Role of hypoxia in cancer therapy by regulating the tumor microenvironment

Abstract

Aim: Clinical resistance is a complex phenomenon in major human cancers involving multifactorial mechanisms, and hypoxia is one of the key components that affect the cellular expression program and lead to therapy resistance. The present study aimed to summarize the role of hypoxia in cancer therapy by regulating the tumor microenvironment (TME) and to highlight the potential of hypoxia-targeted therapy.

Methods: Relevant published studies were retrieved from PubMed, Web of Science, and Embase using keywords such as hypoxia, cancer therapy, resistance, TME, cancer, apoptosis, DNA damage, autophagy, p53, and other similar terms.

Results: Recent studies have shown that hypoxia is associated with poor prognosis in patients by regulating the TME. It confers resistance to conventional therapies through a number of signaling pathways in apoptosis, autophagy, DNA damage, mitochondrial activity, p53, and drug efflux.

Conclusion: Hypoxia targeting might be relevant to overcome hypoxia-associated resistance in cancer treatment.

Keywords: Cancer therapy; Chemotherapy; Drug resistance; Hypoxia; Tumor microenvironment.

Fig. 1

Summary of mechanisms and pathways of HIF-mediated drug therapy failure. HIF-1 confers resistance to conventional therapies through a number of signaling pathways in apoptosis, autophagy, DNA damage, mitochondrial activity, p53, and drug efflux. In addition, hypoxia results in a decrease in pH and creates an acidic TME. Mechanisms by which the tumor acidic microenvironment leads to MDR, including a decreased concentration of the drug caused by “ion trapping,” reduced apoptotic potential, genetic alterations (such as p53 mutations), and elevated activity of a multidrug transporter p-glycoprotein (P-gp)

Fig. 2

Diagram of the modification effect of HIF-1 on mitochondrial activity. HIF-1 is beneficial for glycolysis and lactic acid production by activating pyruvate dehydrogenase kinase-1 (PDK1) and hindering the activity of pyruvate dehydrogenase (PDH). In addition, HIF-1 targets PDK1, directly inhibiting pyruvate from entering the TCA cycle through the inactivation of PDH. HIF-1 also can induce mitochondrial autophagy and inhibit mitochondrial biogenesis, thus avoiding cell death and ultimately leading to HIF-1-mediated drug resistance