Gurunathan Sangiliyandi, Jeyaraj Muniyandi, Kang Min-Hee, Kim Jin-Hoi
Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea.
Nanomaterials (Basel). 2019 Jul 29;9(8):1089. doi: 10.3390/nano9081089.
Osteosarcoma (OS) is the most common type of cancer and the most frequent malignant bone tumor in childhood and adolescence. Nanomedicine has become an indispensable field in biomedical and clinical research, with nanoparticles (NPs) promising to increase the therapeutic efficacy of anticancer drugs. Doxorubicin (DOX) is a commonly used chemotherapeutic drug against OS; however, it causes severe side effects that restrict its clinical applications. Here, we investigated whether combining platinum NPs (PtNPs) and DOX could increase their anticancer activity in human bone OS epithelial cells (U2OS). PtNPs with nontoxic, effective, thermally stable, and thermoplasmonic properties were synthesized and characterized using tangeretin. We examined the combined effects of PtNPs and DOX on cell viability, proliferation, and morphology, reactive oxygen species (ROS) generation, lipid peroxidation, nitric oxide, protein carbonyl content, antioxidants, mitochondrial membrane potential (MMP), adenosine tri phosphate (ATP) level, apoptotic and antiapoptotic gene expression, oxidative stress-induced DNA damage, and DNA repair genes. PtNPs and DOX significantly inhibited U2OS viability and proliferation in a dose-dependent manner, increasing lactate dehydrogenase leakage, ROS generation, and malondialdehyde, nitric oxide, and carbonylated protein levels. Mitochondrial dysfunction was confirmed by reduced MMP, decreased ATP levels, and upregulated apoptotic/downregulated antiapoptotic gene expression. Oxidative stress was a major cause of cytotoxicity and genotoxicity, confirmed by decreased levels of various antioxidants. Furthermore, PtNPs and DOX increased 8-oxo-dG and 8-oxo-G levels and induced DNA damage and repair gene expression. Combination of cisplatin and DOX potentially induce apoptosis comparable to PtNPs and DOX. To the best of our knowledge, this is the first report to describe the combined effects of PtNPs and DOX in OS.
骨肉瘤（OS）是儿童和青少年中最常见的癌症类型以及最频发的恶性骨肿瘤。纳米医学已成为生物医学和临床研究中不可或缺的领域，纳米颗粒（NPs）有望提高抗癌药物的治疗效果。阿霉素（DOX）是一种常用的抗骨肉瘤化疗药物；然而，它会引起严重的副作用，限制了其临床应用。在此，我们研究了铂纳米颗粒（PtNPs）与DOX联合使用是否能增强它们对人骨肉瘤上皮细胞（U2OS）的抗癌活性。使用陈皮素合成并表征了具有无毒、有效、热稳定和热等离子体特性的PtNPs。我们研究了PtNPs与DOX对细胞活力、增殖和形态学、活性氧（ROS）生成、脂质过氧化、一氧化氮、蛋白质羰基含量、抗氧化剂、线粒体膜电位（MMP）、三磷酸腺苷（ATP）水平、凋亡和抗凋亡基因表达、氧化应激诱导的DNA损伤以及DNA修复基因的联合作用。PtNPs和DOX以剂量依赖的方式显著抑制U2OS的活力和增殖，增加乳酸脱氢酶泄漏、ROS生成以及丙二醛、一氧化氮和羰基化蛋白质水平。线粒体功能障碍通过降低的MMP、降低的ATP水平以及上调的凋亡/下调的抗凋亡基因表达得到证实。氧化应激是细胞毒性和遗传毒性的主要原因，各种抗氧化剂水平的降低证实了这一点。此外，PtNPs和DOX增加了8-氧代脱氧鸟苷（8-oxo-dG）和8-氧代鸟嘌呤（8-oxo-G）水平，并诱导了DNA损伤和修复基因表达。顺铂与DOX联合使用可能诱导与PtNPs和DOX相当的细胞凋亡。据我们所知，这是第一份描述PtNPs与DOX在骨肉瘤中的联合作用的报告。
