Department of Biophysics, Panjab University, Chandigarh, 160014, India.
Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90027, USA.
Inflammopharmacology. 2020 Feb;28(1):231-252. doi: 10.1007/s10787-019-00656-8. Epub 2019 Nov 1.
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.
肺癌是全球发病率和死亡率第二高的癌症。吸烟是肺癌发生的主要原因，其他因素如自发性突变、肿瘤抑制基因失活等也与之相关。本研究旨在确定伊马替尼在大鼠实验性肺癌发生中的化学预防作用的机制。通过大体形态观察肿瘤形成、组织学检查、RT-PCR、Western blot、荧光光谱和分子对接研究，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。很明显，实体瘤内免疫抑制的微环境是肿瘤进展和耐药的原因。因此，调节实体瘤内的促炎信号以限制新生血管形成是不可避免的。在本研究中，我们观察到伊马替尼可以下调炎症信号，并具有血管生成抑制作用。此外，伊马替尼还改变了 BAL 细胞的生物物理特性，如质膜电位、流动性和微粘度，以限制它们的浸润和积累，从而在血管生成过程中在实体瘤内形成免疫抑制环境。我们的分子对接研究表明，伊马替尼的免疫调节和血管生成抑制特性可能相互独立，或者只是协同多效性的情况。伊马替尼被观察到激活内在或线粒体凋亡途径，以在癌细胞杀伤中达到预期效果。有趣的是，伊马替尼在 PARP-1 的催化结构域内的结合也表明它在促进癌细胞死亡方面具有 caspase 非依赖性特性。
