Growth Of A549 Research Articles

Upregulation of the miR-212/132 cluster suppresses proliferation of human lung cancer cells.

Lung cancer is the leading cause of cancer-related mortality worldwide. microRNAs (miRNAs) are small post-transcriptional regulatory non-coding RNAs that function as oncogenes or tumor suppressors in human cancers. Emerging evidence reveals that deregulation of miRNAs contributes to the progression of human lung cancer, which is the leading cause of cancer-related deaths worldwide. In the present study, we found that upregulation of the miR-212/132 cluster significantly suppressed the growth and focus formation of A549 and H1299 cells. Moreover, forced expression of this cluster conferred radiosensitivity and inhibited the migration of lung cancer cells, whereas downregulation of miR-212/132 reversed the above effects. Furthermore, miR-212/132 overexpression induced cell cycle arrest at the G1/S phase transition of the lung cancer cells, and inhibition of miR-132 and miR-212 abrogated this arrest. In addition, miR-212/132 overexpression increased the percentage of cells undergoing apoptosis. Cells transfected with the miR-212/132 cluster exhibited upregulated p21 expression and reduced cyclin D1 expression. Conversely, cells transfected with the miR-212/132 inhibitor showed reduced expression of p21 and upregulated expression of cyclin D1, suggesting that miR-212/132 may mediate proliferation and cell cycle arrest through p21 and cyclin D1. Our study provides insight into the biological function of the miR-212/132 cluster in lung cancer. The present study may provide a potential therapeutic target for the treatment of lung cancer.

Antiproliferation and induction of caspase-8-dependent mitochondria-mediated apoptosis by β-tocotrienol in human lung and brain cancer cell lines

The pure vitamin isomer, β-tocotrienol has the least abundance among the other vitamin E isomers that are present in numerous plants. Hence, it is very scarcely studied for its bioactivity. In this study, the antiproliferative effects and primary apoptotic mechanisms of β-tocotrienol on human lung adenocarcinoma A549 and glioblastoma U87MG cells were investigated. It was evidenced that β-tocotrienol had inhibited the growth of both A549 (GI50=1.38±0.334μM) and U87MG (GI50=2.53±0.604μM) cells at rather low concentrations. Cancer cells incubated with β-tocotrienol were also found to exhibit hallmarks of apoptotic morphologies including membrane blebbing, chromatin condensation and formation of apoptotic bodies. The apoptotic properties of β-tocotrienol in both A549 and U87MG cells were the results of its capability to induce significant (P<0.05) double-strand DNA breaks (DSBs) without involving single-strand DNA breaks (SSBs). β-Tocotrienol is said to induce activation of caspase-8 in both A549 and U87MG cells guided by no activation when caspase-8 inhibitor, z-IETD-fmk was added. Besides, disruption on the mitochondrial membrane permeability of the cells in a concentration- and time-dependent manner had occurred. The induction of apoptosis by β-tocotrienol in A549 and U87MG cells was confirmed to involve both the death-receptor mediated and mitochondria-dependent apoptotic pathways. These findings could potentiate the palm oil derived β-tocotrienol to serve as a new anticancer agent for treating human lung and brain cancers.

Anticancer drug-loaded multifunctional nanoparticles to enhance the chemotherapeutic efficacy in lung cancer metastasis.

