Lung Cancer Cell Line NCI-H460 Research Articles

COX-2/PTGS2-targeted herbal-derived oligonucleotide drug HQi-sRNA-2 was effective in spontaneous mouse lung cancer model.

In 2020, the number of deaths caused by lung cancer worldwide reached 1,796,144, making it the leading cause of cancer-related deaths. Cyclooxygenase-2/prostaglandin endoperoxide synthase 2 (COX-2/PTGS2) is overexpressed in lung cancer, which promotes tumor proliferation, invasion, angiogenesis, and resistance to apoptosis. Here, we report that the oligonucleotide drug HQi-sRNA-2 from Traditional Chinese Medicine Huangqin targeting COX-2/PTGS2 significantly inhibited proliferation, migration, and invasion and induced apoptosis in the human lung cancer cell line NCI-H460. Oral delivery of HQi-sRNA-2 bencaosomes prolonged survival, reduced tumor burden, and maintained weight in a spontaneous mouse lung cancer model. Compared with paclitaxel, HQi-sRNA-2 may be less toxic and have approximately equal efficacy in reducing tumor burden. Our previous studies reported that herbal small RNAs (sRNAs) are functional medical components. Our data suggest that sphingosine (d18:1)-HQi-sRNA-2 bencaosomes, targeting COX-2/PTGS2 and downregulating the PI3K and AKT signaling pathways, may provide novel therapeutics for lung cancer.

Design, synthesis, and structure-activity relationship study of novel plinabulin derivatives as anti-tumor agents based on the co-crystal structure.

Plinabulin, a 2, 5-diketopiperazine-type tubulin inhibitor derived from marine natural products, is currently undergoing Phase III clinical trials for the treatment of non-small cell lung cancer (NSCLC) and chemotherapy-induced neutropenia (CIN). To obtain novel 2, 5-diketopiperazine derivatives with higher biological activity, we designed and synthesized two series of 37 plinabulin derivatives at the C-ring, based on the co-crystal structure of compound 1 and tubulin. Their structures were characterized using NMR and HRMS. All compounds were screened in vitro using the lung cancer cell line NCI-H460 using the MTT method, and the compounds with better activity were further screened in BxPC-3 and HT-29 cells. The compounds 16c (IC50 = 2.0, NCI-H460; IC50 = 1.2 nM, BxPC-3; IC50 = 1.97 nM, HT-29) and 26r (IC50 = 0.96, NCI-H460; IC50 = 0.66 nM, BxPC-3; IC50 = 0.61 nM, HT-29) had the best activity. The cytotoxic activity of compound 26r against various tumor cell lines occurred at less than 1nM.

3,3',5,5'-Tetramethoxybiphenyl-4,4'diol triggers oxidative stress, metabolic changes, and apoptosis-like process by reducing the PI3K/AKT/NF-κB pathway in the NCI-H460 lung cancer cell line

Lung cancer is one of the leading causes of cancer-related deaths in men and women worldwide. Current treatments have limited efficacy, cause significant side effects, and cells can develop drug resistance. New therapeutic strategies are needed to discover alternative anticancer agents with high efficacy and low-toxicity. TMBP, a biphenyl obtained by laccase-biotransformation of 2,6-dimethoxyphenol, possesses antitumor activity against A549 adenocarcinoma cells. Without causing damage to sheep erythrocytes and mouse peritoneal macrophages of BALB/c mice. In addition to being classified as a good oral drug according to in-silico studies. This study evaluated the in-vitro cytotoxic effect of TMBP on lung-cancer cell-line NCI-H460 and reports mechanisms on immunomodulation and cell death. TMBP treatment (12.5–200 μM) inhibited cell proliferation at 24, 48, and 72 h. After 24-h treatment, TMBP at IC50 (154 μM) induced various morphological and ultrastructural changes in NCI-H460, reduced migration and immunofluorescence staining of N-cadherin and β-catenin, induced increased reactive oxygen species and nitric oxide with reduced superoxide radical-anion, increased superoxide dismutase activity and reduced glutathione reductase. Treatment also caused metabolic stress, reduced glucose-uptake, intracellular lactate dehydrogenase and lactate levels, mitochondrial depolarization, increased lipid droplets, and autophagic vacuoles. TMBP induced cell-cycle arrest in the G2/M phase, death by apoptosis, increased caspase-3/7, and reduced STAT-3 immunofluorescence staining. The anticancer effect was accompanied by decreasing PI3K, AKT, ARG-1, and NF-κB levels, and increasing iNOS. These results suggest its potential as a candidate for use in future lung anticancer drug design studies.

