2β-methoxy-2-deethoxyphantomolin synergistically enhances epirubicin effect against triple-negative breast cancer via targeted inhibition of AKT and HR pathways

Enhancing the efficacy of chemotherapy in treating triple-negative breast Cancer (TNBC) remains crucial. Understanding the genes involved in Cancer progression and targeted therapies may be beneficial for TNBC chemotherapy. Here, bioinformatics analysis revealed that Akt1 and the key gene of homologous recombination (HR), RAD51, were significantly upregulated in breast Cancer. Meanwhile, we discovered that epirubicin (Epi) could activate Akt and HR pathways in MDA-MB-231 cells. Pharmacological inhibition of Akt or siAKT could reverse the activation of Akt and HR pathways and sensitize Epi. Hence, we sought natural products that could inhibit both Akt and HR pathways to enhance the sensitivity of Epi and expanded its therapeutic effects in TNBC. 2β-methoxy-2-deethoxyphantomolin (EM2) is a natural sesquiterpene lactone extracted from Elephantopus mollis with strong Anticancer activity. We found that EM2 induced Apoptosis of MDA-MB-231 cells by inhibiting Akt and HR pathways. Mechanistically, EM2 impaired transcription of Akt, directly bound to RAD51 protein, and facilitated the degradation of Akt and RAD51 in a caspase-dependent manner. Importantly, we determined that EM2 in combination with Epi treatment exhibited a synergistic anti-tumor effect in MDA-MB-231 cells. Moreover, overexpression of Akt could prevent EM2 from sensitizing Epi. The results of MDA-MB-231 xenograft tumor model confirmed that EM2 could reduce the dose of Epi and achieve anti-TNBC effect in vivo without toxicity to mice tissues. Overall, our work indicates EM2 in combination with Epi can greatly expand the therapeutic effect of Epi in TNBC, underscoring targeting Akt and RAD51 as a promising approach for TNBC chemotherapy sensitization.

AKT; Chemotherapy sensitization; Epirubicin; Homologous recombination; RAD51; Triple-negative breast cancer.