BackgroundInhalation of chemotherapeutic drugs directly into the lungs augments the drug exposure to lung cancers. The inhalation of free drugs however results in over exposure and causes severe adverse effect to normal cells. In the present study, epidermal growth factor (EGF)-modified gelatin nanoparticles (EGNP) was developed to administer doxorubicin (DOX) to lung cancers.ResultsThe EGNP released DOX in a sustained manner and effectively internalized in EGFR overexpressing A549 and H226 lung cancer cells via a receptor-mediated endocytosis. In vitro cytotoxicity assay showed that EGNP effectively inhibited the growth of A549 and H226 cells in a dose-dependent manner. In vivo biocompatibility study showed that both GNP and EGNP did not activate the inflammatory response and had a low propensity to cause immune response. Additionally, EGNP maintained a high therapeutic concentration in lungs throughout up to 24 h comparing to that of free drug and GNP, implying the effect of ligand-targeted tumor delivery. Mice treated with EGNP remarkably suppressed the tumor growth (~90% tumor inhibition) with 100% mice survival rate. Furthermore, inhalation of EGNP resulted in elevated levels of cleaved caspase-3 (apoptotic marker), while MMP-9 level significantly reduced comparing to that of control group.ConclusionsOverall, results suggest that EGF surface-modified nanocarriers could be delivered to lungs via inhalation and controlled delivery of drugs in the lungs will greatly improve the therapeutic options in lung cancer therapy. This ligand-targeted nanoparticulate system could be promising for the lung cancer treatment.

Abstract 4236: Antitumor activity of a novel (-)-antofine analog in human lung cancer cells and paclitaxel-resistant lung cancer cells

Abstract Our previous study revealed that (-)-antofine, a phenanthroindolizidine alkaloid from Cynanchum paniculatum Kitagawa (Asclepiadaceae), exhibited a potent growth inhibition activity against A549 human lung cancer cells. Based on the information several analogs were designed and synthesized to procure new entities. A novel (-)-antofine C-13a analog ((R)-4b) was found to be a potential growth inhibition and antitumor activities in A549 cells. Treatment with (R)-4b for 24 hours did not result in the induction of apoptotic cell death but moderately induced cell cycle arrest in the G0/G1 phase and inhibited the expression of cyclin D1, cyclin E, CDK4 and pRb. In addition, (R)-4b suppressed the phosphorylation of mTOR and its downstream effectors such as 4E-BP-1 and eIF4E. The paclitaxel-resistance was also overcome in human lung cancer cells (A549-Pa) via the suppression of p-glycoprotein expression. Furthermore, (R)-4b significantly inhibited the tumor growth of A549 and A549-Pa xenografts in a nude mouse model. Taken together, these findings suggest that (R)-4b might be a potential candidate for the development of cancer chemotherapeutic agents derived from natural products. Citation Format: Jayoung Song, Song Yi Bae, Yoonho Shin, Won Kyung Kim, Jedo Oh, Tae Joon Choi, Eun Ju Jeong, So Hyun Park, Eun Jeong Jang, Ji In Kang, Hyen Joo Park, Ji-Young Hong, Hwa-Jin Chung, Yongseok Kwon, Sanghee Kim, Sang Kook Lee. Antitumor activity of a novel (-)-antofine analog in human lung cancer cells and paclitaxel-resistant lung cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4236. doi:10.1158/1538-7445.AM2014-4236

Anti-tumor effect of a novel soluble recombinant human endostatin: administered as a single agent or in combination with chemotherapy agents in mouse tumor models.

