Cisplatin-resistant Lung Cancer Research Articles

MiR-526b-3p inhibits lung cancer cisplatin-resistance and metastasis by inhibiting STAT3-promoted PD-L1

Chemotherapy remains the primary treatment of advanced solid cancer, including lung cancer. However, as first-line treatment, cisplatin-based therapy is restricted by the frequent development of drug resistance. Increasing data showed that the programmed cell death protein ligand 1 (PD-L1) plays a vital role in regulating cisplatin resistance. However, the underlying mechanisms are not fully understood. We found that miR-526b-3p expression declined while PD-L1 was elevated in cisplatin-resistant lung cancer compared to that in cisplatin-sensitive lung cancer by analyzing clinical samples. Significantly, miR-526b-3p was associated with response to cisplatin negatively. We further demonstrated that miR-526b-3p reversed cisplatin resistance, suppressed metastasis, and activated CD8+ T cells in a STAT3/PD-L1-dependent manner. Thus, our findings extended the knowledge of PD-L1-mediated cisplatin resistance of lung cancer. In addition, the introduction of miR-526b-3p provided a new clue to improve the anti-tumor effects of the combination of immunotherapy and chemotherapy.

KRAS and EGFR Mutations Differentially Alter ABC Drug Transporter Expression in Cisplatin-Resistant Non-Small Cell Lung Cancer.

Lung carcinoma is still the most common malignancy worldwide. One of the major subtypes of non-small cell lung cancer (NSCLC) is adenocarcinoma (AC). As driver mutations and hence therapies differ in AC subtypes, we theorized that the expression and function of ABC drug transporters important in multidrug resistance (MDR) would correlate with characteristic driver mutations KRAS or EGFR. Cisplatin resistance (CR) was generated in A549 (KRAS) and PC9 (EGFR) cell lines and gene expression was tested. In three-dimensional (3D) multicellular aggregate cultures, both ABCB1 and ABCG2 transporters, as well as the WNT microenvironment, were investigated. ABCB1 and ABCG2 gene expression levels were different in primary AC samples and correlated with specific driver mutations. The drug transporter expression pattern of parental A549 and PC9, as well as A549-CR and PC9-CR, cell lines differed. Increased mRNA levels of ABCB1 and ABCG2 were detected in A549-CR cells, compared to parental A549, while the trend observed in the case of PC9 cells was different. Dominant alterations were observed in LEF1, RHOU and DACT1 genes of the WNT signalling pathway in a mutation-dependent manner. The study confirmed that, in lung AC-s, KRAS and EGFR driver mutations differentially affect both drug transporter expression and the cisplatin-induced WNT signalling microenvironment.

Down-Regulating the Expression of miRNA-21 Inhibits the Glucose Metabolism of A549/DDP Cells and Promotes Cell Death Through the PI3K/AKT/mTOR/HIF-1α Pathway.

miRNA-21 is a single-stranded non-coding RNA that is highly expressed in a variety of tumor cells. It participates in tumor cell proliferation, metabolism, metastasis, and drug resistance. Here, we tested the potential mechanism of miRNA-21 in cisplatin-resistant non-small cell lung cancer A549/DDP (human lung adenocarcinoma drug-resistant cell line) cells. A549 and A549/DDP RNAs were sequenced to show that miRNA-21 was highly expressed in the latter, and this was verified by qRT-PCR. In addition, we found that miRNA-21 combined with cisplatin can significantly inhibit glycolysis and glycolysis rate-limiting enzyme protein expression in A549/DDP cells. We also found that miRNA-21 combined with cisplatin can promote A549/DDP cell death. Further investigations showed that miRNA-21 combined with cisplatin caused excessive inactivation of the pI3K/AKT/mTOR/HIF-1α signaling pathway in cisplatin-resistant A549/DDP cells. Hence, reduction of the expression of miRNA-21 in combination with cisplatin chemotherapy may effectively improve the therapeutic effect on patients with non-small cell lung cancer, and this may provide a theoretical basis for the treatment of this disease.

