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

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 Mucin 1 C-terminal subunit (MUC1-C) 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, and TIGAR, critical to intracellular redox homeostasis. Dual exposure to GO-203 and decitabine resulted in marked downregulation 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 and dual oxidase 2 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 dea...

Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Jain, S., Washington, A., Leaf, R. K., Bhargava, P., Clark, R. A., Kupper, T. S., Stroopinsky, D., Pyzer, A., Cole, L., Nahas, M., Apel, A., Rosenblatt, J., Arnason, J., Kufe, D., Avigan, D. Tags: Cancer Biology and Signal Transduction Source Type: research