Deciphering the Role of Fatty Acid-Metabolizing CYP4F11 in Lung Cancer and Its Potential As a Drug Target.

Lung cancer is the leading cause of cancer deaths worldwide. We found that the cytochrome P450 isoform CYP4F11 is significantly overexpressed in patients with lung squamous cell carcinoma. CYP4F11 is a fatty acid ω-hydroxylase and catalyzes the production of the lipid mediator 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid. 20-HETE promotes cell proliferation and migration in cancer. Inhibition of 20-HETE-generating cytochrome P450 enzymes has been implicated as novel cancer therapy for more than a decade. However, the exact role of CYP4F11 and its potential as drug target for lung cancer therapy has not been established yet. Thus, we performed a transient knockdown of CYP4F11 in the lung cancer cell line NCI-H460. Knockdown of CYP4F11 significantly inhibits lung cancer cell proliferation and migration while the 20-HETE production is significantly reduced. For biochemical characterization of CYP4F11-inhibitor interactions, we generated recombinant human CYP4F11. Spectroscopic ligand binding assays were conducted to evaluate CYP4F11 binding to the unselective CYP4A/F inhibitor HET0016. HET0016 shows high affinity to recombinant CYP4F11 and inhibits CYP4F11-mediated 20-HETE production in vitro with a nanomolar IC 50 Cross evaluation of HET0016 in NCI-H460 cells shows that lung cancer cell proliferation is significantly reduced together with 20-HETE production. However, HET0016 also displays antiproliferative effects that are not 20-HETE mediated. Future studies aim to establish the role of CYP4F11 in lung cancer and the underlying mechanism and investigate the potential of CYP4F11 as a therapeutic target for lung cancer. SIGNIFICANCE STATEMENT: Lung cancer is a deadly cancer with limited treatment options. Cytochrome P450 4F11 (CYP4F11) is significantly upregulated in lung squamous cell carcinoma. Knockdown of CYP4F11 in a lung cancer cell line significantly attenuates cell proliferation and migration with reduced production of the lipid mediator 20-hydroxyeicosatetraenoic acid (20-HETE). Studies with the unselective inhibitor HET0016 show a high inhibitory potency of CYP4F11-mediated 20-HETE production using recombinant enzyme. Overall, our studies demonstrate the potential of targeting CYP4F11 for new transformative lung cancer treatment.

In-silico and in-vitro functional validation of imidazole derivatives as potential sirtuin inhibitor.

Epigenetic enzymes can interact with a wide range of genes that actively participate in the progression or repression of a diseased condition, as they are involved in maintaining cellular homeostasis. Sirtuins are a family of Class III epigenetic modifying enzymes that regulate cellular processes by removing acetyl groups from proteins. They rely on NAD+ as a coenzyme in contrast to classical histone deacetylases (HDACs) (Class I, II, and IV) that depend on Zn+ for their activation, linking their function to cellular energy levels. There are seven mammalian sirtuin isoforms (Sirt1-7), each located in different subcellular compartments. Sirtuins have emerged as a promising target, given that inhibitors of natural and synthetic sources are highly warranted. Imidazole derivatives are often investigated as sirtuin regulators due to their ability to interact with the binding site and modulate their activity. Imidazole bestows many possible substitutions on its ring and neighboring atoms to design and synthesize derivatives with specific target selectivity and improved pharmacokinetic properties, optimizing drug development. Ligand preparation, protein preparation, molecular docking, molecular dynamics, density function theory (DFT) analysis, and absorption, distribution, metabolism, and excretion (ADME) analysis were performed to understand the interacting potential and effective stability of the ligand with the protein. RT-PCR and Western blot analyses were performed to understand the impact of ligands on the gene and protein expression of Class III HDAC enzymes. We evaluated the sirtuin inhibition activity of our in-house compound comprised of imidazole derivatives by docking the molecules with the protein data bank. ADME properties of all the compounds used in the study were evaluated, and it was found that all fall within the favorable range of being a potential drug. The molecule with the highest docking score was analyzed using DFT, and the specific compound was used to treat the non-small cell lung cancer (NSCLC) cell lines A549 and NCI-H460. The gene and protein expression data support the in-silico finding that the compound Ethyl 2-[5-(4-chlorophenyl)-2-methyl-1-H-Imidazole-4-yl) acetate has an inhibitory effect on nuclear sirtuins. In conclusion, targeting sirtuins is an emerging strategy to combat carcinogenesis. In this study, we establish that Ethyl 2-[5-(4-chlorophenyl)-2-methyl-1-H-Imidazole-4-yl) acetate possesses a strong inhibitory effect on nuclear sirtuins in NSCLC cell lines.