BackgroundAngiogenesis has become an attractive target in cancer treatment. Endostatin is one of the potent anti-angiogenesis agents. Its recombinant form expressed in the yeast system is currently under clinical trials. Endostatin suppresses tumor formation through the inhibition of blood vessel growth. It is anticipated that combined therapy using endostatin and cytotoxic compounds may exert an additive effect. In the present study, we expressed and purified recombinant human endostatin (rhEndostatin) that contained 3 additional amino acid residues (arginine, glycine, and serine) at the amino-terminus and 6 histidine residues in its carboxyl terminus. The recombinant protein was expressed in E. Coli and refolded into a soluble form in a large scale purification process. The protein exhibited a potent anti-tumor activity in bioassays. Furthermore, rhEndostatin showed an additive effect with chemotherapy agents including cyclophosphamide (CTX) and cisplatin (DDP).MethodsrhEndostatin cDNA was cloned into PQE vector and expressed in E. Coli. The protein was refolded through dialysis with an optimized protocol. To establish tumor models, nude mice were subcutaneously injected with human cancer cells (lung carcinoma A549, hepatocellular carcinoma QGY-7703, or breast cancer Bcap37). rhEndostatin and/or DDP was administered peritumorally to evaluate the rate of growth inhibition of A549 tumors. For the tumor metastasis model, mice were injected intravenously with mouse melanoma B16 cells. One day after tumor cell injection, a single dose of rhEndostatin, or in combination with CTX, was administered intravenously or at a site close to the tumor.ResultsrhEndostatin reduced the growth of A549, QGY-7703, and Bcap37 xenograft tumors in a dose dependent manner. When it was administered peritumorally, rhEndostatin exhibited a more potent inhibitory activity. Furthermore, rhEndostatin displayed an additive effect with CTX or DDP on the inhibition of metastasis of B16 tumors or growth of A549 tumors.ConclusionSoluble rhEndostatin exhibits a potent anti-tumor activity in mouse xenograft models and it also has an additive effect with CTX and DDP, implying possible applications in clinical settings.

Megakaryocytic potentiating factor and mature mesothelin stimulate the growth of a lung cancer cell line in the peritoneal cavity of mice.

The mesothelin (MSLN) gene encodes a 71 kilodalton (kDa) precursor protein that is processed into megakaryocytic potentiating factor (MPF), a 31 kDa protein that is secreted from the cell, and mature mesothelin (mMSLN), a 40 kDa cell surface protein. The mMSLN binds to CA125, an interaction that has been implicated in the intra-cavitary spread of mesothelioma and ovarian cancer. To better define the role of MPF and mMSLN, growth of the lung cancer cell line A549 was evaluated in immuno-deficient mice with inactivation of the Msln gene. We observed that Msln–/– mice xenografted with intraperitoneal A549 tumors survive significantly long than tumor-bearing Msln+/+ mice. When tumor-bearing Msln–/– mice are supplemented with recombinant MPF (and to a lesser extent mMSLN), most of this survival advantage is lost. These studies demonstrate that MPF and mMSLN have an important role in the growth of lung cancer cells in vivo and raise the possibility that inactivation of MPF may be a useful treatment for lung and other MSLN expressing cancers.

Anti-cancer effect of tectochrysin in NSCLC cells through overexpression of death receptor and inactivation of STAT3

Phenolic compounds (flavonoids and phenolic acid derivatives) are the most important pharmacologically active ingredients, and these compounds could inhibit proliferation of human cancer cells by inducing of apoptotic cell death. Here we focused on the anticancer effects of tectochrysin on human non-small-cell lung cancer (NSCLC) cells and its mechanism of action. We analysed the activity of tectochrysin on NSCLC cells (A549 and NCI-H460) by use of Western blot analysis for major apoptotic proteins and death receptor expression. We also used EMSA for effects on STAT3 DNA binding activity. Tectochrysin (0–80μM) suppressed the growth of A549 and NCI-H460 lung cancer cells by inducing of apoptotic cell death in a concentration dependent manner. Expression of DR3 and Fas as well as DR downstream pro-apoptotic proteins including cleaved caspase-3, cleaved caspase-8, cleaved caspase-9 and Bax were concomitantly increased, but the expression of anti-apoptotic proteins; Bcl-2 was decreased in both cancer cells. In addition, tectochrysin treatment also inhibited phosphorylation of STAT3 in A549 and NCI-H460 cells. However, deletion of DR3 and Fas by small interfering RNA significantly reversed tectochrysin-induced cell growth inhibitory effect as well as down regulation of STAT3 in A549 and NCI-H460 lung cancer cells. Pull down assay and docking model showed interaction of tectochrysin with STAT3. We propose that tectochrysin leads to apoptotic cell death in NSCLC cells through activation of DR3 and Fas expression via inhibition of STAT3 phosphorylation.

