Abstract：
Trastuzumab resistance presents a significant challenge in the treatment of HER2+ breast cancer, necessitating the investigation of combination therapies to overcome this resistance. Honokiol, a compound with broad anticancer activity, has shown promise in this regard. This study aims to discover the effect of honokiol in increasing trastuzumab sensitivity in HER2+ trastuzumab-resistant breast cancer cells HCC1954 and the underline mechanisms behind. A bioinformatics study performed to explore the most potential target hub gene for honokiol in HER2+ breast cancer. Honokiol, trastuzumab and combined treatment cytotoxicity activity was then evaluated in both parental HCC1954 and trastuzumab resistance (TR-HCC1954) cells using MTT assay. The expression levels of these hub genes were then analyzed using qRT-PCR and those that could not be analyzed were subjected to molecular docking to determine their potential. Honokiol showed a potent cytotoxicity activity with an IC50 of 41.05 μM and 69.61 μM in parental HCC1954 and TR-HCC1954 cell line respectively. Furthermore, the combination of honokiol and trastuzumab resulted in significant differences in cytotoxicity in TR-HCC1954 cells at specific concentrations. Molecular docking and the qRT-PCR showed that the potential ERα identified from the bioinformatics analysis was affected by the treatment. Our results show that honokiol has the potential to increase the sensitivity of trastuzumab in HER2+ trastuzumab resistant breast cancer cell line HCC1954 by affecting regulating estrogen receptor signaling. Further research is necessary to validate these findings.
摘要：
曲妥珠单抗耐药在HER2+乳腺癌的治疗中提出了重大挑战，有必要研究联合疗法以克服这种抗性。和厚朴酚,具有广泛抗癌活性的化合物，在这方面表现出了希望。本研究旨在发现和厚朴酚在HER2+曲妥珠单抗耐药乳腺癌细胞HCC1954中增加曲妥珠单抗敏感性的作用及其背后的强调机制。进行了一项生物信息学研究，以探索和厚朴酚在HER2乳腺癌中最潜在的靶hub基因。和厚朴酚,然后使用MTT测定在亲本HCC1954和曲妥珠单抗抗性(TR-HCC1954)细胞中评估曲妥珠单抗和联合治疗的细胞毒性活性。然后使用qRT-PCR分析这些hub基因的表达水平,并且对不能分析的那些进行分子对接以确定它们的潜力。和厚朴酚在亲本HCC1954和TR-HCC1954细胞系中显示出有效的细胞毒性活性，IC50分别为41.05μM和69.61μM。此外，和厚朴酚和曲妥珠单抗的联合使用导致特定浓度下TR-HCC1954细胞的细胞毒性存在显著差异.分子对接和qRT-PCR表明，从生物信息学分析中鉴定出的潜在ERα受到处理的影响。我们的结果表明和厚朴酚具有通过影响调节雌激素受体信号传导来增加曲妥珠单抗在HER2+曲妥珠单抗耐药乳腺癌细胞系HCC1954中的敏感性的潜力。需要进一步的研究来验证这些发现。