Design, synthesis and antitumor activity of novel thiophene- triazine derivatives bearing arylurea unit as potent PI3K/mTOR inhibitorss

In this article, we designed and synthesized a series of novel thiophene-triazine derivatives bearing arylurea unit as potent dual PI3K/mTOR inhibitors. The cytotoxicity of all the target compounds were evaluated against nine cancer cell lines (breast cancer cell line MCF-7, lung cancer cell lines A549, NCI-H460, H2228 and H1975, cervical cancer cell lines Hela and Hela-MDR, ovarian cancer cell lines Ovcar-2 and glioma U87MG) and the kinase inhibitory activity against PI3K/mTOR kinases was also tested. The results demonstrated that most of the target compounds exhibited moderate to excellent activity and high selectivity against one or more cancer cell lines. Among them, seven compounds displayed better activity than lead compound GDC-0941. The inhibitory activity of the most promising compound on nine cancer cell lines was 302.5 times better than that of GDC-0941 with the IC50 values as low as 0.008 ± 0.002 μM, and the inhibitory activity against PI3Kα and mTOR kinase was excellent, with the IC50 values of 177.41 and 12.24 nM, respectively, indicating that it was a potential dual PI3Kα/mTOR inhibitor. The Structure-Activity Relationships (SARs) indicated that the introduction of the arylurea group significantly improved the cellular and kinase activities of the target compounds. Moreover, the results of toxicity and hemolysis experiments demonstrated that the most promising compound had low toxicity and good safety. The results of PCR assay and molecular docking modes showed that it was a potential PI3K/mTOR inhibitor, which was worthy of further study.

Design and synthesis of novel quinazolinone-based derivatives as EGFR inhibitors with antitumor activity

Nineteen new quinazolin-4(3H)-one derivatives 3a–g and 6a–l were designed and synthesised to inhibit EGFR. The antiproliferative activity of the synthesised compounds was tested in vitro against 60 different human cell lines. The most potent compound 6d displayed superior sub-micromolar antiproliferative activity towards NSC lung cancer cell line NCI-H460 with GI50 = 0.789 µM. It also showed potent cytostatic activity against 40 different cancer cell lines (TGI range: 2.59–9.55 µM). Compound 6d potently inhibited EGFR with IC50 = 0.069 ± 0.004 µM in comparison to erlotinib with IC50 value of 0.045 ± 0.003 µM. Compound 6d showed 16.74-fold increase in total apoptosis and caused cell cycle arrest at G1/S phase in breast cancer HS 578T cell line. Moreover, the most potent derivatives were docked into the EGFR active site to determine their binding mode and confirm their ability to satisfy the pharmacophoric features required for EGFR inhibition.

A novel anti-lung cancer agent inhibits proliferation and epithelial-mesenchymal transition.

ObjectiveTo synthesize a novel chalcone-1,3,4-thiadiazole hybrid and investigate its anticancer effects against NCI-H460 cells.Methods(E)-3-(4-bromophenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one, 1,3-dibromopropane and 1,3,4-thiadiazole-2-thiol were used as chemical materials to synthesize compound ZW97. The NCI-H460 lung cancer cell line was selected to explore the antitumor effects of compound ZW97 in vitro and in vivo.ResultsCompound ZW97 selectively inhibited cell proliferation against lung cancer cell lines NCI-H460, HCC-44 and NCI-H3122 with IC50 values of 0.15 μM, 2.06 μM and 1.17 μM, respectively. ZW97 suppressed migration and the epithelial–mesenchymal transition process in NCI-H460 cells in a concentration-dependent manner. Based on the kinase activity results and docking analysis, compound ZW97 is a novel tyrosine-protein kinase Met (c-Met kinase) inhibitor. It also inhibited NCI-H460 cell growth in xenograft models without obvious toxicity to normal tissues.ConclusionsCompound ZW97 is a potential c-Met inhibitor that might be a promising agent to treat lung cancer by inhibiting the epithelial–mesenchymal transition process.