The Synthetic Capsaicin‐analog Arvanil sensitizes Cisplatin‐Resistant Human Lung Cancer Cells to the pro‐apoptotic activity of Irinotecan

Cisplatin-based combination therapy is the standard of care for the treatment of human lung cancer. Initially, cisplatin shows excellent therapeutic response but the tumor inevitably relapses (within a year) and this relapsed tumor is resistant to cisplatin. A few human lung cancers do not respond to cisplatin-based first-line chemotherapy. These patients are said to have platinum-refractory lung tumors. Patients with platinum resistant or refractory disease have very limited options, as the only standard chemotherapy with an FDA-approved drug, irinotecan has an objective response rate of approximately 3% and little or no survival benefit. Therefore, agents which improve the therapeutic response (of human lung cancers) towards irinotecan may be useful for the treatment of cisplatin-resistant human lung cancer. The nutritional compound capsaicin sensitized cisplatin-resistant H69-CPR human small cell lung cancer (SCLC) cells towards irinotecan-induced apoptosis. Arvanil is a synthetic capsaicin-analog which displays enhanced growth-suppressive activity in human SCLC. The present study aims to investigate the combinatorial apoptotic activity of arvanil and irinotecan in cisplatin-resistant lung cancer. Caspase-3 activity assays reveal that the combination of irinotecan and arvanil displayed greater apoptotic activity in H69-CPR human cisplatin-resistant SCLC cells than the drugs used alone. These experiments were repeated in a second cisplatin-resistant lung cancer cell line PC9-CDDP and similar results were obtained. Chou-Talalay isobologram analysis showed the interaction between irinotecan and arvanil is synergistic in H69-CPR and PC9-CDDP cells. The combination of arvanil/irinotecan showed a greater synergistic pro-apoptotic activity than the combination of capsaicin/irinotecan. in H69-CPR and PC9-CDDP cells. The pro-apoptotic activity of arvanil/irinotecan was mediated elevation of intracellular calcium and required the calpain pathway. Taken together, our findings pave the way for the discovery of novel combination therapies for the therapy of cisplatin-resistant human lung cancer.

Poriaic Acid Affecting Epithelial-Mesenchymal Transition and Apoptosis of A549/DDP Cells via Glycogen Synthesis Kinase-3β/Snail Signaling Pathway

Background:The paper explored the mechanism of Poriaic acid-containing serum interfering with EMT and apoptosis of A549/DDP cells. The aim is to find experimental evidence of Poriaic acid intervening cisplatin resistance in lung cancer, searching for effective targets, and to explore the mechanism of cisplatin resistance in lung cancer.Material and methods:Immunochemistry and western blotting were employed to detect the effects of Poriaic acid-containing serum on the expressions of p-GSK-3β(ser9), Snail protein and mRNA in GSK-3β/Snail signaling pathway, and the effects of Poriaic acid-containing serum on the expressions of EMT markers and related apop-totic factors.Results:The results of immunoblotting and immunocytochemistry rendered that the expressions of p-GSK-3β(ser9), Snail protein and mRNA decreased in the administration group as contrast to the blank group. As to the effect of Poriaic acid-containing serum on EMT markers, the immunoblotting results showed that the E-cadherin protein and mRNA expressions increased while the expressions of N-cadherin protein and mRNA decreased. Poriaic acid-containing serum can up-regulate the expressions of P53, Bax protein and mRNA, and down-regulate the expressions of Bcl-2 protein and mRNA.Conclusion:Poriaic acid-containing serum can affect EMT and apoptosis of A549/DDP cells by interfering with GSK-3β/Snail signaling pathway.

