Trident cold atmospheric plasma blocks three cancer survival pathways to overcome therapy resistance

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-12, Vol.118 (51), p.1-8
• Main Authors: Guo, Bo, Pomicter, Anthony D., Li, Francis, Bhatt, Sudhir, Chen, Chen, Li, Wen, Qi, Miao, Huang, Chen, Deininger, Michael W., Kong, Michael G., Chen, Hai-Lan
• Format: Article
• Language: English
• Subjects: AKT protein; Animal models; Animals; Apoptosis; Atmospheric models; Biological Sciences; Breast cancer; Cancer; Carcinogenesis; CD34 antigen; Cell death; Cell Line, Tumor; Chronic myeloid leukemia; Deregulation; Gas discharges; Glycolysis; Hematopoietic stem cells; Humans; Hypoxia-inducible factor 1a; Lactic Acid - metabolism; Lethality; Leukemia; Leukemia, Experimental - mortality; Leukemia, Experimental - therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - therapy; Melanoma; Mice; Mutation; Myeloid leukemia; Oxidation-Reduction; Physical Sciences; Plasma Gases - therapeutic use; Progenitor cells; Reactive oxygen species; Signal transduction; Signaling; Stem cell transplantation; Stem cells; Survival; Therapy; TOR protein; Transplantation; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2107220118

Therapy resistance is responsible for most cancer-related death and is mediated by the unique ability of cancer cells to leverage metabolic conditions, signaling molecules, redox status, and other pathways for their survival. Interestingly, many cancer survival pathways are susceptible to disturbances in cellular reactive oxygen species (ROS) and may therefore be disrupted by exogenous ROS. Here, we explore whether trident cold atmospheric plasma (Tri-CAP), a gas discharge with exceptionally low-level ROS, could inhibit multiple cancer survival pathways together in a murine cell line model of therapy-resistant chronic myeloid leukemia (CML). We show that Tri-CAP simultaneously disrupts three cancer survival pathways of redox deregulation, glycolysis, and proliferative AKT/mTOR/HIF-1α signaling in this cancer model. Significantly, Tri-CAP blockade induces a very high rate of apoptotic death in CML cell lines and in primary CD34⁺ hematopoietic stem and progenitor cells from CML patients, both harboring the therapy-resistant T315I mutation. In contrast, nonmalignant controls are minimally affected by Tri-CAP, suggesting it selectively targets resistant cancer cells. We further demonstrate that Tri-CAP elicits similar lethality in human melanoma, breast cancer, and CML cells with disparate, resistant mechanisms and that it both reduces tumor formation in two mouse models and improves survival of tumor-bearing mice. For use in patients, administration of Tri-CAP may be extracorporeal for hematopoietic stem cell transplantation therapy, transdermal, or through its activated solution for infusion therapy. Collectively, our results suggest that Tri-CAP represents a potent strategy for disrupting cancer survival pathways and overcoming therapy resistance in a variety of malignancies.