Synergic effect of anticancer peptide CIGB-552 and Cisplatin in lung cancer models.

The antitumor peptide CIGB-552 is a new targeted anticancer therapy which molecular mechanism is associated with the inhibition of the transcription factor NF-kB, mediated by COMMD1 protein stabilization. In this study, we examined the antiproliferative capacity of CIGB-552 in combination with chemotherapeutic agents in lung cancer models. We combined of CIGB-552 and the antineoplastic agent Cisplatin (CDDP) in concomitant and pre-treatment scenary in a dose matrix approach. This study was performed in the non-small cell lung cancer cell lines NCI-H460, A549 and in a mouse model of TC-1 lung cancer. Our results demonstrate a clear synergic effect between 37.5μM of CIGB-552 and 5μM of CDDP under concomitant scheme, on proliferation inhibition, cell cycle arrest, apoptosis induction and oxidative stress response. The effect of CIGB-552 (1mg/kg) and CDDP (0.4mg/kg) administrated as a combined therapy was demonstrated in vivo in aTC-1 mouse modelwhere the combination achieved an effective antitumor response, without any deterioration signs or side effects. These findings demonstrate the efficacy of the concomitant combination of both drugs in preclinical studies and support the use of this therapy in clinical trials. This study is the first evidence of synergisticeffect of the combination of the antitumoral peptide CIGB-552 and CDDP.

Development of three-dimensional cell culture spheroid model for non-small-cell lung carcinoma cell line nci-h460 exposed to cisplatin / Desenvolvimento de modelo de cultura celular tridimensional para a linhagem celular de carcinoma de pulmão de não-pequenas células nci-h460 expostas á cisplatina

The three-dimensional culture models have been developed to promote better simulation of in vivo conditions of cellular interactions and phenotypic expressions. Since each cell line behaves differently and not all aggregate three-dimensionally, the objectives of this study were to standardize the conditions for cultivation spheroids produced from the human non-smal-cell lung cancer cell line NCI-H460, and evaluate the effects of cisplatin in this model. We investigated the best cell density for the formation of spheroids and their growth time in culture conditions. For this, spheroids were treated with different concentrations of cisplatin. The analysis was performed by measuring the diameter of the spheroids before treatment and measured 48 h after treatment and then every 3 days. The standard cell density conditions obtained was 10 x 104 cells. Spheroids were collected from the 7th day and isolated in a non-adherent matrix well (covered with 2% agar and culture medium), remaining viable until the 17th day. From the 8th day of isolated culture, the cisplatin promoted a reduction in the growth of spheroids dependent on the concentration used. Thus, it was concluded that it was possible to standardize the effective methodology for the formation and maintenance of spheroids from this cell line, as well as cisplatin inhibited the growth of the spheroids, suggesting its cytotoxic effect also cultures in three-dimensional model.

Structural characterisation and antitumor activity against non-small cell lung cancer of polysaccharides from Sanghuangporus vaninii

The medicinal fungus Sanghuangporus vaninii can be cultivated in large scale and has outstanding antitumour activity. In this study, water-soluble S. vaninii polysaccharides (SVPs) were extracted from fruiting bodies. Four polysaccharide sub-fractions (SVP-W, SVP-1, SVP-2 and SVP-3) were isolated, with molecular weights from 90.50 kDa to 261.70 kDa, and all inhibited the proliferation of non-small cell lung cancer cell lines A549, 95-D and NCI-H460, especially the acidic SVP-1. SVP-1 affected cell morphology and colony formation in NCI-H460 cells. It also promoted cell apoptosis following nuclear fluorescence staining and flow cytometry. Methylation and nuclear magnetic resonance analyses revealed that SVP-1 is a heteroglycan with the main chain →4)-β-D-Glcp-(1 → 6)-β-D-Glcp-(1 → 6)-α-D-Galp-(1 → 6)-β-D-Glcp-(1→, and the branched chain α-D-Manp-(1 → 2)-α-D-Manp-(1 → 3)-β-D-Glcp-(1 → 3,6)-β-D-Glcp-(1→. The findings indicate that this natural acidic polysaccharide has potential for non-small cell lung cancer therapy.

Antitumor activity via apoptotic cell death pathway of water soluble copper(II) complexes: effect of the diamino unit on selectivity against lung cancer NCI-H460 cell line.

