• Targeting Hypoxia to Overcome Chemotherapy Resistance in Breast Cancer
  • Mohammad Amin Dehghani ,1,* Jeiran Haghighi ,2 Fatemeh Dehghani ,3 Khashayar Alikarami ,4
    1. Student Research Committee of Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
    2. School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
    4. Student Research Committee of Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran


  • Introduction: There is evidence that hypoxic microenvironment, critical throughout cancer development, is of utmost importance in terms of regulating breast cancer (BC) progression and metastasis. The impact of hypoxia-inducible factor 1 (HIF-1) transcription factor has been also assumed to enhance adaptation to hypoxia and subsequently accelerate growth of some types of cancers such as triple-negative breast cancer (TNBC).
  • Methods: To meet the study purpose, related articles in English published in the database of PubMed were searched using the keywords including breast cancer, TNBC, hypoxia, HIF-1, HIF-1 inhibitors, drug resistance, and targeted therapy.
  • Results: The findings revealed that HIF-1 blockade could provide anaerobic glycolysis, moderate hypoxic cell proliferation, and consequently improve necrosis/apoptosis; however, it could decrease radiotherapy and chemotherapy resistance. Moreover, approximately 40% of all BCs and 50% of locally advanced types were reported hypoxic and their metabolisms were found to be strongly correlated with radiotherapy and systemic therapy resistance. Furthermore, digoxin and acriflavine as HIF-1 inhibitors demonstrated potential therapeutic effects through lowering primary tumor growth, vascularization, invasion, as well as metastasis in animal models of BC. Recently-published pre-clinical trials similarly implied that a combination of cytotoxic chemotherapy with drugs hindering hypoxia-inducible factors was likely to enhance outcomes in women affected with TNBC.
  • Conclusion: The HIF inhibitors might characterize a newly-established targeted therapy for BCs with regard to the significant overexpression of HIF target genes in TNBC, regulatory role of HIFs in metastasis, and involvement of such inhibitors in cancer stem cells (CSCs) as well as chemotherapy resistance.
  • Keywords: Breast Cancer, Hypoxia, HIF-1 Inhibitors, Drug Resistance, Targeted Therapy.