Anatomy, Section of Medicine, Faculty of Science and Medicine, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland.
Department of Chemistry, Faculty of Science and Medicine, University of Fribourg, Chemin du Musee 9, CH-1700 Fribourg, Switzerland.
Int J Mol Sci. 2022 Apr 2;23(7):3963. doi: 10.3390/ijms23073963.
Malignant mesothelioma (MM) is a currently incurable, aggressive cancer derived from mesothelial cells, most often resulting from asbestos exposure. The current first-line treatment in unresectable MM is cisplatin/pemetrexed, which shows very little long-term effectiveness, necessitating research for novel therapeutic interventions. The existing chemotherapies often act on the cytoskeleton, including actin filaments and microtubules, but recent advances indicate the 'fourth' form consisting of the family of septins, representing a novel target. The septin inhibitor forchlorfenuron (FCF) and FCF analogs inhibit MM cell growth in vitro, but at concentrations which are too high for clinical applications. Based on the reported requirement of the chloride group in the 2-position of the pyridine ring of FCF for MM cell growth inhibition and cytotoxicity, we systematically investigated the importance (cell growth-inhibiting capacity) of the halogen atoms fluorine, chlorine, bromine and iodine in the 2- or 3-position of the pyridine ring. The MM cell lines ZL55, MSTO-211H, and SPC212, and-as a control-immortalized Met-5A mesothelial cells were used. The potency of the various halogen substitutions in FCF was mostly correlated with the atom size (covalent radius); the small fluoride analogs showed the least effect, while the largest one (iodide) most strongly decreased the MTT signals, in particular in MM cells derived from epithelioid MM. In the latter, the strongest effects in vitro were exerted by the 2-iodo and, unexpectedly, the 2-trifluoromethyl (2-CF) FCF analogs, which were further tested in vivo in mice. However, FCF-2-I and, more strongly, FCF-2-CF caused rapidly occurring strong symptoms of systemic toxicity at doses lower than those previously obtained with FCF. Thus, we investigated the effectiveness of FCF (and selected analogs) in vitro in MM cells which were first exposed to cisplatin. The slowly appearing population of cisplatin-resistant cells was still susceptible to the growth-inhibiting/cytotoxic effect of FCF and its analogs, indicating that cisplatin and FCF target non-converging pathways in MM cells. Thus, a combination therapy of cisplatin and FCF (analogs) might represent a new avenue for the treatment of repopulating chemo-resistant MM cells in this currently untreatable cancer.
恶性间皮瘤 (MM) 是一种目前无法治愈的侵袭性癌症，源自间皮细胞，最常见的病因是石棉暴露。不可切除的 MM 的当前一线治疗是顺铂/培美曲塞，其显示出非常低的长期有效性，因此需要研究新的治疗干预措施。现有的化疗药物通常作用于细胞骨架，包括肌动蛋白丝和微管，但最近的进展表明，由 septin 家族组成的“第四种形式”代表了一个新的靶点。septin 抑制剂氟氯苯脲 (FCF) 和 FCF 类似物在体外抑制 MM 细胞生长，但浓度太高，无法用于临床应用。基于报告中 FCF 吡啶环 2-位上的氯原子对 MM 细胞生长抑制和细胞毒性的要求，我们系统地研究了吡啶环 2-或 3-位上的氟、氯、溴和碘等卤素原子的重要性（细胞生长抑制能力）。使用 MM 细胞系 ZL55、MSTO-211H 和 SPC212，以及作为对照的永生化 Met-5A 间皮细胞。各种 FCF 卤代物的效力主要与原子大小（共价半径）相关；较小的氟化物类似物的作用最小，而最大的（碘化物）则最强地降低 MTT 信号，特别是在源自上皮性 MM 的 MM 细胞中。在后者中，2-碘和出乎意料的 2-三氟甲基（2-CF）FCF 类似物在体外表现出最强的作用，进一步在小鼠体内进行了测试。然而，FCF-2-I 和更强烈的 FCF-2-CF 在低于以前用 FCF 获得的剂量下，会迅速引起全身性毒性的强烈症状。因此，我们研究了 FCF（和选定的类似物）在体外对最初暴露于顺铂的 MM 细胞的有效性。缓慢出现的顺铂耐药细胞群体仍然易受 FCF 及其类似物的生长抑制/细胞毒性作用的影响，表明顺铂和 FCF 靶向 MM 细胞中不同的途径。因此，顺铂和 FCF（类似物）的联合治疗可能为治疗这种目前无法治疗的癌症中再增殖的化疗耐药 MM 细胞提供新途径。