MicroRNA expression profiling and biomarker validation in treatment-naïve and drug resistant non-small cell lung cancer

BackgroundIn the absence of targetable mutations or immune checkpoints, cisplatin-doublet chemotherapy remains the standard of care in non-small cell lung cancer (NSCLC). Drug resistance has however become a significant clinical challenge. Exploring a role for small non-coding microRNAs (miRNA) as biomarker candidates in cisplatin resistant (CisR) lung cancer is lacking and warrants further investigation.MethodsmiRNA expression profiling was assessed in a panel of cisplatin sensitive and resistant NSCLC cell lines and validated by qPCR. Modulation of altered miRNAs was studied using antagomiRs and pre-miRs while functional assays were used to assess cisplatin response. The translational relevance of these miRNAs as potential biomarkers was assessed in serum and matched normal and tumour lung tissues from chemo-naïve NSCLC patients, in addition to xenograft formalin-fixed paraffin-embedded (FFPE) tumours derived from cisplatin sensitive and resistant cell lines.ResultsDifferential expression of a 5-miR signature (miR-30a-3p, miR-30b-5p, miR-30c-5p, miR-34a-5p, miR-4286) demonstrated their ability to distinguish between normal and tumour lung tissue and between NSCLC histologies. In squamous cell carcinoma (SqCC), tissue miRNA expression was associated with poor survival. miR-4286 showed promise as a blood-based diagnostic biomarker that could distinguish between adenocarcinoma and SqCC histologies. In a xenograft model of cisplatin resistance, using 7-9 week old female NOD/SCID mice (NOD.CB17-Prkdcscid/NCrCrl), a 5-miRNA panel showed altered expression between sensitive and resistant tumours.ConclusionsThis study identified a panel of miRNAs which may have diagnostic and prognostic potential as novel biomarkers in lung cancer and furthermore, may have a predictive role in monitoring the emergence of resistance to cisplatin.

Baicalin attenuates XRCC1-mediated DNA repair to enhance the sensitivity of lung cancer cells to cisplatin

Baicalin plays important roles in different types of cancer. A previous report showed that baicalin attenuates cisplatin resistance in lung cancer. However, its mechanism remains unclear. In this study, we investigated the effect and mechanism of baicalin on DNA repair and sensitivity of lung cancer cells to cisplatin. A549 and A549/DPP cells were treated with baicalin and cisplatin. A549/DPP cells were transfected with XRCC1 and siXRCC1. Cell viability and DNA damage were detected by MTT and comet assay. Apoptosis rate and cell cycle were detected by flow cytometry assay. The expressions of Bax, Bcl-2, and Cyclin D1 were detected by western blot. XRCC1 expression was detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. Baicalin and cisplatin decreased cell viability in A549 and A549/DPP cells in dose-dependent manner. Baicalin enhanced the effect of cisplatin on promoting apoptosis, arresting cell on S stage and triggering DNA damage accompanied with the upregulation of Bcl-2-associated X protein (Bax) and downregulation of B-cell lymphoma 2 (Bcl-2) and Cyclin D1 in A549/DPP cells. Moreover, baicalin promoted the inhibitory effect of cisplatin on XRCC1 expression in A549 and A549/DPP cells. However, the synthetic effects of baicalin and cisplatin on A549/DPP cells were partially inhibited by XRCC1 overexpression and promoted by XRCC1 knockdown. This study demonstrates that baicalin interferes with XRCC1-mediated cellar DNA repair to sensitize lung cancer cells to cisplatin.

LY6K-AS lncRNA is a lung adenocarcinoma prognostic biomarker and regulator of mitotic progression.

Recent advances in genomics unraveled several actionable mutational drivers in lung cancer, leading to promising therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors. However, the tumors' acquired resistance to the newly-developed as well as existing therapies restricts life quality improvements. Therefore, we investigated the noncoding portion of the human transcriptome in search of alternative actionable targets. We identified an antisense transcript, LY6K-AS, with elevated expression in lung adenocarcinoma (LUAD) patients, and its higher expression in LUAD patients predicts poor survival outcomes. LY6K-AS abrogation interfered with the mitotic progression of lung cancer cells resulting in unfaithful chromosomal segregation. LY6K-AS interacts with and stabilizes 14-3-3 proteins to regulate the transcription of kinetochore and mitotic checkpoint proteins. We also show that LY6K-AS regulates the levels of histone H3 lysine 4 trimethylation (H3K4me3) at the promoters of kinetochore members. Cisplatin treatment and LY6K-AS silencing affect many common pathways enriched in cell cycle-related functions. LY6K-AS silencing affects the growth of xenografts derived from wildtype and cisplatin-resistant lung cancer cells. Collectively, these data indicate that LY6K-AS silencing is a promising therapeutic option for LUAD that inhibits oncogenic mitotic progression.