Monocyte to macrophage differentiation-associated (MMD) targeted by miR-140-5p regulates tumor growth in non-small cell lung cancer

Monocyte to macrophage differentiation-associated (MMD) is identified in macrophages as a gene associated with the differentiation from monocytes to macrophages. Recent microarray analysis for non-small cell lung cancer (NSCLC) suggests that MMD is an important signature associated with relapse and survival among patients with NSCLC. Therefore, we speculate that MMD likely plays a role in lung cancer. In this study, we found that the protein level of MMD was increased in lung cancer compared to benign lung tissues, and knockdown of MMD inhibited the growth of A549 and Lewis lung cancer cells (LLC) in vitro and in vivo. Integrated analysis demonstrated that MMD was a direct functional target of miR-140-5p. Furthermore, we found that miR-140-5p/MMD axis could affect the cell proliferation of lung cancer cells by regulating Erk signaling. Together, our results highlight the significance of miR-140-5p/MMD axis in lung cancer, and miR-140-5p/MMD axis could serve as new molecular targets for the therapy against lung cancer.

Isodeoxyelephantopin from Elephantopus scaber (Didancao) induces cell cycle arrest and caspase-3-mediated apoptosis in breast carcinoma T47D cells and lung carcinoma A549 cells.

BackgroundIsodeoxyelephantopin (IDOE) isolated from Elephantopus scaber L. (Didancao) is used in Chinese medicine for the treatment of some types of cancer. The anti-cancer mechanism of IDOE remains unclear. This study aims to investigate the antiproliferative activity of IDOE on breast carcinoma T47D cells and lung carcinoma A549 cells.MethodsThe growth inhibitory effects of IDOE on breast carcinoma T47D cells, lung carcinoma A549 cells, and normal lymphocytes were evaluated by the MTT assay. Morphological analysis of apoptosis induction was performed by acridine orange/ethidium bromide dual-staining and Hoechst 33342 nuclear staining. The cell cycle profile, caspase-3 expression, and annexin V staining were evaluated by flow cytometry.ResultsIDOE inhibited the growth of A549 and T47D cells in a dose- and time-dependent manner with IC50 values of 10.46 and 1.3 μg/mL, respectively. IDOE was not significantly toxic to normal lymphocytes. The cells became detached from the monolayer and rounded up, had fragmented nuclei and condensed chromatin, and the numbers of apoptotic cells increased (P = 0.0003). IDOE-induced cell death was associated with activated caspase-3 expression followed by cell cycle arrest at G2/M phase.ConclusionsIDOE inhibited the proliferation of breast cancer cells and lung carcinoma cells and induced caspase-3-mediated apoptosis and cell cycle arrest in the treated cells.

Synthesis, biological evaluation, and molecular docking studies of novel 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety as FAK inhibitors with anticancer activity

A series of 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety (3a–3r) has been designed, synthesized and their biological activities were also evaluated as potential antiproliferation and focal adhesion kinase (FAK) inhibitors. Among all the compounds, 3p showed the most potent activity in vitro which inhibited the growth of A549 with IC50 value of 3.11μM and Hela with IC50 value of 2.54μM respectively. Compound 3p also exhibited significant FAK inhibitory activity (IC50=0.45μM). Docking simulation was performed for compound 3p into the FAK structure active site to determine the probable binding model.

A new diketopiperazine from South China Sea marine sponge Callyspongia sp.

Further chemical investigation on the marine sponge Callyspongia sp. collected from South China Sea led to the isolation of a new diketopiperazine, named callysponine A (1), as well as four known diketopiperazines, namely cyclo-(Gly-Pro) (2), cyclo-(Thr-Pro) (3), cyclo-(Ile-Pro) (4) and cyclo-(Pro-Pro) (5). The new structure was determined on the basis of NMR and MS analysis, and the absolute stereochemistry was defined by analysis of the coupling constants and optical rotation. The structures of the known compounds were identified by comparing their spectroscopic data with those reported in the literature. Compounds 1–5 did not inhibit the growth of HepG2 (hepatoma carcinoma cell), A549 (lung carcinoma cell) and HeLa (cervical cancer cell) cell lines.

