GLP2-GLP2R signal affects the viability and EGFR-TKIs sensitivity of PC9 and HCC827 cells

Background The resistance to epidermal growth factor receptor (EGFR)- tyrosine kinase inhibitors (TKIs) therapy is currently the major clinical challenge in the treatment of lung cancer. This study aims to reveal the role of glucagon-like peptide (GLP) 2 and GLP-2 receptor (GLP2R) signaling on the EGFR-TKIs and cisplatin resistance of lung cancer cells. Methods The common differentially expressed genes in PC9 and HCC827 cells that were individually resistant to one of the three EGFR-TKIs (dacomitinib, osimertinib and afatinib) were screened. The data were from GSE168043 and GSE163913. The expression of GLP2R in drug-resistant cells was detected by western blot. The effect of GLP2R expression down- or up-regulation on resistance to dacomitinib, osimertinib, afatinib or cisplatin was measured by CCK-8 and flow cytometry assays. The long-acting analog of GLP-2, teduglutide, treated the parental cells. Results A total of 143 common differentially expressed genes were identified. Compared with the parent cells, the GLP2R expression in drug-resistant cell lines was significantly up-regulated. The exogenous expression of GLP2R in parental cells enhanced cell viability, while knockdown of GLP2R levels in drug-resistant cell lines inhibited cell viability. In addition, teduglutide treatment also enhanced the viability of lung cancer cells. Conclusion GLP2-GLP2R signal may change the sensitivity of cells to EGFR-TKIs and cisplatin. The development of GLP-2 or GLP2R inhibitors may be beneficial to the clinical treatment of lung cancer.

Ad-VT enhances the sensitivity of chemotherapy-resistant lung adenocarcinoma cells to gemcitabine and paclitaxel in vitro and in vivo

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.

Nanophytotherapeutics for Cancer

Phytochemicals have been attributed beneficial health properties, mainly their anticancer potential. Cancer treatment seeks to shrink the tumor and kill cancer cells; however, the conventional treatment available frequently fails due to the emergence of drug-resistant cell lines. Plant-derived compounds have been studied for their potential anticancer effects or as adjuvant drug to conventional treatment. However, some of the physicochemical properties and stability characteristics of the phytocompounds generate biopharmaceuticals difficulties that limit their efficacy and clinical applications in oncology. In this sense, nanomedicine offers an alternative for the development of biocompatible, biodegradable, safe, and efficacy phytoformulations. Nanostructured delivery systems show immense potential in the bioavailability of phytodrugs by providing better alternatives to conventional dosage forms, through improving physicochemical and biopharmaceutical properties of the phytocompounds and along with it to enhance the therapeutic efficacy.

Nanozyme-Natural Enzymes Cascade Catalyze Cholesterol Consumption and Reverse Cancer Multidrug Resistance

Multidrug resistance is still a major obstacle to cancer treatment. The most studies are to inhibit the activity of the drug transporter P-glycoprotein (P-gp), but the effect is not ideal. Herein, a nanosystem was built based on cascade catalytic consumption of cholesterol. Cholesterol oxidase (natural enzyme, COD) was immobilized on the carrier (NH2-MIL-88B, MOF) through amide reaction, COD catalyzed the consumption of cholesterol, the reaction product H2O2 was further produced by the MOF with its peroxidase-like activity to produce hydroxyl radicals (•OH) with killing effect. Due to the high expression of CD44 receptor on the surface of tumor cells, we encapsulated chondroitin sulfate gel shell (CS-shell) with CD44 targeting and apoptosis promoting effect on the surface of DOX@MOF-COD nanoparticles, which can accurately and efficiently deliver the drugs to the tumor site and improve the effect of reversing drug resistance. Taking drug-resistant cell membrane as "breakthrough", this paper will provide a new idea for reversing multidrug resistance of tumor.

Exosomal miR-331 from Chemoresistant Osteosarcoma Cells induced Chemoresistance through Autophagy

