Tri-Phenyl-Phosphonium-Based Nano Vesicles: a New In Vitro Nanomolar-Active Weapon to Eradicate PLX-Resistant Melanoma Cells

Cutaneous metastatic melanoma (CMM) is the most aggressive form of skin cancer with poor prognosis, chemotherapy-induced secondary tumorigenesis and emergency of drug resistance. Triphenyl phosphonium (TPP)-based nanovesicles (BPPB), having amphiphilic properties, recently demonstrated potent ROS-dependent anticancer effects against PLX-sensitive MeOV BRAFV600E and MeTRAV BRAFV600D mutants cell lines, evidencing a more marked sensitiveness of MeOV cells. Here, BPPB was tested on in vitro selected vemurafenib (PLX)-resistant MeOV BRAFV600E and MeTRAV BRAFV600D mutants cell lines and we found strong antiproliferative effects, regardless of their acquired resistance to PLX, that correlated with ROS overproduction only for 24-hours treatments. MeTRAV PLX-R demonstrated a remarkable higher tolerance than MeOV PLX-R to BPPB, after 24 hours, while exposure for longer periods induced similar responses in both cell lines (IC50 = 87.8-106.5 nM on MeOV and 81.0-140.6 nM on MeTRAV). Noteworthy, the cytotoxicity of BPPB to non-tumorigenic human keratinocytes (HaCaT) was low, allowing for selectivity index values (SIs) up to 11.58; instead, the BPPB concentration causing 50% hemolysis (HC50) was found 16-173 and 4-192-fold higher than the IC50 calculated for MeOV and MeTRAV PLX-R cells, respectively. By due correlations studies, it was established that BPPB exerted cytotoxic effect on MeOV and MeTRAV PLX-R cells by a time-dependent mechanism, while a concentration-dependent mechanism is observed only at 24 hour-exposure. Finally, a ROS-dependent mechanism can be assumed only in MeTRAV at 72 hour-exposure.