新型铂纳米簇激活 PI3K/AKT/mTOR 信号通路介导的自噬用于顺铂耐药的卵巢癌治疗,ACS Applied Materials & Interfaces

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新型铂纳米簇激活 PI3K/AKT/mTOR 信号通路介导的自噬用于顺铂耐药的卵巢癌治疗
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2022-10-19 , DOI: 10.1021/acsami.2c15143
Mengjun Zhang ₁ , Haodi Yue ₂ , Xin Huang ₃ , Jialin Wang ₄ , Zengbei Li ₃ , Xinjie Deng ₃

Affiliation

以铂类（Pt）为基础的化疗药物如顺铂是卵巢癌（OC）治疗的一线和核心选择，而顺铂耐药的患者预后较差，5年生存率较低。由纳米材料合成的化疗药物在生物医学领域显示出巨大的潜力；然而，很少讨论它们在抗 OC 方面的应用。本研究旨在阐明聚乙烯亚胺 (PEI) 笼式铂纳米簇 (Pt NCs) 对顺铂耐药 OC 的抗肿瘤作用。共聚焦显微镜的结果表明，Pt NCs 剂量依赖性地进入耐顺铂的 OC 细胞，并在细胞质和细胞核内聚集。随后，根据CCK8试验、伤口愈合试验、克隆形成试验、Transwell试验的结果，Ki-67免疫荧光检测和流式细胞仪检测，Pt NCs抑制顺铂耐药OC细胞的增殖和迁移，促进其凋亡。此外，我们通过单丹磺酰尸胺 (MDC) 染色、透射电子显微镜观察自噬超微结构、LC3-II-GFP 和 P62-GFP 腺病毒单标记免疫荧光和蛋白质印迹验证了 Pt NCs 对调节自噬的抗肿瘤作用。 ; 同时，验证了 Pt NCs 通过调节 PI3K-AKT-mTOR 信号传导调节自噬的作用。基于这些结果，当 Pt NCs 通过抑制 PI3K/AKT/mTOR 通路激活自噬时，似乎顺铂耐药的 OC 细胞会发生凋亡，

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Novel Platinum Nanoclusters Activate PI3K/AKT/mTOR Signaling Pathway-Mediated Autophagy for Cisplatin-Resistant Ovarian Cancer Therapy

Platinum (Pt)-based chemotherapy drugs such as cisplatin are the first line and core options for the treatment of ovarian cancer (OC), while cisplatin resistance has a worse prognosis and low 5 year survival rate for patients. Chemotherapeutic drugs synthesized from nanomaterials have shown great potential in biomedicine; however, research into their application for OC resistance is rarely discussed. This study is proposed to elucidate the anti-tumor effects of polyethylenimine (PEI)-caged platinum nanoclusters (Pt NCs) on cisplatin-resistant OC. The results of confocal microscopy showed that Pt NCs entered cisplatin-resistant OC cells dose-dependently and aggregated both in the cytoplasm and inside the nucleus. Subsequently, according to the results of CCK8 assay, wound healing assay, clone formation assay, Transwell assay, Ki-67 immunofluorescence assay, and flow cytometry assay, the proliferation and migration of cisplatin-resistant OC cells were inhibited by Pt NCs, as well as their apoptosis was promoted. In addition, we validated the anti-tumor effect of Pt NCs on regulating autophagy via monodansylcadaverine (MDC) staining, transmission electron microscopy observation of the autophagic ultrastructure, LC3-II-GFP and P62-GFP adenovirus single-label immunofluorescence, and western blotting; meanwhile, the role of Pt NCs in adjusting autophagy through modulation of the PI3K-AKT-mTOR signaling was verified. Based on these results, it appears that cisplatin-resistant OC cells can undergo apoptosis when Pt NCs activate autophagy by inhibiting the PI3K/AKT/mTOR pathway, exhibiting a promising potential of Pt NCs in the development of a novel chemotherapeutic agent for patients suffering from cisplatin-resistant OC.

更新日期：2022-10-19

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