MiR-21: A Non-invasive Biomarker and Potential Therapeutic Target for Lung Cancer?

We read with great interest the article, published in Cell Biochem Biophys, showing that serum level of miR-21 was significantly elevated in lung cancer patients compared with controls. Receiver operating characteristic (ROC) curve analysis showed that miR-21 could differentiate lung cancer from healthy controls with an AUC (the area under the curve) of 0.85, and the optimal sensitivity and specificity were 85.7 and 86.5 %, respectively [1]. These findings suggest that miR-21 can be a potential non-invasive biomarker for lung cancer patients and miR-21 may be a potential therapeutic target for lung cancer. Lung cancer is one of the most common malignant tumors and is the leading cause of cancer mortality in the world [2]. Non-small cell lung cancer (NSCLC) accounts for approximately 80–85 % of all cases of lung cancer [3]. Despite much advances in lung cancer therapy, the survival rate for lung cancer patients remains very poor [4]. Recent advances in functional genomics provide an increasingly comprehensive portrayal of lung tumorigenesis, but the molecular pathogenesis of lung cancer remains poorly understood. These findings highlight the need for a better understanding of novel molecular mechanisms to guide treatment of lung cancer. MicroRNAs (miRNAs) are small non-coding RNAs that repress target gene expression by a combination of mRNA degradation and translation inhibition [5]. Recently, miR-21 expression was found to be higher in lung cancer serum samples than in control serum samples [3, 6–9]. High serum miR-21 was significantly correlated with tumor node metastases stage and lymph node metastasis of NSCLC patients [3, 5]. Overexpression of miR-21 showed a highly discriminative ROC curve profile, clearly distinguishing cancer patients from cancer-free subjects, and the detection of miR-21 expression yielded high sensitivity and specificity in the diagnosis of lung cancer [7–9]. Furthermore, miR-21 expression was elevated in human lung cancer cell lines (NCI-H446 and NCI-H460) [2]. Human mutS homolog 2 (hMSH2), one of the core mismatch repair genes, is affected in lung cancer development. Zhong et al. [2] found that hMSH2 was directly regulated by miR-21, and miR-21 expression was inversely correlated with hMSH2 expression in human lung cancer cell lines [2]. Notably, upregulation of miR-21 markedly promoted cell proliferation and revealed a higher proportion of cells at S phase. However, knockdown of miR-21 expression led to cell cycle arrest at G2/M phase and inhibited cell proliferation [2]. Similarly, tumor tissues showed an inverse correlation between high expression of miR-21 and low amounts of PTEN protein, where miR-21 suppresses PTEN by direct binding to the 30-UTR of PTEN [5]. Lung cancer cell lines (A549, H1703, and 801D) transfected with miR-21 inhibitor showed decreased endogenous miR-21 levels but significantly increased PTEN protein expression [5]. In addition, A549 and H1703 cells transfected with miR-21 inhibitor could restrain the growth of A549 and H1703 cells, and downregulation of miR-21 with miR-21 inhibitor in 801D cells could restrain its invasion ability [5]. Collectively, available evidence suggests that miR-21 may be a good biomarker for detection of lung cancer, and miR-21 may play an important role in lung cancer. However, further studies, especially in human systems, are needed to comprehensively explore the role of miR-21 in lung cancer, and miR-21 may be a potential therapeutic target for lung cancer. S.-C. Wang (&) Y.-F. Zhang Q. Xie PET/CT Center, Anhui Provincial Hospital, 17 Lujiang Road, Hefei 230001, Anhui, People’s Republic of China e-mail: wangsc3329@163.com

MicroRNA-198 inhibits proliferation and induces apoptosis of lung cancer cells via targeting FGFR1.

