Episensitization: Therapeutic Tumor Resensitization by Epigenetic Agents: A Review and Reassessment
Bryan Oronsky, Neil Oronsky, Susan Knox, Gary Fanger and Jan Scicinski
Affiliation: RadioRx, Inc, 800 W El Camino Real, Suite 180, Mountain View CA 94040.
Resistance to chemotherapy, biological and targeted therapies is an important clinical problem. Resistance can arise and/or be
selected for multiple mechanisms of action. Unfortunately, acquired resistance to antitumor agents or regimens is nearly inevitable in all
patients with metastatic disease. Until recently, it was believed that this resistance was unalterable and irreversible, rendering retreatment
with the same or similar drugs futile in most cases. However, the introduction of epigenetic therapies, including HDAC inhibitors and
DNA methyltransferase inhibitors (DNMTIs), has provided oncologists with new strategies to potentially overcome this resistance. For
example, if chemoresistance is the product of multiple non-genetic alterations, which develop and accumulate over time in response to
treatment, then the ability to epigenetically modify the tumor to reconfigure it back to its baseline non-resistant state, holds tremendous
promise for the treatment of advanced, metastatic cancer. This minireview aims (1) to explore the potential mechanisms by which a group
of small molecule agents including HDACs (entinostat and vorinostat), DNA hypomethylating agents such as the DNMTIs (decitabine
(DEC), 5-azacytidine (5-AZA)) and redox modulators (RRx-001) may reprogram the tumors from a refractory to non-refractory state, (2)
highlight some recent findings in this area, and (3) discuss the therapeutic potential of resensitization approaches with formerly failed
Keywords: Epigenetics, HDAC inhibitors, reactive oxygen species, resensitization.
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