Abstract
SummaryBackground One of the main challenges in the clinical treatment of lung cancer is resistance to chemotherapeutic drugs. P-glycoprotein (P-gp)-mediated drug resistance is the main obstacle to successfully implementing microtubule-targeted tumor chemotherapy. Purpose In this study, we explored the effect of Ad-hTERTp-E1a-Apoptin (Ad-VT) on drug-resistant cell lines and the molecular mechanism by which Ad-VT combined with chemotherapy affects drug-resistant cells and parental cells. Methods In vitro, cell proliferation, colony formation, resistance index (RI), apoptosis and autophagy assays were performed. Protein expression was analyzed by Western blotting. Finally, a xenograft tumor model in nude mice was used to detect tumor growth and evaluate histological characteristics. Results Our results showed that Ad-VT had an obvious killing effect on A549, A549/GEM and A549/Paclitaxel cancer cells, and the sensitivity of drug-resistant cell lines to Ad-VT was significantly higher than that of parental A549 cells. Compared with A549 cells, A549/GEM and A549/Paclitaxel cells had higher autophagy levels and higher viral replication ability. Ad-VT decreased the levels of p-PI3k, p-Akt and p-mTOR and the expression of P-gp. In vivo, Ad-VT combined with chemotherapy can effectively inhibit the growth of chemotherapy-resistant tumors and prolong the survival of mice. Conclusions Thus, the combination of Ad-VT and chemotherapeutic drugs will be a promising strategy to overcome chemoresistance.
Highlights
Lung cancer is one of the most common malignant tumors the worldwide
Primary antibodies against p-mTOR, mTOR, p-AKT, AKT, p-PI3K, PI3K, multidrug resistance gene 1 (MDR1), cleaved caspase-3, Beclin-1, LC3A/B and GAPDH were purchased from Cell Signaling Technology, Inc
The results showed that the expression levels of the autophagy-related proteins ATG5, Beclin1, p-mTOR and LC3B in A549/GEM cells were significantly higher than those in A549 cells (Fig. 4a), and the expression trend in A549/Paclitaxel cells was similar to that in A549/GEM cells
Summary
Lung cancer is one of the most common malignant tumors the worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers and causes 1.7 million deaths worldwide annually. Lung cancer is the leading cause of cancer-related death primarily due to drug resistance, which has always been a major obstacle to successful cancer treatment. The vast majority of patients will gradually develop drug resistance to chemotherapy or targeted drugs even if they show a good initial response [1]. Multidrug efflux is one of the most important mechanisms of chemotherapy resistance and functions by exporting chemotherapeutic drugs from cells, protecting them from their antitumor activities [2, 3]. P-glycoprotein (P-gp) is a typical multidrug resistance (MDR) protein that can reduce the intracellular
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