Plasma enhance drug sensitivity to bortezomib by inhibition of cyp1a1 in myeloma cells

Multiple myeloma (MM), an incurable B cell disease, is characterized by the accumulation of malignant plasma cells in patients’ bone marrow (BM) (1). Patients with MM are at an increased risk of developing infections, anemia, thrombocytopenia, renal failure, and bone disease (2,3). Drug resistance is one of the major problems in MM clinical therapy (4). The interactions between MM cells and the BM microenvironment is considered to play a critical role in MM drug resistance (5). In between, the Notch pathway is important for MM cell growth, migration and drug resistance (6,7). We have demonstrated that Notch activation could induce drug resistance to bortezomib in murine and human MM cells by up-regulating cyp1a1, which was involved in drug metabolism (8). In this study, we used a new technology, called cold atmosphere plasma (CAP), to treat MM cells (9,10). CAP is mainly consisted of free electron and charged ions, which generates reactive oxygen species (ROS) and reactive nitrogen species (RNS) that could have various biological effects (11,12). Thus, gas plasma has been applied in many biomedical fields such as sterilization, dentistry, cosmetology, wound healing, skin disease and cancer therapy (13-15). Combination of different drugs or therapy for a better anti-cancer effect is a common strategy in cancer therapy. Here, we demonstrated for the first time that gas plasma and bortezomib had a synergistic reduction of cell viability in myeloma cells. Gas plasma could enhance the sensitivity to bortezomib in myeloma cells, by inhibiting Notch signaling and cyp1a1, which could be applied as a new combination treatment for a better anti-cancer effect and a lower drug side effect