The cytotoxicity against five human tumor cell lines (THP-1, U937, Molt-4, Colo-205 and NCI-H460) of three water soluble copper(II) coordination compounds containing the ligands 3,3'-(ethane-1,2-diylbis(azanediyl))dipropanamide (BCEN), 3,3'-(piperazine-1,4-diyl)dipropanamide (BPAP) or 3,3'-and (1,4-diazepane-1,4-diyl)dipropanamide (BPAH) are reported in this work. The ligands contain different diamine units (ethylenediamine, piperazine or homopiperazine) and two propanamide units attached to the diamine centers, resulting in N2O2 donor sets. The complex containing homopiperazine unit presented the best antiproliferative effect and selectivity against lung cancer cell line NCI-H460, showing inhibitory concentration (IC50) of 58μmoldm-3 and Selectivity Index (SI) > 3.4. The mechanism of cell death promoted by the complex was investigated by Sub-G1 cell population analysis and annexin V and propidium iodide (PI) labeling techniques, suggesting that the complex promotes death by apoptosis. Transmission electron microscopy investigations are in agreement with the results presented by mitochondrial membrane potential analysis and also show the impairment of other organelles, including endoplasmic reticulum.

Foeniculum vulgare seed extract induces apoptosis in lung cancer cells partly through the down-regulation of Bcl-2

The factors behind the pathogenesis of lung cancer are not clear, and treatment failure is generally caused by drug resistance, recurrence, and metastasis. Development of new therapeutic agents to overcome drug-resistance remains a challenge clinically. Various extracts of Foeniculum vulgare have shown promising anticancer activity; however, effects on lung cancer and the underlying molecular mechanisms of action are not clear. In the present study, we found that the ethanol extract of Foeniculum vulgare seeds (EEFS) significantly reduced lung cancer cell growth in vitro and in vivo. EEFS decreased the viability of and triggered apoptosis in the lung cancer cell lines NCI-H446 and NCI-H661. EEFS induced apoptosis mainly through inhibition of Bcl-2 protein expression, reduction of mitochondrial membrane potential, and release of Cytochrome C. Moreover, EEFS significantly inhibited colony formation and cell migration in lung cancer cells. EEFS also effectively inhibited the growth of xenograft tumors derived from NCI-446 cells by reducing Bcl-2 protein expression and inducing apoptosis. Taken together, these findings suggest that EEFS exerts anti-lung cancer activity by targeting the Bcl-2 protein and may have potential as a therapeutic drug for lung cancer.

The Anticancer Peptide CIGB-552 Exerts Anti-Inflammatory and Anti-Angiogenic Effects through COMMD1.

CIGB-552 is a synthetic anti-tumor peptide capable of reducing tumor size and increasing the lifespan of tumor-bearing mice. Part of its anti-cancer effects consists of inducing apoptosis, modulating NF-kB signaling pathway, and the angiogenesis process. Although one of its major mediators, the COMMD1 protein, has been identified, the mechanism by which CIGB-552 exerts such effects remains elusive. In the present study, we show the role of COMMD1 in CIGB-552 mechanism of action by generating the COMMD1 knock-out from the human lung cancer cell line NCI-H460. A microarray was performed to analyze both wild-type and KO cell lines with regard to CIGB-552 treatment. Additionally, different signaling pathways were studied in both cell lines to validate the results. Furthermore, the interaction between CIGB-552 and COMMD1 was analyzed by confocal microscopy. By signaling pathway analysis we found that genes involved in cell proliferation and apoptosis, oncogenic transformation, angiogenesis and inflammatory response are potentially regulated by the treatment with CIGB-552. We then demonstrated that CIGB-552 is capable of modulating NF-kB in both 2D and 3D cell culture models. Finally, we show that the ability of CIGB-552 to negatively modulate NF-kB and HIF-1 pathways is impaired in the COMMD1 knock-out NCI-H460 cell line, confirming that COMMD1 is essential for the peptide mechanism of action.

