Radiation and chemotherapy variable response induced by tumor cell hypoxia: impact of radiation dose, anticancer drug, and type of cancer

Abstract

Hypoxia is a condition in which proliferating tumor cells are deprived of oxygen due to limited blood supply from abnormal tumor microvasculature. This study aimed to investigate the molecular changes that occur in tumor cell hypoxia with special emphasis placed on the efficacy of chemotherapeutic and radiation-related effects. Four commercially available chemotherapeutic agents: cisplatin, cyclophosphamide, doxorubicin, and 5-fluorouracil, were tested for their cytotoxic activity on the cancer cell lines PC3 (prostate), HepG2 (liver), and MCF-7 (breast). Tumor cell lines under hypoxia were treated with both IC50 concentrations of the different chemotherapeutic agents and irradiated with 5 and 10 Gy using a 137Cs gamma source. Hypoxia-inducible factor-1α (HIF-1α) protein levels were examined using an ELISA assay. Hypoxic cells showed a significant change in cell viability to all chemotherapeutic agents in comparison to normoxic controls. HepG2 cells were more resistant to the cytotoxic drug doxorubicin compared to other cancer cell lines. The flow cytometric analysis showed that hypoxic cells have lower levels of total apoptotic cell populations (early and late apoptosis) compared to normoxic cells suggesting decreased hypoxia-induced apoptosis in cancer cells. The highest reduction in HIF-1α level was observed in the MCF-7 cell line (95.5%) in response to the doxorubicin treatment combined with 10 Gy irradiation of cells. Chemoradiotherapy could result in minimal as well as a high reduction of HIF-1α based on cell type, type of chemotherapy, and amount of ionizing radiation. This study highlights future research work to optimize a combined chemoradiotherapeutic regime in individual cancer cell hypoxia.