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

Abstract

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.

The potential of gas plasma technology for targeting breast cancer

“…Also other cell lines were found before to be more sensitive to He/O 2 than He direct plasma jet treatment 137 . Direct Ar plasma jet treatment of breast cancer cell lines was also reported in various studies 72,138–146 . With regard to plasma jets, one study compared nitrogen (N 2 ) against humid nitrogen (N 2 /H 2 O) and found the latter to be significantly more toxic than the former 147 .…”

“… 137 Direct Ar plasma jet treatment of breast cancer cell lines was also reported in various studies. 72 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 With regard to plasma jets, one study compared nitrogen (N 2 ) against humid nitrogen (N 2 /H 2 O) and found the latter to be significantly more toxic than the former. 147 This can be explained based on earlier findings identifying a critical role of humidity in the feed but not in ambient air.…”

“…137 Direct Ar plasma jet treatment of breast cancer cell lines was also reported in various studies. 72,[138][139][140][141][142][143][144][145][146] With regard to plasma jets, one study compared nitrogen ▪ Additive toxicity of gas plasma and radiotherapy observed in the cell lines tested ▪ Cell lines sensitive to gas plasma exposure were also sensitive to radiotherapy (high correlation). ▪ The addition of O 2 into the plasma gas inlet increased the cytotoxicity of gas plasma ▪ Gas plasma in combination with the drug olaparib has higher toxicity, hence DNA repair inhibitors like olaparib may increase the effectiveness of gas plasma.…”

Cold Atmospheric Plasma Targeting Hematological Malignancies: Potentials and Problems of Clinical Translation

“…Specific techniques of CAP administration have been employed in the treatment of this disease. In an experimental animal model of resistant CML, the authors considered whether trident cold atmospheric plasma (Tri-CAP), a CAP with extremely low concentration of ROS, could block different survival system pathways [ 78 ]. They showed that Tri-CAP disturbed the CML survival signaling involved in glycolysis, redox deregulation, and the AKT/mTOR/HIF-1α pathway.…”

“…The possibility of utilizing Tri-CAP in CML patients was reported in that study. The technique might be extracorporeal for hematopoietic stem cell transplant or transdermal administration, or by its stimulated solution for infusion treatment [ 78 ]. In addition, Tri-CAP might represent a powerful approach in CML patients, especially in overwhelming chemoresistance.…”