Lung cancer is the most common cause of death from cancer worldwide and recent studies have revealed that microRNAs play critical roles to regulate lung carcinogenesis. Here we present evidence to show the role of miR-198 in lung cancer development. Our results showed that ectopic expression of miR-198 inhibits the viability and induces the apoptosis of human non-small cell lung cancer cells A549 and NCI-H460, while miR-198 inhibition resulted in opposite changes. In nude mice miR-198 inhibits A549 growth of tumor graft. We further demonstrated that miR-198 directly targets fibroblast growth factor receptor 1 (FGFR1) in lung cancer cells. Restoring FGFR1 expression blocked the inhibitory function of miR-198, while FGFR1 inhibition achieved the similar phenotypes of miR-198 overexpression. Hence, our data delineates the molecular pathway by which miR-198 inhibits lung cancer cellular proliferation and induces apoptosis, and may have important implication for the treatment of lung carcinogenesis.

Effects of microRNA-126 on proliferation of lung adenocarcinoma A549 cells

Objective To explore the effect of microRNA-126 (miR-126) on the proliferation of lung adenocarcinoma A549 cells.Methods 549 cells in vitro were divided into 3 groups:group A treated only with liposomes,group B with miR-126 control,and group C with miR-126.The expression of miR-126 was detected by using Real-time quantitative polymerase chain reaction (Real-time PCR),and that of vascular endothelial growth factor (VEGF) protein by Western blotting,and methyl thiazol tetrazolium (MTr) assay was used to examine the growth of A549 cells.Results In group C,the expression level of miR-126 was increased to (0.786 ±0.132) as compared with group A (0.453 ±0.085) and group B (0.432 ±0.092) (P ＜0.01),and the VEGF protein expression was decreased to (0.312 ± 0.075) as compared with group A (0.633 ±0.172) and group B (0.597 ±0.095) (P ＜0.01).The growth of A549 cells in group C was inhibited significantly as compared with group A and group B (P ＜ 0.05).Conclusion MiR-126 transfection can significantly increase its expression in A549 cells,decrease the expression of VEGF protein,and suppress the cells growth. Key words: MicroRNA-126 ; Vascular endothelial growth factor; Proliferation ; Lung adenocarcinoma

Molecular mechanism of synergistic antitumor activity and induced apoptosis of zoledronic acid and paclitaxel

Objective: This study aimed to investigate the inhibitory effect of zoledronic acid(ZOL) alone or the combined treatment of ZOL and paclitaxel(PTX) on the cell growth of lung cancer cell line in vitro. Methods: The effects of different concentrations of ZOL alone, 2 nM PTX, and combined treatment of ZOL and PTX on the growth of A-549 cell line were determined using methyl thiazolyl tetrazolium(MTT) method. The mechanism of the curative effect was analyzed by flow cytometry on the basis of apoptotic rate. AKT, phospho-AKT, ERK, phospho-ERK, and Bcl-2 expressions were determined by western blot analysis. AKT and ERK gene expressions were determined by RT-PCR. Results: MTT results showed that ZOL alone could inhibit the growth of lung cancer cell line A-549 in a dose-dependent manner. The combined therapy of ZOL and PTX could inhibit cell growth. This combined treatment is more effective than the single treatment with either ZOL or PTX alone. The synergistic inhibition rate is dependent on drug sequencing. Furthermore, maximum inhibition was induced by sequence order, i.e., initial treatment with PTX and then with ZOL. RT-PCR results demonstrated that the mRNA of ERK and AKT of the group treated with PTX and then ZOL were lower than that in other treatment groups. Western blot analysis results demonstrated that the ERK and AKT levels of the treated groups were parallel in the cell line. However, the lowest phospho-ERK, phospho-AKT, and Bcl-2 levels were observed in the PTX then ZOL group. The cell lines treated with PTX alone and ZOL alone ranked second and third among the lowest results, respectively. The highest level was observed in the control group. Conclusion: The combined ZOL and PTX treatment induced the downregulation of phospho-ERK, phospho-AKT, and Bcl-2 protein expressions in RAF/MEK/ERK and PI3K/AKT signaling pathway. This pathway could be one of the synergistic antitumor mechanisms of the two drugs.