Exosomes Derived From Macrophages Enhance Aerobic Glycolysis and Chemoresistance in Lung Cancer by Stabilizing c-Myc via the Inhibition of NEDD4L.

As one of the most common and lethal cancer, lung cancer severely threatens the health of human. It has been reported that tumor-associated macrophages promote initiation, progression, as well as chemoresistance in human cancers. However, the underneath molecular mechanism that drives chemoresistance in lung cancer is yet not fully characterized. In this article, we demonstrated that M2 macrophage-derived exosomes (MDE) is the key factor to promote cisplatin-resistance in lung cancer. MDE exhibited high expression level of several miRNA including miR-3679-5p. Mechanistically, miR-3679-5p was delivered to lung cancer cells by MDE, downregulating the expression of a known E3 ligase, NEDD4L, which has been identified as a key regulator controlling the stability of c-Myc. Such decreased NEDD4L expression level resulted in the stabilization of c-Myc and elevated glycolysis. The enhanced glycolysis drives the chemoresistance in lung cancer. Taken together, our findings not only show that M2 macrophage induce chemoresistance in lung cancer through MDE mediated miR-3679-5R/NEDD4L/c-Myc signaling cascade, but also shed the light on the mechanism of the cross-talk between M2 macrophage and lung cancers. By pinpointing a potential novel survival signaling pathway, our data could provide a new potential therapeutic target for lung cancer treatment and management.

Exploitation of the vitamin A/retinoic acid axis depletes ALDH1-positive cancer stem cells and re-sensitises resistant non-small cell lung cancer cells to cisplatin

Despite advances in personalised medicine and the emerging role of immune checkpoints in directing treatment decisions in subsets of lung cancer patients, non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related deaths worldwide. The development of drug resistance plays a key role in the relapse of lung cancer patients in the clinical setting, mainly due to the unlimited renewal capacity of residual cancer stem cells (CSCs) within the tumour cell population during chemotherapy. In this study, we investigated the function of the CSC marker, aldehyde dehydrogenase (ALDH1) in retinoic acid cell signalling using an in vitro model of cisplatin resistant NSCLC. The addition of key components in retinoic acid cell signalling, all-trans retinoic acid (ATRA) and retinol to cisplatin chemotherapy, significantly reduced ALDH1-positive cell subsets in cisplatin resistant NSCLC cells relative to their sensitive counterparts resulting in the re-sensitisation of chemo-resistant cells to the cytotoxic effects of cisplatin. Furthermore, combination of ATRA or retinol with cisplatin significantly inhibited cell proliferation, colony formation and increased cisplatin-induced apoptosis. This increase in apoptosis may, at least in part, be due to differential gene expression of the retinoic acid (RARα/β) and retinoid X (RXRα) nuclear receptors in cisplatin-resistant lung cancer cells. These data support the concept of exploiting the retinoic acid signalling cascade as a novel strategy in targeting subsets of CSCs in cisplatin resistant lung tumours.

SIRT3 promotion reduces resistance to cisplatin in lung cancer by modulating the FOXO3/CDT1 axis.

