Tetrandrine potentiated apoptosis and mitophagy to overcome Adriamycin resistance in MCF-7/Adr cells by regulating the Hippo pathway

1.Breast cancer ranks among the most prevalent malignant tumors worldwide, characterized by high rates of morbidity and mortality.2.Adriamycin (Adr) remains one of the primary treatments for breast cancer; however, its efficacy is often undermined by the development of drug resistance, resulting in treatment failure. Recent studies have highlighted that the combination of natural products with Adr can effectively mitigate side effects and counteract drug resistance.3.In this study, the co-administration of Tetrandrine (Tet) demonstrated a significant reversal of Adr resistance, reduced the IC50 of Adr in MCF-7/Adr cells, downregulated the expression of multi-drug resistance proteins, including P-gp, BCRP, and MRP1, and inhibited the migration of MCF-7/Adr cells.4.Flow cytometry results revealed that Tet markedly enhanced cell apoptosis rates compared to Adr treatment alone. Western blot analysis further indicated that Tet, in combination with Adr, significantly increased the expression of Bax while reduced Bcl-2 levels. Moreover, Tet was found to upregulate Parkin expression and downregulate p62 expression, thereby promoting mitophagy.5.Additional experiments demonstrated that Tet substantially enhanced Hippo pathway activity. Upon inactivating the Hippo pathway using si-SAV1, results showed that suppression of this pathway significantly diminished Tet's effects on Adr resistance, multi-drug resistance protein expression, apoptosis, and mitophagy.6.Taken together, the findings from this research indicate that Tet reverses Adr resistance in MCF-7/Adr cells primarily by enhancing apoptosis and mitophagy, at least partially through modulation of Hippo pathway activity.