Background: Defects in apoptosis regulation are one of the classical features of cancer cells, often associated with more aggressiveness and failure to therapeutic options. We investigated the combinatorial antitumor effects of a natural product, physachenolide C (PCC) and bortezomib, in KRASmut/P53mutlung cancer cells and xenograft mice models. Methods: The in vitro anticancer effects of the bortezomib and PCC combination were investigated using cell viability, migration, and invasion assays in 344SQ, H23, and H358 cell lines. Furthermore, the effects of combination treatment on the critical parameters of cellular metabolism, including extracellular acidification rate (ECAR) and mitochondrial oxidative phosphorylation based on the oxygen consumption rate of cancer cells were assessed using Seahorse assay. Finally, the antitumor effect of the bortezomib (1 mg/kg) and PCC (10 mg/kg) combination was evaluated using xenograft mice models. Results: Our data showed that the bortezomib–PCC combination was more effective in reducing the viability of lung cancer cells in comparison with the individual treatments. Similarly, the combination treatment showed a significant inhibition of cell migration and invasion of cancer cells. Additionally, the key anti-apoptotic protein c-FLIP was significantly inhibited along with a substantial reduction in the key parameters of cellular metabolism in cancer cells. Notably, the bortezomib or PCC inhibited the tumor growth compared to the control group, the tumor growth inhibition was much more effective when bortezomib was combined with PCC in tumor xenograft mice models. Conclusion: These findings demonstrate that PCC sensitizes cancer cells to bortezomib, potentially improving the antitumor effects against KRASmut/P53mutlung cancer cells, with an enhanced efficacy of combination treatments without causing significant side effects.
背景：细胞凋亡调控缺陷是癌细胞的典型特征之一，常与肿瘤侵袭性增强及治疗失败相关。本研究探讨了天然产物Physachenolide C（PCC）与硼替佐米在KRAS突变/P53突变肺癌细胞及移植瘤小鼠模型中的联合抗肿瘤效应。方法：通过细胞活力、迁移及侵袭实验，在344SQ、H23和H358细胞系中评估硼替佐米与PCC联合治疗的体外抗癌效果。采用Seahorse能量代谢分析系统检测联合治疗对细胞代谢关键参数的影响，包括基于癌细胞耗氧率的细胞外酸化率（ECAR）和线粒体氧化磷酸化水平。最后通过移植瘤小鼠模型评估硼替佐米（1 mg/kg）与PCC（10 mg/kg）联合给药的抗肿瘤效果。结果：数据显示，与单药治疗相比，硼替佐米-PCC联合方案能更有效降低肺癌细胞活力。联合治疗对癌细胞迁移和侵袭同样表现出显著抑制作用。此外，关键抗凋亡蛋白c-FLIP表达显著受抑，同时癌细胞代谢关键参数大幅降低。值得注意的是，在移植瘤小鼠模型中，虽然硼替佐米或PCC单药均能抑制肿瘤生长，但二者联合治疗时的肿瘤生长抑制效果显著增强。结论：本研究表明PCC能增强癌细胞对硼替佐米的敏感性，可能通过提升联合治疗方案疗效而不引起显著毒副作用，为KRAS突变/P53突变肺癌的抗肿瘤治疗提供新策略。
肿瘤(癌症)患者之家