Paris saponin II-induced paraptosis-associated cell death increased the sensitivity of cisplatin

Paris Saponin II (PSII) has been regarded as an effective and imperative component isolated from Rhizoma Paridis saponins (RPS) and exhibited strong anti-tumor effects on a variety of cancer. Our results revealed that human non-small lung cancer cell lines NCI-H460 and NCI-H520 were exposed to 1 μM of PSII, which inhibited the proliferation of lung cancer cells and activated apoptosis, autophagy and paraptosis. PSII induced paraptosis-associated cell death prior to apoptosis and autophagy. It induced paraptosis based on ER stress through activation of the JNK pathway. Meanwhile, PSII increased the cytotoxicity of cisplatin through paraptosis-associated pathway. All in all, PSII induced paraptosis based on induction of non-apoptotic cell death, which would be a possible approach to suppress the multi-drug resistant to apoptosis.

Antitumor Activity of TRAIL-Mu3 Protein in vitro and in vivo and the Mechanisms

TRAIL-Mu3 was obtained by mutating the N-terminus of human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene to an eight continuous arginine sequence. The present study was designed to explore the antitumor effect of this soluble mutant protein and the underlying mechanisms. The inhibitory effect of TRAIL-Mu3 on the proliferation of lung cancer cell lines NCI-H460, A549, NCI-H1299 and calu-1 was tested by CCK8 assay. The apoptotic rates of A549 and NCI-H460 treated by TRAIL-Mu3 were detected by flow cytometer (FCM). The expressions of apoptosis related proteins death receptor (DR) 4, DR5, Caspase-3, Caspase-8 and X-linked inhibitor of apoptosis protein (XIAP) were detected by Western blot .Moreover, a subcutaneous xenograft tumor mouse model of NCI-H460 was established and treated with TRAIL-Mu3 daily or every other day or three times a week. The expressions of DR4, DR5, Caspase-3, Caspase-8 and XIAP were detected by immunohistochemical staining. The in vitro study demonstrated that as compared to the TRAIL, the TRAIL-Mu3 was more toxic and pro-apoptotic by up-regulation of the expression and activity of DR4, Caspase-3 and Caspase-8. Also, the animal study showed a similar antitumor effect between treatment with TRAIL-Mu3 every other day and three time a week, which was better than daily use. All treatments significantly suppressed the growth of xenograft tumor, increased the expression or activity of DR4 and Caspase-3, and down-regulated the expression of XIAP ( P<0.05). TRAIL-Mu3 could improve antitumor activity in vivo and in vitro through elevating DR4 expression, activating Caspase-3/-8, and inhibiting XIAP activation.

Apatinib Combined with CCI-779 Inhibits the Proliferation and Migration of Small Cell Lung Cancer NCI-H446 Cells In Vitro

背景与目的肺癌是世界上最常见的恶性肿瘤，其中小细胞肺癌是恶性程度最高的亚型，具有生长迅速、早期转移和高度血管化等特点。阿帕替尼（Apatinib）是我国自主研发的血管内皮生长因子受体2抑制剂，在多种实体瘤中疗效显著。本研究旨在探讨Apatinib对小细胞肺癌细胞株NCI-H446的体外作用以及联合哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin, mTOR）抑制剂CCI-779对小细胞肺癌的体外作用。方法体外培养小细胞肺癌细胞株NCI-H446，CCK8法、细胞凋亡实验、细胞周期实验及Transwell实验检测Apatinib及联合mTOR抑制剂CCI-779对NCI-H446细胞增殖、凋亡、周期及迁移的影响；Western blot实验检测血管内皮生长因子受体和细胞周期相关蛋白的表达。结果CCK8实验结果显示高浓度Apatinib能抑制NCI-H446细胞增殖；细胞凋亡实验结果显示高浓度Apatinib诱导NCI-H446细胞凋亡；Transwell实验结果显示高浓度Apatinib抑制NCI-H446细胞迁移；联合mTOR抑制剂CCI-779后，低浓度Apatinib便能抑制NCI-H446细胞增殖和迁移，诱导细胞凋亡。结论Apatinib对小细胞肺癌细胞株NCI-H446的作用具有浓度依赖性特征，高浓度Apatinib能够抑制NCI-H446细胞增殖和迁移，诱导细胞凋亡，与mTOR抑制剂CCI-779联用能增加NCI-H446细胞对Apatinib的敏感性。

Zunyimycin C inhibits the proliferation of lung cancer cells by inducing apoptosis through an AKT-related mechanism

