Combination Therapy with MAPK-Pathway-Specific Inhibitor and Folic-Acid-Receptor-Targeted Selenium Nanoparticles Induces Synergistic Antiproliferative Response in BRAF Mutant Cancer Cells.

Abstract

Combination chemotherapy, where drugs with a nonoverlapping mode of action achieve better efficacy at lower doses with reduced dose-dependent side effects, holds promise for complete remission of the tumor. Herein, we report a combination therapeutic module comprised of the folic acid receptor (FAR)-targeted SeNPs (FA-SeNPs) and MAPK-pathway inhibitor PD98059 (PD98). While aberrant signaling leading to an uncontrolled proliferation in BRAF mutation bearing cancer cells including MDAMB231 (breast cancer) and A375 (melanoma) cells was inhibited by PD98, high expression of FAR by these cells also led to selective internalization of FA-SeNPs. Consequently, the combination treatment of PD98 and FA-SeNPs demonstrated synergistic antiproliferative efficacy in MDAMB231 and A375 cells involving apoptotic modes of cell death. The selective nature of the present combination module was supported by the low off-target response in L132 noncancerous lung cells. Moreover, the size of the three-dimensional MDAMB231 spheroids was successfully reduced because of the combination therapy projecting its potential in eradicating tumors in vivo.