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Tri-Phenyl-Phosphonium-Based Nano Vesicles: A New In Vitro Nanomolar-Active Weapon to Eradicate PLX-Resistant
Silvana Alfei1, Carola Torazza1, Francesca Bacchetti1
1Department of Pharmacy, University of Genoa, Viale Cembrano, 16148 Genoa, Italy.
Abstract:
Cutaneous metastatic melanoma (CMM) is the most aggressive form of skin cancer, with characteristics including a poor prognosis, chemotherapy-induced secondary tumorigenesis, and the emergence of drug resistance. Our recent study demonstrated that triphenyl phosphonium (TPP)-based nanovesicles (BPPB), which have amphiphilic properties, exert potent ROS-dependent anticancer effect against PLX4032 (PLX)-sensitive MeOV BRAFV600E and MeTRAV BRAFV600D mutant cell lines, evidencing more marked efficacy on MeOV cells. Here, taking advantage of this in vitro model, the antitumoral effect of BPPB was tested on PLX-resistant (PLX-R) MeOV BRAFV600E and MeTRAV BRAFV600D mutant cell lines to find a new potential strategy to fight melanoma therapy resistance. Specifically, we investigated both its effects on cell viability in dose- and time-dependent experiments and those on ROS generation. Our results show that BPPB exerted strong antiproliferative effects, regardless of their acquired resistance of cells to PLX, that correlated with ROS overproduction for 24 h treatments only. Moreover, in terms of cell viability, PLX-R MeTRAV cells demonstrated a remarkably higher tolerance to 24 h BPPB treatment than PLX-R MeOV. On the contrary, BPPB 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). Notably, BPPB cytotoxicity on non-tumorigenic human keratinocytes (HaCaT) was low, thus establishing that BPPB is appreciably selective for CMM cells, allowing for selectivity index values (SIs) up to 11.58. Furthermore, the BPPB concentration causing 50% hemolysis (HC50) was found to be 16-173 and 4-192-fold higher than the IC50 calculated for PLX-R MeOV and MeTRAV cells, respectively. Correlation studies established that BPPB exerts cytotoxic effects on PLX-R MeOV and MeTRAV cells by a time-dependent mechanism, while a concentration-dependent mechanism was observed only at 24 h of exposure. Finally, a ROS-dependent mechanism can be assumed only in PLX-R MeTRAV cells in 72 h treatment.
Insights
Triphenyl phosphonium (TPP)-based nanovesicles (BPPB) show potent anticancer effects against drug-resistant melanoma cells. BPPB demonstrates selectivity for melanoma cells over normal keratinocytes, offering a promising strategy against therapy resistance.
Area of Science:
- Oncology
- Nanotechnology
- Biochemistry
Background:
- Cutaneous metastatic melanoma (CMM) is an aggressive skin cancer with poor prognosis and challenges in treatment due to drug resistance.
- Triphenyl phosphonium (TPP)-based nanovesicles (BPPB) have shown ROS-dependent anticancer effects in PLX4032 (PLX)-sensitive melanoma cell lines.
Purpose of the Study:
- To evaluate the antitumoral effect of BPPB on PLX-resistant (PLX-R) CMM cell lines (MeOV BRAFV600E and MeTRAV BRAFV600D).
- To investigate BPPB's impact on cell viability and ROS generation in drug-resistant melanoma models.
- To explore BPPB as a potential strategy to overcome melanoma therapy resistance.
Main Methods:
- In vitro testing of BPPB on PLX-resistant MeOV and MeTRAV melanoma cell lines.
- Dose- and time-dependent experiments to assess cell viability and ROS generation.
- Cytotoxicity assays on non-tumorigenic human keratinocytes (HaCaT) and hemolysis assays.
Main Results:
- BPPB exhibited significant antiproliferative effects on PLX-resistant melanoma cells, irrespective of their resistance.
- ROS overproduction was observed with BPPB treatment at 24 hours, correlating with antiproliferative effects.
- BPPB showed low cytotoxicity to HaCaT cells (Selectivity Index up to 11.58) and high HC50 values compared to IC50, indicating good selectivity.
- A time-dependent cytotoxic mechanism was observed for BPPB in PLX-R cells, with a concentration-dependent mechanism apparent only at 24 hours.
- A ROS-dependent mechanism was suggested for PLX-R MeTRAV cells after 72 hours of BPPB treatment.
Conclusions:
- BPPB effectively reduces cell viability in PLX-resistant melanoma cells, suggesting its potential as a therapeutic agent against melanoma therapy resistance.
- BPPB demonstrates significant selectivity towards CMM cells compared to normal keratinocytes.
- The findings support BPPB as a promising candidate for developing novel strategies to combat drug-resistant melanoma.
