Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
Department of Medical Laboratory Sciencess, Catastega Institue of Medical Sciences, Mashhad, Iran.
Eur J Pharmacol. 2023 Oct 15;957:175991. doi: 10.1016/j.ejphar.2023.175991. Epub 2023 Aug 22.
The use of repurposing drugs that may have neoplastic and anticancer effects increases the efficiency and decrease resistance to chemotherapy drugs through a biochemical and mechanical transduction mechanisms through modulation of fibroblast/fibrosis remodeling in tumor microenvironment (TME). Interestingly, fibroblast/fibrosis remodeling plays a vital role in mediating cancer metastasis and drug resistance after immune chemotherapy. The most essential hypothesis for induction of chemo-immunotherapy resistance is via activation of fibroblast/fibrosis remodeling and preventing the infiltration of T cells after is mainly due to the interference between cytoskeleton, mechanical, biochemical, metabolic, vascular, and remodeling signaling pathways in TME. The structural components of the tumor that can be targeted in the fibroblast/fibrosis remodeling include the depletion of the TME components, targeting the cancer-associated fibroblasts and tumor associated macrophages, alleviating the mechanical stress within the ECM, and normalizing the blood vessels. It has also been found that during immune-chemotherapy, TME injury and fibroblast/fibrosis remodeling causes the up-regulation of inhibitory signals and down-regulation of activated signals, which results in immune escape or chemo-resistance of the tumor. In this regard, repurposing or neo-adjuvant drugs with various transduction signaling mechanisms, including anti-fibrotic effects, are used to target the TME and fibroblast/fibrosis signaling pathway such as angiotensin 2, transforming growth factor-beta, physical barriers of the TME, cytokines and metabolic factors which finally led to the reverse of the chemo-resistance. Consistent to many repurposing drugs such as pirfenidone, metformin, losartan, tranilast, dexamethasone and pentoxifylline are used to decrease immune-suppression by abrogation of TME inhibitory signal that stimulates the immune system and increases efficiency and reduces resistance to chemotherapy drugs. To overcome immunosuppression based on fibroblast/fibrosis remodeling, in this review, we focus on inhibitory signal transduction, which is the physical barrier, alleviates mechanical stress and prevents mechano-metabolic activation.
重新利用可能具有肿瘤和抗癌作用的药物可以通过调节肿瘤微环境 (TME) 中的成纤维细胞/纤维化重塑来提高化疗药物的效率并降低其耐药性，其通过生化和机械转导机制实现。有趣的是，成纤维细胞/纤维化重塑在介导免疫化疗后的癌症转移和耐药性方面起着至关重要的作用。诱导化疗免疫耐药性的最基本假设是通过激活成纤维细胞/纤维化重塑和防止 T 细胞浸润来实现的，主要是由于 TME 中的细胞骨架、机械、生化、代谢、血管和重塑信号通路之间的干扰。在成纤维细胞/纤维化重塑中可以靶向的肿瘤结构成分包括耗尽 TME 成分、靶向癌症相关成纤维细胞和肿瘤相关巨噬细胞、减轻细胞外基质内的机械应力以及使血管正常化。还发现，在免疫化疗期间，TME 损伤和成纤维细胞/纤维化重塑会导致抑制信号上调和激活信号下调，从而导致肿瘤免疫逃逸或化疗耐药。在这方面，重新利用或新辅助药物具有各种转导信号机制，包括抗纤维化作用，用于靶向 TME 和成纤维细胞/纤维化信号通路，如血管紧张素 2、转化生长因子-β、TME 的物理屏障、细胞因子和代谢因子，最终导致化疗耐药性的逆转。与许多重新利用的药物（如吡非尼酮、二甲双胍、氯沙坦、曲尼司特、地塞米松和己酮可可碱）一样，这些药物通过阻断刺激免疫系统并提高化疗药物效率和降低耐药性的 TME 抑制信号来减少免疫抑制作用。为了克服基于成纤维细胞/纤维化重塑的免疫抑制，在这篇综述中，我们重点关注抑制信号转导，这是一种物理屏障，可以减轻机械应激并防止机械代谢激活。