Cytotoxicity and DNA damage properties of tert-butylhydroquinone (TBHQ) food additive

Tert-butylhydroquinone (TBHQ) was tested for potential cytotoxicity and genotoxicity upon A549 lung cancer cells and Human Umbilical Vein Endothelial Cells (HUVEC). Cytotoxicity was evaluated by MTT assay and flow cytometry analysis, while genotoxicity was assessed in vitro by alkaline comet, DNA fragmentation and DAPI staining assays. TBHQ dose- and time-dependently decreased the growth of A549 and HUVEC cells. Flow cytometry analyses determined early and late apoptosis in the treated cells. Also, single strand DNA breaking has been observed through comet assay technique. In addition, morphology of DAPI stained cells and DNA fragmentation assay using gel electrophoresis showed clear fragmentation in the chromatin and DNA rings within the nucleus of cell’s treated TBHQ.

Anticancer drug-loaded multifunctional nanoparticles to enhance the chemotherapeutic efficacy in lung cancer metastasis

BackgroundInhalation of chemotherapeutic drugs directly into the lungs augments the drug exposure to lung cancers. The inhalation of free drugs however results in over exposure and causes severe adverse effect to normal cells. In the present study, epidermal growth factor (EGF)-modified gelatin nanoparticles (EGNP) was developed to administer doxorubicin (DOX) to lung cancers.ResultsThe EGNP released DOX in a sustained manner and effectively internalized in EGFR overexpressing A549 and H226 lung cancer cells via a receptor-mediated endocytosis. In vitro cytotoxicity assay showed that EGNP effectively inhibited the growth of A549 and H226 cells in a dose-dependent manner. In vivo biocompatibility study showed that both GNP and EGNP did not activate the inflammatory response and had a low propensity to cause immune response. Additionally, EGNP maintained a high therapeutic concentration in lungs throughout up to 24 h comparing to that of free drug and GNP, implying the effect of ligand-targeted tumor delivery. Mice treated with EGNP remarkably suppressed the tumor growth (~90% tumor inhibition) with 100% mice survival rate. Furthermore, inhalation of EGNP resulted in elevated levels of cleaved caspase-3 (apoptotic marker), while MMP-9 level significantly reduced comparing to that of control group.ConclusionsOverall, results suggest that EGF surface-modified nanocarriers could be delivered to lungs via inhalation and controlled delivery of drugs in the lungs will greatly improve the therapeutic options in lung cancer therapy. This ligand-targeted nanoparticulate system could be promising for the lung cancer treatment.

Synthesis of amino acid esters of the ruthenium naphthalene complex [(C5Me4CH2OH)Ru(C10H8)

Ruthenium naphthalene complex [(C5Me4CH2OH)Ru(C10H8)]+ (2) with hydroxy-substituted cyclopentadienyl ligand reacts with N-Boc-protected alanine, methionine, phenylalanine, and tryptophan in the presence of dicyclohexylcarbodiimide giving organometallic esters of amino acids [(C5Me4CH2OOCCH(CH2R)NHBoc)Ru(C10H8)]+ (3a–d) in 70–86% yields. Irradiation of phenylalanine derivative 3c at 365nm results in replacement of the naphthalene ligand by the phenyl group giving ansa-complex [(η5-C5Me4)CH2OOCCH(CH2-η6-Ph)NHBoc)Ru]+ (4) in 47% yield. Complexes [3c,d]BF4 containing phenylalanine and tryptophan residues effectively inhibit growth of cancer cell lines B16, MeWo, SCOV3, SKBR3, and A549 (IC50=21–96μM) with activity and selectivity being close to those of the cisplatin. The structure of the alanine derivative [3a]BPh4 was established by X-ray diffraction.

