Decitabine Priming Enhances Mucin 1 Inhibition Mediated Disruption of Redox Homeostasis in Cutaneous T-Cell Lymphoma

Abstract

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous neoplasm and patients with relapsed/refractory disease exhibit resistance to standard therapies. We have previously demonstrated that the MUC1-C oncoprotein plays a critical role in protection from oxidative stress in CTCL cells. Targeting of MUC1-C with a pharmacologic inhibitor, GO-203, was associated with apoptosis in CTCL. However, disease responses were incomplete underscoring the need for combinatorial strategies that could exploit the vulnerability of CTCL cells to oxidative signals. Cell lines, primary samples and xenograft models of CTCL were used to assess synergy of GO-203 with decitabine, a hypomethylating agent. Present studies demonstrate that exposure of CTCL cells to decitabine in combination with GO-203, increased the generation of reactive oxygen species (ROS) levels and decreased levels of scavenger molecules, NADP, NADPH, glutathione (GSH), and TIGAR, critical to intracellular redox homeostasis. Dual exposure to GO-203 and decitabine resulted in marked down-regulation of DNA methyl transferases demonstrating significant synergy of these agents in inducing global and gene specific hypomethylation. Accordingly, treatment with decitabine and GO-203 upregulated the ROS generating enzymes, NADPH oxidase 4 (Nox4) and Dual oxidase 2 (Duox2) potentially due to their effect on epigenomic regulation of these proteins. In concert with these findings, exposure to decitabine and GO-203 resulted in heightened apoptotic death in CTCL cell lines, patient derived primary samples and in a murine xenograft model. These findings indicate that decitabine intensifies MUC1-C inhibition induced redox imbalance and provides a novel combination of targeted and epigenetic agents for patients with CTCL.

Combination of Decitabine and a Modified Regimen of Cisplatin, Cytarabine and Dexamethasone: A Potential Salvage Regimen for Relapsed or Refractory Diffuse Large B-Cell Lymphoma After Second-Line Treatment Failure

“…Treatment with a combination of DAC and temozolomide (TMZ) has also produced similar synergistic results in vitro and in vivo, resulting in complete response in TMZ-resistant diffuse large B-cell lymphoma murine xenograft models (20). Additionally, a xenograft murine model of CTCL showed that DAC and Mucin-1 C-terminal subunit inhibition (GO-203) resulted in a significant reduction in tumor volume compared to either agent alone (10). A phase I study found that DAC resulted in better treatment activation and safety in patients with advanced solid tumors and non-Hodgkin's lymphomas (21).…”

Potential Applications of NRF2 Modulators in Cancer Therapy

“…Moreover, due to patients' individualities and tumors heterogeneity, variable response rates are often observed making the identification of more effective drugs very urgent [272,273]. In this regard, the concomitant inhibition of antioxidant circuits and metabolic pathways that support the redox balance of malignant cells, delineates a promising anti-cancer strategy [274][275][276][277][278][279][280][281][282][283]. It is known that most of the metabolic changes promoting cancer cells proliferation and tumor growth induce also an increased ROS generation, counterbalanced by an antioxidant response that prevents cell death [234,284,285].…”

Key Role of Reactive Oxygen Species (ROS) in Indirubin Derivative-Induced Cell Death in Cutaneous T-Cell Lymphoma Cells

“…It is induced already at 2 h in response to indirubin treatment and resides upstream of the downregulation of XIAP and c-FLIP as well as upstream of the loss of MMP, suggesting a signaling cascade as shown in Figure 6c. Also for other treatments in CTCL cells, relations of ROS and apoptosis induction have been reported, such as for an inhibitor of the antioxidative protein mucin 1 [37], for silencing of the enhancer of zeste homolog 2 (EZH2) [38] and for doxycycline [39]. Thus, ROS production appears to be an important cellular signaling step related to the induction of apoptosis.…”