BackgroundCisplatin is an extensively used chemotherapy agent for lung cancer, but its drug resistance serves as a huge obstacle for chemotherapy failure of lung cancer patients. Hence, researchers aimed to determine role of sirtuin 3 (SIRT3) considering its action in cisplatin resistance of lung cancer.MethodsThe expression patterns of SIRT3, FOXO3, and CDT1 were determined using RT‐qPCR and Immunoblotting in lung cancer. Immunofluorescence and Co‐IP were adopted to detect co‐localization and interaction of FOXO3 and CDT1. Loss‐ and gain‐function assays were conducted to determine roles of SIRT3, FOXO3, and CDT1 in resulting pathological changes, while biological behavior of cells was determined using a combination of CCK‐8, flow cytometry, colony formation, and Transwell assays. The effects of SIRT3 and CDT1 were determined in the nude mice xenografted with the tumor. The proliferation‐, angiogenesis‐, and apoptosis‐associated factors levels were determined using Immunoblotting.ResultsSIRT3, FOXO3, and CDT1 expression was suppressed in the lung cancer tissues and cells. FOXO3 positively regulates the CDT1 expression pattern and SIRT3 elevation inhibits FOXO3 at the acetylated level, thus, elevating FOXO3 expression. The elevation of SIRT3, FOXO3, or CDT1 inhibited cell cisplatin resistance of lung cancer cells as well as inhibited viability, proliferation, and invasion in vitro. In vivo experiments, SIRT3 depletion elevated Ki‐67 and VEGFA levels, but downregulated cleaved caspase 3 level.ConclusionCollectively, overexpressed SIRT3 elevates expression of FOXO3a/CDT1 axis, thus, contributing to enhanced sensitivity of lung cancer cells.

Effect of Nano-Platinum on Proliferation and Apoptosis of Non-Small Cell Lung Cancer Cells via P53 Pathway.

This paper studies the non-small cell lung cancer with interventional treatment of polyethylene imine-coated platinum nanoclusters. The relationship between the inhibition of non-small cell lung cancer cell proliferation, apoptosis, and the expression of its related apoptotic protein p53. Apoptosis experiments were applied was used to detect the effect of nanoplatin on A549 cells. Western blot was used to detect the expression of p53 protein in A549 cells after nanoplatin treatment. We co-cultured nanoplatin with cells for 4 hours and performed nuclear staining. Observed by laser confocal microscopy, we found that nanoplatin can enter the nucleus and cytoplasm of non-small cell lung cancer A549 cells, and the phenomenon of drug entering the nucleus is very obvious. Treatment of non-small cell lung cancer with A549 cells at different concentrations of nanoplatin for 24 hours, with the increase of the concentration, the proliferation inhibition rate of non-small cell lung cancer gradually increased. Treatment of cisplatin-resistant non-small cell lung cancer cells with different concentrations of nanoplatin for 24 hours, as the concentration increases, the proliferation inhibition rate of non-small cell lung cancer gradually increases. After treatment of A549 cells with different concentrations of nanoplatin for 24 hours, the apoptosis rate of A549 cells gradually increased with the increase of drug concentration. Finally, we conclude that nanoplatin has not only inhibitory and pro-apoptotic effects on non-small cell lung cancer cells, but also fluorescent labeling. Compared with cisplatin, nanoplatin can significantly inhibit the proliferation of non-small cell lung cancer cells and overcome its cisplatin resistance. The p53-related signaling pathway may participate in the process of apoptosis and reverse the process of cisplatin resistance, but the specific mechanism and whether there are other signaling pathways involved Further research is needed.

Cisplatin resistance reversal in lung cancer by tumor acidity-activable vesicular nanoreactorsviatumor oxidative stress amplification

Drug resistance of cisplatin significantly limits its therapeutic efficacy in clinical applications against different cancers. Herein, we develop a novel strategy to overcome cisplatin drug resistance through sensitizing cisplatin-resistant human lung cancer cells (A549R) under amplified oxidative stress using a vesicular nanoreactor for simultaneous cisplatin delivery and H2O2 generation. We engineer the nanoreactor by the self-assembly of the amphiphilic diblock copolymers to co-deliver glucose oxidase (GOD) and cisplatin (Cis) (Cis/GOD@Bz-V). Cis/GOD@Bz-V was rationally designed to stay impermeable during blood circulation while mild acidity (pH 6.5-6.8) can activate its molecular-weight selective membrane permeability and release cisplatin locally. Diffusion of small molecules such as oxygen and glucose across the membranes can induce the in situ generation of superfluous H2O2 to promote cellular oxidative stress and sensitize A549R cells via activation of pro-apoptotic pathways. Cis/GOD@Bz-V nanoreactors could effectively kill A549R at pH 6.8 in the presence of glucose by the combination of H2O2 generation and cisplatin release. Growth of A549R xenograft tumors can be inhibited efficiently without the obvious toxic side effects via the systemic administration of Cis/GOD@Bz-V. Accordingly, the tumor acidity-activable cisplatin-loaded nanoreactors show great potential to enhance the therapeutic efficacy against cisplatin-resistant cancers.