BackgroundOsteosarcoma (OS) is a highly malignant tumor. Improving chemotherapeutic resistance is very important to improve the survival rate of OS. Exosomes and microRNAs (MiRNA) play important roles in the mechanism of chemotherapeutic resistance transmission. More and more researches focus the mechanism of miRNAs carried by exosomes in the transmission of chemotherapeutic resistance of OS. This study focused on exploring the mechanism of exosomal miR-331 in the transmission of chemoresistance in OS.MethodsWe cultured OS drug-resistant cells and extracted exosomes of these cells. The secretion and uptake of exosomes in OS drug-resistant cells and OS cells (OSCs) were confirmed by fluorescence tracking assay and transwell experiments. The differential expression of microRNA-331 (miR-331) in exosomes of OS resistant and OS cells was investigated by RT-PCR. The effects of drug-resistant exosomes on proliferation and migration of OS cells were determined by MTT assay and scratches assay. MDC staining, RT-PCR, and Western blot were used to detect the role of autophagy which regulated by drug-resistant cell-derived exosom-miR-331.ResultsWe found that the expression difference of miR-331 between MG63/CDDP and MG63 was the most significant. Drug resistant OSCs secreted exosomes and were ingested by OSCs, which then promoted OSCs to acquire drug resistance. In addition, exosomes secreted by drug-resistant OSCs promote drug resistance by carrying miRNAs. Interestingly, inhibition of miRNA resulted in reduced drug resistance transmission of exosomes. Finally, we found that the exosomes secreted by drug-resistant OSCs could induce autophagy of OSCs by carrying miR-331, thus making OSCs acquire drug resistance. Inhibition of miR-331 can effectively improve drug resistance of OSCs.ConclusionsChemoresistant OSCs-derived exosomes promote the transmission of drug resistance by carrying miR-331 and inducing autophagy. Inhibition of miR-331 could effectively alleviate drug resistance of OSCs.

Exosomal miR-331 from Chemoresistant Osteosarcoma Cells Induced Chemoresistance Through Autophagy

Background Osteosarcoma (OS) is a highly malignant tumor. Improving chemotherapeutic resistance is very important to improve the survival rate of OS. Exosomes and microRNAs (MiRNA) play important roles in the mechanism of chemotherapeutic resistance transmission. More and more researches focus the mechanism of miRNAs carried by exosomes in the transmission of chemotherapeutic resistance of OS. This study focused on exploring the mechanism of exosomal miR-331 in the transmission of chemoresistance in OS. Methods We cultured OS drug-resistant cells and extracted exosomes of these cells. The secretion and uptake of exosomes in OS drug-resistant cells and OS cells (OSCs) were confirmed by fluorescence tracking assay and transwell experiments. The differential expression of microRNA-331 (miR-331) in exosomes of OS resistant and OS cells was investigated by RT-PCR. The effects of drug-resistant exosomes on proliferation and migration of OS cells were determined by MTT assay and scratches assay. MDC staining, RT-PCR, and Western blot were used to detect the role of autophagy which regulated by drug-resistant cell-derived exosom-miR-331. Results We found that the expression difference of miR-331 between drug-resistant cells of MG63 and HOS cell lines and tumor cells was the most significant. Drug resistant OSCs secreted exosomes and were ingested by OSCs, which then promoted OSCs to acquire drug resistance. In addition, exosomes secreted by drug-resistant OSCs promote drug resistance by carrying miRNAs. Interestingly, inhibition of miRNA resulted in reduced drug resistance transmission of exosomes. Finally, we found that the exosomes secreted by drug-resistant OSCs could induce autophagy of OSCs by carrying miR-331, thus making OSCs acquire drug resistance. Inhibition of miR-331 can effectively improve drug resistance of OSCs. Conclusions Chemoresistant OSCs-derived exosomes promote the transmission of drug resistance by carrying miR-331 and inducing autophagy. Inhibition of miR-331 could effectively alleviate drug resistance of OSCs.

Drug-resistant cancer cell-derived exosomal EphA2 promotes breast cancer metastasis via the EphA2-Ephrin A1 reverse signaling

Tumor metastasis induced by drug resistance is a major challenge in successful cancer treatment. Nevertheless, the mechanisms underlying the pro-invasive and metastatic ability of drug resistance remain elusive. Exosome-mediated intercellular communications between cancer cells and stromal cells in tumor microenvironment are required for cancer initiation and progression. Recent reports have shown that communications between cancer cells also promote tumor aggression. However, little attention has been regarded on this aspect. Herein, we demonstrated that drug-resistant cell-derived exosomes promoted the invasion of sensitive breast cancer cells. Quantitative proteomic analysis showed that EphA2 was rich in exosomes from drug-resistant cells. Exosomal EphA2 conferred the invasive/metastatic phenotype transfer from drug-resistant cells to sensitive cells. Moreover, exosomal EphA2 activated ERK1/2 signaling through the ligand Ephrin A1-dependent reverse pathway rather than the forward pathway, thereby promoting breast cancer progression. Our findings indicate the key functional role of exosomal EphA2 in the transmission of aggressive phenotype between cancer cells that do not rely on direct cell–cell contact. Our study also suggests that the increase of EphA2 in drug-resistant cell-derived exosomes may be an important mechanism of chemotherapy/drug resistance-induced breast cancer progression.