Title:Targeting Hypoxia for Sensitization of Tumors to Radio- and Chemotherapy
VOLUME: 13 ISSUE: 6
Author(s):Khaled Ghattass, Rana Assah, Marwan El-Sabban and Hala Gali-Muhtasib
Affiliation:Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Lebanon.
Keywords:Bioreductive drugs, cancer stem cells, epithelial to mesenchymal transition, hypoxia inducible factor, metastasis,
radiosensitizers.
Abstract:The heterogeneous distribution of hypoxic regions within solid tumors renders them refractive to chemo- and
radio-therapies and contributes positively to tumor invasion and metastasis. Moreover, hypoxia favors the enrichment of
cancer stem cells by interacting with differentiation signals via the maintenance of stem cell properties of undifferentiated
cells or via the induction of cellular dedifferentiation. The discovery of the hypoxia inducible factor 1alpha (HIF-1α) has
led to the current extensive interest in the signal molecules related to tumor hypoxia and the major regulatory pathways
that control the family of hypoxia-inducible factors as potential molecular targets for cancer therapeutics. Multiple
approaches have been developed to circumvent hypoxia-induced resistance, such as oxygenating tumors, using radiosensitizers
and more recently using bio-reductively activated pro-drugs. Recent evidence suggests that radio-sensitization
has undergone a paradigm shift from compounds that enhance the effect of radiation via mimicking oxygen, to
compounds that target HIF-mediated signaling pathways eventually reducing radio-resistance. In this paper, we give an
overview of our recent understandings in hypoxia research, discuss the mechanisms of resistance of hypoxic tumors and
of hypoxia-induced cancer stem cells and highlight the latest advances in cancer treatments that target tumor hypoxia and
the resistant populations of cancer stem cells. Classical and novel radio-sensitization methods, mainly the molecular
inhibition of HIFs and downstream targets and the use of hypoxia-activated drugs are compared and contrasted. Such
multi-faceted targeted therapies ultimately enhance treatment outcomes and reduce normal tissue toxicity by the selective
targeting of solid tumors.
