Resistance to doxorubicin therapy in breast cancer cells could be attenuated by ligustilide: impact on autophagy and LncRNA H19

Abstract

BACKGROUND: Resistance to DOX in breast cancer (BC) treatment is attributed to multiple mechanisms. The potential of autophagy inhibition in mitigating DOX resistance in BC has yet to be clarified. Despite showing anti-tumorigenic activity, the role of ligustilide (LIG) in BC treatment remains limited. AIM: To evaluate LIG-mediated autophagy inhibition in DOX-treated MCF-7, MCF-7/DOX, and MDA-MB-231 cells, and investigate LncRNA H19's role in BC resistance. METHODS: The three cell lines were treated with DOX, LIG, or both of them. Autophagic flux and expression of ERα, metastasis-associated protein (MTA1) complex components, autophagy-related 7 gene (ATG7), multidrug resistance gene 1 (MDR1) and LncRNA H19 were assessed. KEY FINDINGS: Both individual treatments showed dose-dependent cytotoxicity. When combined together, LIG increased DOX cytotoxicity in MCF-7/DOX and MDA-MB-231. LIG inhibited DOX-induced autophagic flux, indicated by elevated LC3BII and p62 levels, and reversed MDR1 in MCF-7/DOX and MDA-MB-231. LIG monotherapy upregulated ERα in MCF-7/DOX and restored its expression in MDA-MB-231. In MCF-7/DOX, combined treatment upregulated ERα and downregulated LncRNA H19 relative to DOX monotherapy, whereas in MDA-MB-231, it upregulated LncRNA H19 compared with DOX monotherapy. CONCLUSION: LIG mitigated DOX-induced resistance through inhibiting autophagy, restoring ERα expression, and downregulating LncRNA H19 in the DOX-resistant BC cell line, thereby presenting a potential therapeutic approach in BC treatment.