Inner Mongolia University Research Center for Glycochemistry of Characteristic Medicinal Resources, Department of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010021, People's Republic of China.
Institute of Integrative Biosciences, CECOS University of IT and Emerging Sciences, Peshawar, KPK, Pakistan; Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, People's Republic of China.
Eur J Med Chem. 2022 Jan 5;227:113920. doi: 10.1016/j.ejmech.2021.113920. Epub 2021 Oct 14.
Cancer is one of the most aggressive diseases with poor prognosis and survival rates. Lipids biogenesis play key role in cancer progression, metastasis and tumor development. Suppression of SREBP-mediated lipid biogenesis pathway has been linked with cancer inhibition. Platinum complexes bearing good anticancer effect and multiple genes activation properties are considered important and increase the chances for development of new platinum-based drugs. In this study, we synthesized pyridine co-ligand functionalized cationic complexes and characterized them using multiple spectroscopic and spectrophotometric methods. Two of these complexes were studied in solid state by single crystal X-ray analysis. The stability of these complexes were measured in solution state using H NMR methods. These complexes were further investigated for their anticancer activity against human breast, lung and liver cancer cells. MTT assay showed potential cytotoxic activity in dose-dependent manner and decrease survival rates of cancer cells was observed upon treatment with these complexes. Biological assays results revealed higher cytotoxicity as compared to cisplatin and oxaliplatin. Further we studied C2, C6 and C8 in detailed mechanistic anticancer analyses. Clonogenic assay showed decrease survival of MCF-7, HepG2 and A549 cancer cells treated with C2, C6 and C8 as compared to control cells treated with DMSO. TUNEL assay showed more cell death, these complexes suppressed invasion and migration ability of cancer cells and decreased tumor spheroids formation, thus suggesting a potential role in inhibition of cancer metastasis and cancer stem cells formation. Mechanistically, these complexes inhibited sterol regulatory element-binding protein 1 (SREBP-1) expression in cancer cells in dose-dependent manner and thereby reduced lipid biogenesis to suppress cancer progression. Furthermore, expression level was decreased for the key genes LDLR, FASN and HMGCR, those required for sterol biosynthesis. Taken together, these complexes suppressed cancer cell growth, migration, invasion and spheroids formation by inhibiting SREBP-1 mediated lipid biogenesis pathway.
癌症是预后和生存率最差的最具侵袭性的疾病之一。脂类生物发生在癌症进展、转移和肿瘤发展中起着关键作用。抑制 SREBP 介导的脂类生物发生途径与癌症抑制有关。具有良好抗癌作用和多种基因激活特性的铂配合物被认为是重要的，并增加了开发新的基于铂的药物的机会。在这项研究中，我们合成了吡啶共配体功能化的阳离子配合物，并使用多种光谱和分光光度法对其进行了表征。其中两种配合物通过单晶 X 射线分析在固态下进行了研究。使用 H NMR 方法在溶液状态下测量了这些配合物的稳定性。进一步研究了这些配合物对人乳腺癌、肺癌和肝癌细胞的抗癌活性。MTT 测定法显示出剂量依赖性的潜在细胞毒性活性，并观察到用这些配合物处理后癌细胞的存活率降低。生物测定结果显示，与顺铂和奥沙利铂相比，这些配合物具有更高的细胞毒性。进一步我们详细研究了 C2、C6 和 C8 的抗肿瘤机制。集落形成实验显示，与用 DMSO 处理的对照细胞相比，C2、C6 和 C8 处理的 MCF-7、HepG2 和 A549 癌细胞的存活率降低。TUNEL 分析显示更多的细胞死亡，这些配合物抑制了癌细胞的侵袭和迁移能力，并减少了肿瘤球体的形成，因此提示其在抑制癌症转移和癌症干细胞形成方面具有潜在作用。从机制上讲，这些配合物以剂量依赖性方式抑制癌细胞中固醇调节元件结合蛋白 1 (SREBP-1)的表达，从而减少脂质生物发生以抑制癌症进展。此外，关键基因 LDLR、FASN 和 HMGCR 的表达水平降低，这些基因是固醇生物合成所必需的。综上所述，这些配合物通过抑制 SREBP-1 介导的脂类生物发生途径抑制癌细胞生长、迁移、侵袭和球体形成。