Retraction notice to 'The miR 495-UBE2C-ABCG2/ERCC1 axis reverses cisplatin resistance by downregulating drug resistance genes in cisplatin-resistant non-small cell lung cancer cells' [EBioMedicine 35 (2018) 204-221

Retraction notice to 'The miR 495-UBE2C-ABCG2/ERCC1 axis reverses cisplatin resistance by downregulating drug resistance genes in cisplatin-resistant non-small cell lung cancer cells' [EBioMedicine 35 (2018) 204-221

LncRNA XIST acts as a MicroRNA-520 sponge to regulate the Cisplatin resistance in NSCLC cells by mediating BAX through CeRNA network.

Background: In recent years, LncRNA acts as a member of competing endogenous RNA (ceRNA), playing an important role in drug resistance of lung cancer. The aim of this study was to identify potential biomarkers about cisplatin resistant lung cancer cells using a comprehensive ceRNA network.Methods: GSE6410 (GPL-201) analyzed gene expression changes about cisplatin resistance in A549 NSCLC cells. GSE43249 (GPL-14613) included noncoding RNA expression profiling derived from the cisplatin resistant A549 lung cells. GEO2R, an online analysis tool, analyzed the differentially expressed mRNAs and miRNAs (DEmRNAs and DEmiRNAs). To explore the functional enrichment implication of differentially expressed mRNAs, we used the GO (Gene ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis. Through miRDB, Targetscan, Starbase and miRWalk, we found targeted miRNAs. The Kaplan-Meier curve method was used to show clinical survival analysis of targeted RNAs (P<0.05). The Starbase database predicted potential lncRNAs mediated targeted miRNAs. Eventually, the novel ceRNA network of lncRNAs, miRNAs, mRNA was constructed by cytoscape3.7.2.Results: 118 differentially expressed mRNAs were the basis of the mediated ceRNA network. DAVID and Kaplan-Meier picked out BAX, an apoptosis regulator. Venn diagram demonstrated 8 miRNAs commonly regulating BAX. Starbase predicted lncRNA XIST mediated miRNAs. Finally, lncRNA XIST may be a useful biomarker regulating cisplatin resistance in lung cancer cells and further, we explored the BAX may effect tumor-infiltrating immune cells.Conclusions: LncRNA XIST competitively bound to miRNA 520 in the regulation of cisplatin resistance by BAX, participating apoptosis in the p53 signaling pathway.

Unprecedented collateral sensitivity for cisplatin-resistant lung cancer cells presented by new ruthenium organometallic compounds

Ru compounds exhibit collateral sensitivity in cisplatin-resistant NSCLC and increase cisplatin activity by inhibiting efflux pumps.

Aspirin overcomes cisplatin resistance in lung cancer by inhibiting cancer cell stemness.

BackgroundLung cancer is the leading cause of cancer death and is commonly treated by cisplatin. Although cisplatin treatment may initially be successful, its effectiveness usually reduces significantly in disease‐recurrent patients. Aspirin, a nonselective COX inhibitor, has been shown to help reverse the status of cisplatin sensitivity in recurrent human ovarian cancer cells. This study aimed to explore the effect of aspirin on cisplatin resistance through the perspective of cancer cell stemness.MethodsWe used clustering analysis to predict the H460 cisplatin resistance from the GSE21656 dataset. The increased lung cancer cell stemness may contribute to enhanced tolerance. In this study, we used aspirin, a nonselective COX inhibitor, with cisplatin for several hours in cells and days in vivo, and studied the inhibition against human cisplatin‐resistant H460 cells. H460 cisplatin‐sensitive and H460 cisplatin‐resistant cells were treated with 16 μM aspirin or/and 0.3 μg/mL cisplatin for 72 hours.ResultsH460 cisplatin‐resistant cells showed stronger resistance, stemness, and invasiveness than H460 cisplatin‐sensitive, and cisplatin significantly reduced the survival of cisplatin‐sensitive cells, while cisplatin with aspirin dramatically reduced the surviving fractions of cisplatin‐resistant cells.ConclusionsThis study revealed that stemness is a latent inhibitor of the resistance of lung cancer cisplatin‐resistant cells and might be effectively inhibited by aspirin.

