Chemico-Biological Interactions ( IF 4.7 ) Pub Date : 2020-11-25 , DOI: 10.1016/j.cbi.2020.109326 Marina Petrenko 1 , Antje Güttler 1 , Anne Funtan 2 , Jacqueline Keßler 1 , Daniel Emmerich 2 , Reinhard Paschke 2 , Dirk Vordermark 1 , Matthias Bache 1
Hypoxia plays a key role in tumor progression and resistance to radiotherapy. Expression of the transmembrane-tethered enzyme carbonic anhydrase IX (CA IX) is strongly induced by hypoxia. High CA IX expression levels correlate with poor prognosis in cancer patients. Previously, we showed that the downregulation of CA IX expression by siRNA interference and the inhibition of CA IX activity results in increased cytotoxicity, inhibition of migration and radiosensitization of hypoxic cancer cells. Betulinic acid (BA) is a natural compound derived from birch bark. It has shown promising anti-tumor effects due to its cancer cell specific cytotoxic properties. We have shown that BA inhibits the HIF-1α pathway, resulting in apoptosis, inhibition of migration and enhanced cytotoxicity of breast cancer cells. In this study, we investigate the effects of the novel betulin derivative 3-O-acetylbetulin (3-AC) and carbonic anhydrase inhibitors (CAI) octyl disulfamate (OCT) or 4-(3-[4-fluorophenyl]ureido)benzenesulfonamide (SLC-0111), on cellular and radiobiological parameters in MDA-MB-231 and MCF-7 cells. Treatment with 3-AC or OCT alone only caused moderate cytotoxicity, reduction in cell migration, ROS production and DNA damage. However, the combined treatment with 3-AC and CAI strongly enhanced radiosensitivity, increased cytotoxicity, inhibited cell motility and enhanced DNA damage. Our findings suggest that the combination of two bioactive drugs 3-AC and a CAI, such as OCT or SLC-0111, could be a promising therapeutic approach for targeting hypoxic tumor cells.
中文翻译:
3-O-乙酰桦木醇联合治疗和碳酸酐酶 IX 抑制可对人乳腺癌细胞产生累加效应
缺氧在肿瘤进展和放疗抵抗中起着关键作用。缺氧会强烈诱导跨膜酶碳酸酐酶 IX (CA IX) 的表达。 CA IX 高表达水平与癌症患者的不良预后相关。此前,我们发现,通过siRNA干扰下调CA IX表达并抑制CA IX活性会导致缺氧癌细胞的细胞毒性增加、迁移抑制和放射增敏。桦木酸 (BA) 是从桦树皮中提取的天然化合物。由于其癌细胞特异性的细胞毒特性,它显示出有希望的抗肿瘤作用。我们已经证明 BA 抑制 HIF-1α 通路,导致乳腺癌细胞凋亡、抑制迁移并增强细胞毒性。在这项研究中,我们研究了新型桦木醇衍生物 3- O-乙酰桦木醇 (3-AC) 和碳酸酐酶抑制剂 (CAI) 二氨基磺酸辛酯 (OCT) 或 4-(3-[4-氟苯基]脲基)苯磺酰胺的作用。 SLC-0111),关于 MDA-MB-231 和 MCF-7 细胞的细胞和放射生物学参数。单独使用 3-AC 或 OCT 治疗仅引起中度细胞毒性、细胞迁移、ROS 产生和 DNA 损伤减少。然而,3-AC 和 CAI 的联合治疗强烈增强了放射敏感性,增加了细胞毒性,抑制了细胞运动并增强了 DNA 损伤。我们的研究结果表明,两种生物活性药物 3-AC 和 CAI(例如 OCT 或 SLC-0111)的组合可能是针对缺氧肿瘤细胞的一种有前途的治疗方法。