The multifactorial nature of hypoxia-induced drug resistance in cancer: involvement of hypoxia-inducible factor 1

Abstract

The development of intratumoral hypoxia is associated with resistance to therapy in many forms of human cancer, and pre-exposure of tumor cells to hypoxia confers multidrug resistance. Research over the last several years has led to considerable advances in the understanding of the cellular response to oxygen deprivation, however the hypoxia-induced mechanisms that contribute to the chemoresistance phenotype are still not well understood. Recent studies have identified hypoxia-inducible factor 1 (HIF-1), a master transcriptional regulator of oxygen homeostasis, as an important mediator of hypoxia-induced chemoresistance in cancer cells. The research described in this thesis confirms these findings and demonstrates HIF-1 is required for hypoxia-induced resistance to doxorubicin and etoposide in human tumor cells. In addition, novel findings revealed that hypoxia-induced drug resistance occurred independently of changes in the apoptotic fraction and was associated with decreased drug-induced senescence. DNA damage measured at the single-cell level revealed that the increase in survival correlated well with a HIF-1-dependent decrease in etoposide-induced DNA strand breaks, providing direct evidence that exposure of tumor cells to hypoxia leads to protection against some forms of drug-induced DNA damage. Characterization of several classical mechanisms of drug resistance upstream of DNA damage identified multiple determinants of cellular resistance to anticancer agents. The relative contributions of each varied depending on the particular drug and cancer cell line studied. Together, the findings presented here support a model in which hypoxia-induced chemoresistance is a multifactorial phenomenon that is regulated, at least in part, through HIF-1-dependent mechanisms.