Effect of TRPV receptor agonists in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by accumulation of immature cells in bone marrow and peripheral blood. Although successful results were obtained with tyrosine kinase inhibitors, several patients show resistance. For this reason, the identification of new strategies and therapeutic biomarkers represent an attractive goal. The role of Transient Receptor Potential (TRP) ion channels as possible drug targets has been elucidated in different types of cancer. Among natural compounds known to activate TRPs, cannabidiol (CBD) and Capsaicin (CPS) display anti-cancer properties. By using FACS analysis, confocal microscopy, gene silencing and cell growth assay, we demonstrated that CBD, through TRPV2, inhibits cell proliferation and cell cycle in CML cells. It promoted mitochondria dysfunction and mitophagy as shown by mitochondrial mass reduction and up-regulation of several mitophagy markers. These effects were associated with changes in the expression of OCT-4 and PU.1 markers involved in stemness, and reduction of CD34 stemness marker. Moreover CBD, through the activation of autophagy, modulates the expression of CD274 gene in CML cells. Interestingly, a synergistic effect by combining CBD with the standard drug imatinib was found and imatinib-resistant cells remain susceptible to CBD effects. In addition, we demonstrated that CML cells are resistant to CPS, but not to N-oleoyldopamine (OLDA), another TRPV1 bioactive agonist whose biological functions are not yet fully explored, with anti-inflammatory activities. Our preliminary results show that OLDA induce CML cell death through reactive oxygen species (ROS) production, DNA damages and endoplasmatic reticulum (ER) stress activation. In conclusion, the targeting of TRPV2 by using CBD, and the targeting TRPV1 by using OLDA could be a promising strategy to enhance conventional therapy and improve the prognosis of CML patients.