Effects of respiratory mechanical forces on the pharmacological response of lung cancer cells to chemotherapeutic agents
Effects of respiratory mechanical forces on the pharmacological response of lung cancer cells to chemotherapeutic agents
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DOI：
10.1111/j.1472-8206.2011.00964.x
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发表时间：
2012-10-01
影响因子：
2.9
通讯作者：
Nirmalanandhan, Victor Sanjit
中科院分区：
文献类型：
--
作者：
Hendricks, Peter;Diaz, Francisco J.;Nirmalanandhan, Victor Sanjit
化疗药物的体外筛选通常在静态单层细胞培养物中进行。然而，给予患者的药物在体内存在各种微环境的情况下发挥作用。例如，在肺部肿瘤中，机械力持续存在并且确实影响肺组织对各种治疗剂的生理反应。我们假设机械力可能影响肺部肿瘤对化疗药物的反应，并在模拟条件下研究了其影响。首先，我们检查了近似正常呼吸的模拟力对 NCI-H358 和 A549 细胞系增殖和形态的影响。然后，我们研究了模拟力对紫杉醇、阿霉素、顺铂、Zactima 和实验药物在两种细胞系中诱导细胞毒性的能力的影响。在存在或不存在模拟力（20% 最大应变和 15 个循环/分钟）的情况下用药物处理细胞，这些模拟力接近人类肺的扩张和收缩。评估了细胞增殖和药物的有效性。使用标准指数细胞生长模型，确定机械力显着降低了两种细胞系的增殖。有趣的是，在 A549 细胞中，力还显着降低了除 Zactima 之外的所有药物的有效性，而在 NCI-H358 细胞中，Zactima 是唯一因施加力而显示出有效性增加的药物。我们的结果表明，机械力对细胞存活和化疗功效具有显着影响，并且可能对于设计改进的抗肿瘤药物发现筛选测定具有重要意义。
In vitro screening of chemotherapeutic agents is routinely carried out in static monolayer cell cultures. However, drugs administered to patients act in the presence of various microenvironments in vivo. For example, in lung tumors, mechanical forces are constantly present and do affect the physiological response of the lung tissue to a variety of therapeutic agents. We hypothesized that mechanical forces may affect the response of lung tumors to chemotherapeutic agents and studied the effects under simulated conditions. First, we examined the effects of simulated forces that approximate normal respiration on the proliferation and morphology of NCI-H358 and A549 cell lines. Then, we studied the effects of the simulated forces on the ability of Paclitaxel, Doxorubicin, Cisplatin, Zactima and an experimental drug to induce cytotoxicity in both cell lines. Cells were treated with the drugs in the presence or absence of simulated forces (20% maximum strain and 15 cycles/minute) that approximate human lung expansion and contraction. Cell proliferation and the effectiveness of the drugs were assessed. Using a standard exponential cell growth model, it was determined that mechanical forces significantly reduced the proliferation of both cell lines. Interestingly, forces also significantly lowered the effectiveness of all drugs except Zactima in A549 cells, while in NCI-H358 cells, Zactima was the only drug that demonstrated an increase in effectiveness owing to applied forces. Our results demonstrate that mechanical forces have significant impact on cell survival and chemotherapeutic efficacy and may be of significance in engineering improved screening assays for antitumor drug discovery.