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Abstract：
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/P53mut lung 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.
CONCLUSIONS: These findings demonstrate that PCC sensitizes cancer cells to bortezomib, potentially improving the antitumor effects against KRASmut/P53mut lung cancer cells, with an enhanced efficacy of combination treatments without causing significant side effects.
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.
CONCLUSIONS: These findings demonstrate that PCC sensitizes cancer cells to bortezomib, potentially improving the antitumor effects against KRASmut/P53mut lung cancer cells, with an enhanced efficacy of combination treatments without causing significant side effects.
摘要：
背景：凋亡调节缺陷是癌细胞的经典特征之一，通常与更积极的治疗选择和失败有关。我们研究了天然产物的组合抗肿瘤作用，physachenolideC（PCC）和硼替佐米，在KRASmut/P53mut肺癌细胞和异种移植小鼠模型中。
方法：使用细胞活力研究了硼替佐米和PCC组合的体外抗癌作用，迁移,和344SQ的侵袭试验，H23和H358细胞系。此外，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使用海马测定法进行评估。最后,使用异种移植小鼠模型评价硼替佐米(1mg/kg)和PCC(10mg/kg)组合的抗肿瘤作用.
结果：我们的数据表明，与单独治疗相比，硼替佐米-PCC组合在降低肺癌细胞活力方面更有效。同样，联合治疗对癌细胞的迁移和侵袭有显著的抑制作用。此外,关键的抗凋亡蛋白c-FLIP被显著抑制,同时癌细胞中细胞代谢的关键参数显著降低.值得注意的是,与对照组相比，硼替佐米或PCC抑制肿瘤生长，在异种移植瘤小鼠模型中,硼替佐米联合PCC对肿瘤生长的抑制作用更为有效.
结论：这些发现表明PCC使癌细胞对硼替佐米敏感，有可能改善对KRASmut/P53mut肺癌细胞的抗肿瘤作用，具有增强的联合治疗的功效而不引起显著的副作用。
方法：使用细胞活力研究了硼替佐米和PCC组合的体外抗癌作用，迁移,和344SQ的侵袭试验，H23和H358细胞系。此外，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使用海马测定法进行评估。最后,使用异种移植小鼠模型评价硼替佐米(1mg/kg)和PCC(10mg/kg)组合的抗肿瘤作用.
结果：我们的数据表明，与单独治疗相比，硼替佐米-PCC组合在降低肺癌细胞活力方面更有效。同样，联合治疗对癌细胞的迁移和侵袭有显著的抑制作用。此外,关键的抗凋亡蛋白c-FLIP被显著抑制,同时癌细胞中细胞代谢的关键参数显著降低.值得注意的是,与对照组相比，硼替佐米或PCC抑制肿瘤生长，在异种移植瘤小鼠模型中,硼替佐米联合PCC对肿瘤生长的抑制作用更为有效.
结论：这些发现表明PCC使癌细胞对硼替佐米敏感，有可能改善对KRASmut/P53mut肺癌细胞的抗肿瘤作用，具有增强的联合治疗的功效而不引起显著的副作用。
