Episensitization: Therapeutic Tumor Resensitization by Epigenetic Agents: A Review and Reassessment

Abstract

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 chemotherapies.

RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials

“…These modified red blood cells act as nanosized anticancer bioagents: their tendency to aggregate is based on an altered deformability as well as the binding of PS, CD36, CD47, CD71, and ICAM-1, the 'Velcro' of the red blood cell membrane, to cognate receptors on the tumor vasculature, which contributes to persistent or recurrent tumor microvascular clogging and stasis [19]. This microvascular occlusion leads to further increase in acidosis and hypoxia, conditions which are required for the hemoglobin-mediated reduction of nitrite to nitric oxide, thereby making RRx-001 a hypoxia-activated anti-cancer agent that induces its own hypoxia [3,21] (Figure 5 (b-d)). …”

A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells

“…Importantly, DNMTs have been targeted in therapeutic approaches: specifically, DNMT inhibitors 5-Azacytidine (AZA) and Decitabine are FDA approved for the treatment of hematological malignancies, myelodysplasia, and acute myeloid leukemia 16 .…”

“…Preclinical studies of RRx-001 have demonstrated anti-tumor activity in refractory solid tumor models 16, 17 . A phase-1 clinical trial of RRx-001 in advanced solid tumors showed promising anti-tumor activity in a heavily pretreated population, without dose-limiting toxicities 20 .…”

MicroRNA-mediated epigenetic targeting of Survivin significantly enhances the antitumor activity of paclitaxel against non-small cell lung cancer

“…Its clinic activity against NSCLC is being tested in combination with DNA methyltransferase (DNMT) inhibitor Azacitidine or EGFR inhibitor Erlotinib (Tarceva), but not conventional chemotherapy (http://www.clinicaltrial.gov/ct2/results?term=entinostat&Search=Search). While epigenetic therapy emerges as a new strategy to overcome drug resistance and re-sensitize cancer cells to chemotherapy [22, 23], we wondered whether entinostat might possess such activity as a chemo-sensitizer via inhibition of Survivin. In the current report, we investigated the mechanism of action of entinostat in potentiation of paclitaxel-mediated antitumor activity against NSCLC.…”