Abd Al Moaty Mohamed Nabil, El Ashry El Sayed H, Awad Laila Fathy, Mostafa Asmaa, Abu-Serie Marwa M, Teleb Mohamed
Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.
Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria 21934, Egypt.
ACS Omega. 2022 Jun 7;7(24):21267-21279. doi: 10.1021/acsomega.2c02410. eCollection 2022 Jun 21.
Based on the "canonical" view of reactive oxygen species' (ROS) contribution to carcinogenesis, ROS induce oxidative stress and promote various tumor progression events. However, tumor cells also need to defend themselves against oxidative damage. This "heresy" was supported by several recent studies underlining the role of cellular antioxidant capacity in promoting metastasis and resistance to chemotherapy. Accordingly, harnessing the ROS-induced oxidative stress via selective suppression of the cancer antioxidant defense machinery has been launched as an innovative anticancer strategy. Within this approach, pharmacological inhibition of superoxide dismutases (SODs), the first-line defense antioxidant enzymes for cancer cells, selectively kills tumor cells and circumvents their acquired resistance. Various SOD inhibitors have been introduced, of which some were tolerated in clinical trials. However, the hit SOD inhibitors belong to diverse chemical classes and lack comprehensive structure-activity relationships (SAR). Herein, we probe the potential of newly synthesized benzylidene thiazolidinedione derivatives to inhibit SOD in colorectal cancer with special emphasis on their effects on correlated antioxidant enzymes aldehyde dehydrogenase 1 (ALDH1) and glutathione peroxidase (GPx). This may possibly bring a new dawn for utilizing thiazolidinediones (TZDs) in cancer therapy through SOD inhibition mechanisms. The preliminary 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that all of the evaluated TZDs exhibited excellent safety profiles on normal human cells, recording an EC100 of up to 47.5-folds higher than that of doxorubicin. Compounds , , and (IC50 = 4.4-4.7 μM) were superior to doxorubicin and other derivatives against Caco-2 colorectal cancer cells within their safe doses. The hit anticancer agents inhibited SOD (IC50 = 97.2-228.8 μM). Then, they were selected for further in-depth evaluation on the cellular level. The anticancer IC50 doses of , , and diminished the antioxidant activities of SOD (by 29.7, 70.1, and 33.3%, respectively), ALDH1A (by 85.92, 95.84, and 86.48%, respectively), and GPX (by 50.17, 87.03, and 53.28%, respectively) in the treated Caco-2 cells, elevating the Caco-2 cellular content of ROS by 21.42, 7.863, and 8.986-folds, respectively. Docking simulations were conducted to display their possible binding modes and essential structural features. Also, their physicochemical parameters and pharmacokinetic profiles formulating drug-likeness were computed.
基于活性氧（ROS）对致癌作用的“经典”观点，ROS会诱导氧化应激并促进各种肿瘤进展事件。然而，肿瘤细胞也需要保护自身免受氧化损伤。最近的几项研究支持了这种“异端”观点，这些研究强调了细胞抗氧化能力在促进转移和化疗耐药性方面的作用。因此，通过选择性抑制癌症抗氧化防御机制来利用ROS诱导的氧化应激已作为一种创新的抗癌策略被提出。在这种方法中，超氧化物歧化酶（SOD）是癌细胞的一线防御抗氧化酶，对其进行药理抑制可选择性地杀死肿瘤细胞并规避其获得性耐药性。已经引入了各种SOD抑制剂，其中一些在临床试验中是可耐受的。然而，成功的SOD抑制剂属于不同的化学类别，并且缺乏全面的构效关系（SAR）。在此，我们探究新合成的亚苄基噻唑烷二酮衍生物抑制结直肠癌中SOD的潜力，特别强调它们对相关抗氧化酶醛脱氢酶1（ALDH1）和谷胱甘肽过氧化物酶（GPx）的影响。这可能会为通过SOD抑制机制在癌症治疗中利用噻唑烷二酮（TZDs）带来新的曙光。初步的3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）试验表明，所有评估的TZDs对正常人类细胞均表现出优异的安全性，其半数有效浓度（EC100）比阿霉素高47.5倍。化合物 、 和 （半数抑制浓度（IC50）=4.4 - 4.7 μM）在其安全剂量范围内对Caco-2结直肠癌细胞的抑制作用优于阿霉素和其他衍生物。成功的抗癌药物抑制SOD（IC50 = 97.2 - 228.8 μM）。然后，选择它们在细胞水平上进行进一步深入评估。 、 和 的抗癌IC50剂量分别使处理后的Caco-2细胞中SOD的抗氧化活性降低29.7%、70.1%和33.3%，使ALDH1A的抗氧化活性分别降低85.92%、95.84%和86.48%，使GPX的抗氧化活性分别降低50.17%、87.03%和53.28%，同时分别使Caco-2细胞中的ROS细胞含量提高21.42倍、7.863倍和8.986倍。进行对接模拟以展示它们可能的结合模式和基本结构特征。此外，还计算了它们的理化参数和制定药物相似性的药代动力学特征。
