HIF-1 as a Target for Cancer Chemotherapy, Chemosensitization and Chemoprevention

Elena      Monti; Marzia      B. Gariboldi

Abstract

Cells in rapidly growing solid tumors are commonly exposed to chronic or intermittent hypoxia. Hypoxia can induce cell death by multiple mechanisms; however, some cells may adapt by orchestrating dramatic changes in gene expression patterns. In addition, hypoxia exerts a powerful selective pressure on tumor cells, resulting in the emergence of clonal populations whose defects in DNA repair mechanisms favor genomic instability and tumor progression, whereas disabling of apoptotic pathways makes them more resistant to both environmental stresses and therapeutic interventions. The transcription factor HIF-1 (Hypoxia-Inducible Factor 1) is generally considered as the major regulator of the hypoxic adaptive response, and as such it is viewed as a viable prospective target for novel pharmacologic approaches to the clinical management of solid tumors. Several agents have been identified that inhibit HIF-1 transcriptional activity, and some of them are currently undergoing clinical trials, mostly based on their antiangiogenic properties. This article reviews the role played by HIF-1 in tumorigenesis and chemoresistance and provides an overview of current and prospective pharmacologic strategies designed to inhibit HIF-1 activity, emphasizing their direct and indirect effects on tumor growth, as well as their potential for chemoprevention and chemosensitization.

Keywords: Apoptosis, chemoprevention, drug resistance, HIF-1 (Hypoxia-Inducible Factor 1), hypoxia, microenvironment, tumorigenesis, hepatocytes, cardiomyocytes, HIF-1, pO2, bHLH, ODD, TAD, N-TAD, C-TAD, PHD, VHL, ARD1, FIH, CBP, PHDs, ROS, SUMOylation, transcription factors, phosphorylation, cytokines, DNA damage, AKT, mTOR, PI3K/AKT/mTOR, MAPK, STAT, mutation, PIKC3A, MDM2, NF-B, RACK1, HSP90 acetylation, RCC, HREs, microRNA, JMJD1A, IGF-2, TGF/EGFR, SDF1, PDGF-BB, hTERT, hRT, GLUT1, GLUT3, glycolysis, phenotype, VEGF, VEGFR1, NBS, MRN, ABCB1, MDR1, BCRP, topoisomerase II, carcinoma, MMR, RNA, TRAIL, APO2L, BNIP3, shRNA, Transcription, Translation, Torisel, Afinitor, YC-1, doxorubicin, daunorubicin, xenografts