3'-epi-12β-hydroxyfroside induces autophagic degradation of ABCG2 to overcome drug resistance in lung cancer cells.

AIMS

ABCG2 contributes to multidrug resistance by transporting chemicals across cell membranes. 3'-epi-12β-hydroxyfroside (HyFS) is known for its anticancer properties as an autophagy inducer. This study investigates whether HyFS can overcome drug resistance by promoting autophagy-mediated ABCG2 degradation.

METHODS

Two non-drug-resistant lung cancer cell lines, H460 and A549, along with their drug-resistant sublines, H460/MX20 and A549/MX10, were used as experimental models. Immunoblotting, immunofluorescence, and flow cytometry were used to assess the expression of ABCG2 and autophagy-related molecules. Flow cytometry was also used for quantitative analysis of ABCG2 efflux and cell death. Cell viability was assessed using the MTT assay. Additionally, murine models of H460/MX20 and A549/MX10 were established to evaluate the efficacy of various combination therapies and ABCG2 expression.

RESULTS

The efficacy of HyFS treatment depends on dosage and duration, which influence autophagy flux in treated cells. Inhibition of autophagy restores ABCG2 expression, causing intracellular accumulation of ABCG2 substrates and promoting their efflux. HyFS treatment sensitizes mitoxantrone-resistant H460/MX20 and A549/MX10 cells to mitoxantrone, enhancing mitoxantrone-induced reduction in cell viability and triggering cell apoptosis. Inhibiting autophagy mitigates these effects. In addition, HyFS treatment reduces mitoxantrone resistance mediated by ABCG2 and hinders tumor progression. Moreover, the combination of mitoxantrone with HyFS shows promising synergistic antitumor effects in both MX-sensitive and MX-resistant murine tumor models without inducing any obvious side effects.

SIGNIFICANCE

These findings highlight the potential of HyFS in overcoming drug resistance through autophagy-dependent degradation of ABCG2, suggesting its promise as a therapeutic approach against ABCG2-mediated drug resistance in lung cancer cells.