Hydroxychloroquine enhances anticancer effect of DOX/folate-phytosterol-carboxymethyl cellulose nanoparticles in A549 lung cancer cells

摘要

Purpose: To study the in vitro anticancer effect of doxorubicin-loaded folate-phytosterol-carboxymethyl cellulose nanoparticles (DOX/FPCMC NPs), alone and in combination with the antimalarial drug hydroxychloroquine (HCQ) on human lung cancer cells (A549 cells). Methods: Human lung adenocarcinoma A549 cell line was treated with blank FPCMC NPs, HCQ, free DOX, DOX/FPCMC NPs, free DOX + HCQ or DOX/FPCMC NPs + HCQ. The concentrations of HCQ, DOX and FPCMC NPs varied within the ranges of 20-120 μmol/L, 2-12 mg/L and 50-500 mg/L, respectively. Cell viability and free folate competitive inhibition were determined using MTT assay. Cell proliferation and migration were investigated with wound healing assay, while confocal laser scanning microscopy (CLSM) was used to determine cellular uptake of drugs. Results: In all formulations, the DOX/FPCMC NPs + HCQ produced the highest cytotoxicity in A549 cells due to high cytotoxicity arising from folate-receptor-mediated endocytosis and HCQ-induced inhibition of autophagy. Free folate competitively inhibited the cytotoxicity of DOX/FPCMC NPs on A549 cells. Wound healing assay showed that A549 cells treated with DOX/FPCMC NPs + HCQ had the lowest cell levels of proliferation and migration capacity. The cellular uptake of DOX/FPCMC NPs by A549 cells was higher than that of free DOX. Conclusion: The combination of DOX/FPCMC NPs and HCQ produced the best antitumor effect and had a promising potential for reversal of MDR.