Trident cold atmospheric plasma blocks three cancer survival pathways to overcome therapy resistance
Menée à l'aide de cellules humaines de mélanome, de cancer du sein ou de leucémie myéloïde chronique et menée à l'aide de modèles murins, cette étude met en évidence l'intérêt d'un plasma à pression atmosphérique, capable de générer une faible concentration d'espèces réactives et d'agir sur trois processus biologiques impliqués dans la survie des cellules cancéreuses, pour lever la résistance thérapeutique
In many malignancies, resistance to targeted therapy emerges rapidly and leads to disease progression and mortality. Here, we show that trident cold atmospheric plasma (Tri-CAP), a reactive oxygen species–producing gas discharge, simultaneously blocks three cancer survival pathways, including deregulated redox balance, glycolysis, and proliferative signaling, in a mouse cell line model of therapy-resistant chronic myeloid leukemia (CML). This activity leads to high-rate apoptotic death in these CML cell lines and primary CD34+ hematopoietic stem and progenitor cells from CML patients, while minimally affecting nonmalignant control cells. Furthermore, Tri-CAP reduces tumor formation and prolongs the survival of tumor-bearing mice in mouse models of CML. Thus, treatment with Tri-CAP may be an effective strategy for overcoming therapy resistance in human cancers.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.