Synthesis and evaluation of (Z)-2,3-diphenylacrylonitrile analogs as anti-cancer and anti-microbial agents

In the present study, a series of (Z)-2,3-diphenylacrylonitrile analogs were synthesized and then evaluated in terms of their cytotoxic activities against four human cancer cell lines, e.g. lung cancer (A549), ovarian cancer (SK-OV-3), skin cancer (SK-MEL-2), and colon cancer (HCT15), as well as anti-microbial activities against three microbes, e.g. Staphylococcus aureus, Salmonella typhi, and Aspergillus niger. The title compounds were synthesized by Knoevenagel condensation reaction of benzyl cyanide or p-nitrobenzyl cyanide with substituted benzaldehydes in good yields. Most of the compounds exhibited significant suppressive activities against the growth of all cancer cell lines. Compound 3c was most active in inhibiting the growth of A549, SK-OV-3, SK-MEL-2, and HCT15 cells lines with IC50 values of 0.57, 0.14, 0.65, and 0.34 mg/mL, respectively, followed by compounds 3f, 3i, and 3h. Compound 3c exhibited 2.4 times greater cytotoxic activity against HCT15 cells, whereas it showed similar potency against SK-OV-3 cells to that of the standard anti-cancer agent doxorubicin. Structure–activity relationship study revealed that electron-donating groups at the para-position of phenyl ring B were more favorable for improved cytotoxic activity, whereas the presence of electron-withdrawing groups was unfavorable compare to unsubstituted acrylonitrile. An optimal electron density on phenyl ring A of (Z)-2,3-diphenylacrylonitrile analogs was crucial for their cytotoxic activities against human cancer cell lines used in the present study. Qualitative structure–cytotoxic activity relationships were studied using physicochemical parameters; a good correlation between calculated polar surface area (PSA), a lipophobic parameter, and cytotoxic activity was found. Moreover, all compounds showed significant anti-bacterial activities against S. typhi, whereas compound 3k showed potent inhibition against both S. aureus and S. typhi bacterial strains.

YL529, a novel, orally available multikinase inhibitor, potently inhibits angiogenesis and tumour growth in preclinical models.

Targeted chemotherapy using small-molecule inhibitors of angiogenesis and proliferation is a promising strategy for cancer therapy. YL529 was developed via computer-aided drug design, de novo synthesis and high-throughput screening. The biochemical, pharmacodynamic and toxicological profiles of YL529 were investigated using kinase and cell viability assays, a mouse tumour cell-containing alginate bead model, a zebrafish angiogenesis model and several human tumour xenograft models in athymic mice. In vitro, YL529 selectively inhibited the activities of VEGFR2/VEGFR3 and serine/threonine kinase RAF kinase. YL529 inhibited VEGF165 -induced phosphorylation of VEGFR2, as well as the proliferation, migration, invasion and tube formation of human umbilical vascular endothelial cells. It also significantly blocked vascular formation and angiogenesis in the zebrafish model. Moreover, YL529 strongly attenuated the proliferation of A549 cells by disrupting the RAF/mitogen-activated protein (MAP) or extracellular signal-regulated kinase (Erk) kinase (MEK) kinase kinase/MAPK pathway. Oral administration of YL529 (37.5-150 mg(-1) ·kg(-1) ·day(-1) ) to nude mice bearing established tumour xenografts significantly prevented the growth (60-80%) of A549, SPC-A1, A375, OS-RC-2 and HCT116 tumours without detectable toxicity. YL529 markedly reduced microvessel density and increased tumour cell apoptosis in the tumours formed in mice inoculated with the lung cancer cells, SPC-A1 and A549, and the colon carcinoma cells, HCT116. YL529, an orally active multikinase inhibitor, shows therapeutic potential for solid tumours, and warrants further investigation as a possible anticancer agent.