Lung cancer has second highest rate of incidence and mortality around the world. Smoking cigarettes is the main stream cause of lung carcinogenesis along with other factors such as spontaneous mutations, inactivation of tumor suppressor genes. The present study was aimed to identify the mechanistic role of Imatinib in the chemoprevention of experimental lung carcinogenesis in rat model. Gross morphological observations for tumor formation, histological examinations, RT-PCR, Western blotting, fluorescence spectroscopy and molecular docking studies were performed to elucidate the chemopreventive effects of Imatinib and support our hypothesis by various experiments. It is evident that immuno-compromised microenvironment inside solid tumors is responsible for tumor progression and drug resistance. Therefore, it is inevitable to modulate the pro-inflammatory signaling inside solid tumors to restrict neoangiogenesis. In the present study, we observed that Imatinib could downregulate the inflammatory signaling and also attributed angiostatic effects. Moreover, Imatinib also altered the biophysical properties of BAL cells such as plasma membrane potential, fluidity and microviscosity to restrict their infiltration and thereby accumulation to mount immuno-compromised environment inside the solid tumors during angiogenesis. Our molecular docking studies suggest that immunomodulatory and angiostatic properties of Imatinib could be either independent of each other or just a case of synergistic pleiotropy. Imatinib was observed to activate the intrinsic or mitochondrial pathway of apoptosis to achieve desired effects in cancer cell killings. Interestingly, binding of Imatinib inside the catalytic domain of PARP-1 also suggests that it has caspase-independent properties in promoting cancer cell deaths.

中文翻译：

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伊马替尼可调节促炎性微环境，并在实验性肺癌发生中具有血管抑制作用。

肺癌在全球范围内的发病率和死亡率第二高。吸烟与其他因素（例如自发突变，抑癌基因失活）一起是肺癌致癌的主要原因。本研究旨在确定伊马替尼在大鼠模型化学预防实验性肺致癌中的作用。进行了关于肿瘤形成的大体形态观察，组织学检查，RT-PCR，蛋白质印迹，荧光光谱和分子对接研究，以阐明伊马替尼的化学预防作用并通过各种实验支持我们的假设。显然，实体瘤内部免疫功能低下的微环境是导致肿瘤进展和耐药性的原因。因此，调节实体瘤内部的促炎信号以限制新血管生成是不可避免的。在本研究中，我们观察到伊马替尼可下调炎症信号，并归因于血管抑制作用。此外，伊马替尼还改变了BAL细胞的生物物理特性，例如质膜电位，流动性和微粘度，以限制其浸润，从而在血管生成过程中积聚，从而在实体瘤内部形成免疫受损的环境。我们的分子对接研究表明，伊马替尼的免疫调节和血管抑制特性可能彼此独立，也可能只是协同多效性的情况。观察到伊马替尼激活细胞凋亡的内在或线粒体途径，从而在杀死癌细胞中达到所需的效果。有趣的是