Abstract
BackgroundLung cancer is one of the important health threats worldwide, of which 5-year survival rate is less than 15%. Non-small-cell lung cancer (NSCLC) accounts for about 80% of all lung cancer with high metastasis and mortality.MethodsCisplatin loaded multiwalled carbon nanotubes (Pt-MWNTS) were synthesized and used to evaluate the anticancer effect in our study. The NSCLC cell lines A549 (cisplatin sensitive) and A549/DDP (cisplatin resistant) were used in our in vitro assays. MTT was used to determine Cancer cells viability and invasion were measured by MTT assay and Transwell assay, respectively. Apoptosis and epithelial-mesenchymal transition related marker proteins were measured by western blot. The in vivo anti-cancer effect of Pt-MWNTs were performed in male BALB/c nude mice (4-week old).ResultsPt-MWNTS were synthesized and characterized by X-ray diffraction, Raman, FT-IR spectroscopy and scan electron microscopy. No significant cytotoxicity of MWNTS was detected in both A549/DDP and A549 cell lines. However, Pt-MWNTS showed a stronger inhibition effect on cell growth than free cisplatin, especially on A549/DDP. We found Pt-MWNTS showed higher intracellular accumulation of cisplatin in A549/DDP cells than free cisplatin and resulted in enhanced the percent of apoptotic cells. Western blot showed that application of Pt-MWNTS can significantly upregulate the expression level of Bax, Bim, Bid, Caspase-3 and Caspase-9 while downregulate the expression level of Bcl-2, compared with free cisplatin. Moreover, the expression level of mesenchymal markers like Vimentin and N-cadherin was more efficiently reduced by Pt-MWNTS treatment in A549/DDP cells than free cisplatin. In vivo study in nude mice proved that Pt-MWNTS more effectively inhibited tumorigenesis compared with cisplatin, although both of them had no significant effect on body weight.ConclusionPt-MWNT reverses the drug resistance in the A549/DDP cell line, underlying its possibility of treating NSCLC with cisplatin resistance.
Highlights
Carbonbased materials including multiwall carbon nanotubes (MWCNTs) recently have attracted significant attention in a series of reports concerning their potential use in cancer treatment [32, 33]
We found that cisplatin-resistant lung adenocarcinoma cell line (A549/DDP) show enhanced migration and invasion ability than A549, and Pt-MWNTS could significantly inhibit its migration and invasion ability (Fig. 5a, b)
We found that application of Pt- MWNTS can significantly promote the apoptosis of human cisplatin-resistant lung adenocarcinoma cell line A549/DDP and inhibit the expression of epithelial-mesenchymal transition (EMT) marker proteins and downstream transcription factors, and suppress the migration and invasion ability of cancer cells in vitro
Summary
Lung cancer is one of the important health threats worldwide, of which 5-year survival rate is less than 15%. Non-small-cell lung cancer (NSCLC) accounts for about 80% of all lung cancer with high metastasis and mortality. Cisplatin is one of the chemotherapeutic drugs widely used in clinic. It has shown anticancer activity in a variety of tumors including cancers of the ovaries, lung, and solid tumors of the head and neck [8,9,10]. The sensitivity of tumor cells to cisplatin will be significantly reduced after long-term use, resulting in acquired drug resistance [11]. Dysregulation of primary transporters were responsible for cisplatin resistance by influencing platinum cell accumulation [12,13,14,15]. Decreased apoptosis and increased autophagy responsible for platinum-resistant, since platinum-resistant tumor cells usually have a lower level of apoptosis induction and increased autophagy [20,21,22,23]
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