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

Abstract

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.

• Authors: Mengjun Zhang, Haodi Yue, Xin Huang, Jialin Wang, Zengbei Li, Xinjie Deng
• Journal: ACS applied materials & interfaces (ACS Appl Mater Interfaces) Vol. 14 Issue 43 Pg. 48502-48514 (Nov 02 2022) ISSN: 1944-8252 [Electronic] United States
• PMID: 36261925 (Publication Type: Journal Article)

Chemical References

• Cisplatin
• Proto-Oncogene Proteins c-akt
• Phosphatidylinositol 3-Kinases
• Platinum
• TOR Serine-Threonine Kinases
• Antineoplastic Agents
• MTOR protein, human

Topics

• Humans
• Female
• Cisplatin (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Platinum (pharmacology)
• Cell Line, Tumor
• Cell Proliferation
• TOR Serine-Threonine Kinases (metabolism)
• Autophagy
• Signal Transduction
• Ovarian Neoplasms (drug therapy)
• Antineoplastic Agents (pharmacology)