Protein Profiling of Extracellular Vesicles Associated With Cisplatin Resistance in Lung Cancer.

Extracellular vesicles (EVs) can mediate drug resistance within the tumor microenvironment by delivering bioactive molecules, including proteins. Here, we performed a comparative proteomic analysis of EVs secreted by A549 lung cancer cells and their cisplatin-resistant counterparts in order to identify proteins involved in drug resistance. Cells were co-cultivated using a transwell system to evaluate EV exchange. EVs were isolated by ultracentrifugation and analyzed using microscopy and nanoparticle tracking. EV proteome was analyzed by mass spectrometry. EV-mediated communication was observed between co-cultured A549 and A549/CDDP cells. EVs isolated from both cells were mainly exosome-like structures. Extracellular matrix components, cell adhesion proteins, complement factors, histones, proteasome subunits and membrane transporters were found enriched in the EVs released by cisplatin-resistant cells. Proteins identified in this work may have a relevant role in modulating the chemosensitivity of the recipient cells and could represent useful biomarkers to monitor cisplatin response in lung cancer.

Exploring the mechanism of cisplatin resistance by transcriptome sequencing and reversing the chemoresistance by autophagy inhibition in small cell lung cancer

Cisplatin plays a key role in treating small cell lung cancer (SCLC); however, the rapid development of cisplatin resistance limits its treatment effect. The detailed mechanisms of cisplatin-resistance, particularly in SCLC, remain unclear. We analyzed the differentially expressed genes (DEGs) between cisplatin-resistant small cell lung cancer cell line H446/CDDP and its parental cell line H446, using the transcriptome sequencing technique. Gene ontology (GO) analysis and the subsequent tests demonstrated that the functions of protein ubiquitination and autophagy are more active in the H446/CDDP cells. Autophagy plays a protective role in the H446/CDDP cells by using the autophagy inhibitors, 3-methyladenine and bafilomycin A1. Moreover, antimalarial drugs that inhibit autophagy by increasing the pH of lysosomes can also enhance cisplatin-induced cell death.

Increased efficacy of gefitinib on cisplatin-resistant wild-type epidermal growth factor receptor non-small cell lung cancer cells.

BackgroundGefitinib is a first-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that has become first-line treatment for patients with mutant EGFR non-small cell lung cancer (NSCLC). Despite its anti-tumor activity, the benefit of gefitinib in patients with wild-type EGFR NSCLC is debated. This work aimed to evaluate the effects of gefitinib on cisplatin-resistant wild-type EGFR NSCLC cells in in vitro and in vivo animal xenografts.MethodsWe established a cisplatin-resistant wild-type EGFR NSCLC cell line, H358R, to evaluate the cells’ sensitivity to gefitinib compared with that of parental cell line H358. We first tested the p-EGFR of gefitinib’s target in H358R and H358 cell line by western blot and immunofluorescence. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clone formation assay, flow cytometry and annexin V-fluorescein/propidium iodide staining were used to investigate cellular proliferation and apoptosis of H358R/H358 cells treated with gefitinib, and the anti-tumor effect was evaluated in female BALB/c nude mice models of xenografts in vivo.ResultsEGFR and the downstream node molecules ERK and AKT were significantly more phosphorylated in H358R than in the parental cells and were inhibited by gefitinib. In H358R cells, gefitinib increased the inhibition of cell survival/proliferation, and the promotion of apoptosis in vitro. The increased anti-tumor effect was present also in H358R xenografts in vivo.ConclusionsAbnormal activation of EGFR in H358R cells results in enhanced sensitivity to gefitinib. The improved efficacy of gefitinib on cisplatin-resistant wild-type EGFR NSCLC cells suggests that gefitinib as sequential therapy for patients with cisplatin-resistant wild-type EGFR NSCLC should be considered.