Zunyimycin C is a novel halogenated type II polyketide derived from the fermentation product of the Streptomyces species with notable antibiotic activity. However, it is still unclear whether zunyimycin C could inhibit the activity of cancer cells. In this study, human lung adenocarcinoma cell line A549, the large-cell lung cancer cell line NCI-H460 and the non-small-cell lung cancer cell line NCI-H1299 were employed to determine the in vitro anticancer properties of zunyimycin C and underlying molecular mechanisms. The cellular viability and proliferative properties of lung cancer cells were investigated using the Cell Counting Kit-8 and colony formation assay, respectively. The mRNA expression of apoptotic genes related to lung cancer was studied using reverse-transcription polymerase chain reaction. The apoptotic ratio was measured through flow cytometry. The protein expression was visualized via western blotting using specific antibodies. Zunyimycin C could inhibit cell proliferation and induce apoptosis in a dose-dependent manner. The expression levels of apoptosis-related proteins (i.e., BAX, cleaved-caspase-3, and cleaved-caspase-9) were increased compared with the control group. However, the levels of Bcl-2 and phosphorylated AKT were decreased by administration by zunyimycin C. Collectively, these results implied that zunyimycin C could inhibit cell proliferation and induce apoptosis via AKT phosphorylation.

Discovery of 7-bromo-1,4-dihydrothieno[3’,2’:5,6]thiopyrano[4,3-c]pyrazole-3-carboxamide derivatives as the potential epidermal growth factor receptors for tyrosine kinase inhibitors

Small molecule tyrosine kinase inhibitors (TKIs) targeting at epidermal growth factor receptor (EGFR) in recent years have made great progress in the treatment of advanced non-small cell cancer (NSCLC). Although as the first-line treatment for sensitizing EGFR mutation-positive metastatic NSCLC, gefitinib has also behaved quite a lot of side effect and EGFR tolerance. Herein, a novel series of 7-bromo-1,4-dihydrothieno[3’,2’:5,6]thiopyrano[4,3-c]pyrazole-3-carboxamide derivatives were designed and synthesized, and screened for their inhibitory activity on the EGFR high-expressing human lung adenocarcinoma cell line A549 and human large cell lung cancer cell line NCI-H460 by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide colorimetric assay. The calculated IC50 values were reported. Compound 8h demonstrated the most potent inhibitory activity (IC50 = 9.57 ± 2.20 μmol L–1 for A549 and IC50 = 13.04 ± 1.21 μmol L–1 for NCI-H460), comparable to the positive-control gefitinib (IC50 = 8.58 ± 1.65 μmol L–1 for A549 and IC50 = 18.66 ± 5.01 μmol L–1 for NCI-H460). Conclusively, 7-bromo- 1,4-dihydrothieno[3’,2’:5,6]thiopyrano[4,3-c]pyrazole-3-carboxamide derivatives as the EGFR–TKIs were discovered, and could be used as potential leading compounds for further research.

Y6, an Epigallocatechin Gallate Derivative, Reverses ABCG2-Mediated Mitoxantrone Resistance.

Multidrug resistance is reported to be related to the transmembrane transportation of chemotherapeutic drugs by adenosine triphosphate-binding cassette (ABC) transporters. ABC subfamily G member 2 (ABCG2) is a member of the ABC transporter superfamily proteins, which have been implicated as a key contributor to the development of multidrug resistance in cancers. A new epigallocatechin gallate derivative, Y6 was synthesized in our group. Our previous study revealed that Y6 increased the sensitivity of drug-resistant cells to doxorubicin, which was associated with down-regulation of P-glycoprotein expression. In this study, we further determine whether Y6 could reverse ABCG2-mediated multidrug resistance. Results showed that, at non-toxic concentrations, Y6 significantly sensitized drug-selected non-small cell lung cancer cell line NCI-H460/MX20 to substrate anticancer drugs mitoxantrone, SN-38, and topotecan, and also sensitized ABCG2-transfected cell line HEK293/ABCG2-482-R2 to mitoxantrone and SN-38. Further study demonstrated that Y6 significantly increased the accumulation of [3H]-mitoxantrone in NCI-H460/MX20 cells by inhibiting the transport activity of ABCG2, without altering the expression levels and the subcellular localization of ABCG2. Furthermore, Y6 stimulated the adenosine triphosphatase activity with a concentration-dependent pattern under 20 μM in membranes overexpressing ABCG2. In addition, Y6 exhibited a strong interaction with the human ABCG2 transporter protein. Our findings indicate that Y6 may potentially be a novel reversal agent in ABCG2-positive drug-resistant cancers.