Decitabine Priming Enhances Mucin 1 Inhibition Mediated Disruption of Redox Homeostasis in Cutaneous T-Cell Lymphoma
Year: 2017
Type: article
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 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 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. Mol Cancer Ther; 16(10); 2304–14. ©2017 AACR.
Source: Molecular Cancer Therapeutics
Language: English
Subfield: Dermatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: CTCL immunobiology: lessons from alemtuzumab, MUC1-C Oncoprotein Evades Immune Destruction in Non-small Cell Lung Cancer, Immunotherapeutic Approaches Targeting the MUC1-C Oncoprotein in Triple-Negative Breast Cancer, Transforming the diagnosis and care of patients with CTCL using TCR sequencing, SPORE in Multiple Myeloma, Immune Evasion in Human Squamous Cell Carcinomas of the Skin, Vaccination to generate protective tissue resident T cells, Human Skin Disease Resource-based Center
OpenAlex ID: W2737072798