycin, camptothecin, etoposide, methyl methanesulfonate, cisplatin, mitomycin C, and Taxol in canine tumor cells and V79 cells. These results suggest that broad inhibition of DNA repair may play a role in SQAP induced radiosensitization and chemosensitization.