Targeted therapies for non-small cell lung cancer

Dempke, Wolfram; Sütö, Tamás; Reck, Martin

doi:10.1016/j.lungcan.2009.10.012

Cited by 139 publications

(122 citation statements)

References 137 publications

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“…31 Although platinum-based combination chemotherapy is the first-line therapy of choice, the prognosis for patients with advanced NSCLC remains poor. 32 Frequent multidrug resistance to chemotherapeutic agents is a main barrier to possibly curative treatments for advanced NSCLC. 33 It is therefore required new therapeutic agents that selectively target altered signaling pathways.…”

Section: Downregulation Of Pc4 Inhibits Tumorigenicity Of A549 Cells mentioning

confidence: 99%

Human positive coactivator 4 is a potential novel therapeutic target in non-small cell lung cancer

et al. 2012

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Transcriptional positive coactivator 4 (PC4) is a multifunctional nuclear protein that has important roles in DNA transcription, replication, repair and heterochromatinization. However, the role of PC4 in cancer remains to be clarified. Several studies propose that PC4 may act as a putative tumor suppressor. Here, we demonstrate for the first time that PC4 may represent a potential therapeutic target in non-small cell lung cancer (NSCLC). PC4 protein expression is significantly upregulated in NSCLC carcinoma tissues compared with their adjacent noncancerous counterparts as shown by immunohistochemical staining and western blotting in 104 pairs of formalin-fixed human NSCLC specimens and 6 fresh NSCLC samples. Knockdown of PC4 expression by sequence-specific small interfering RNA (siRNA) in human NSCLC cells (A549, H460 and H358) significantly inhibits the growth of cancer cells by the induction of cell cycle arrest and the increase of cell apoptosis in vitro. Interrupting the PC4 signaling pathway by injection of the PC4 siRNA liposome complex produced an effective regression of pre-established A549 cell xenografts in mice through growth inhibition and increased apoptosis. These results indicated that PC4 could be an attractive new therapeutic target for the treatment of NSCLC.

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Section: Downregulation Of Pc4 Inhibits Tumorigenicity Of A549 Cells mentioning

confidence: 99%

Human positive coactivator 4 is a potential novel therapeutic target in non-small cell lung cancer

et al. 2012

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“…Non-small cell lung cancer (NSCLC) accounts for ∼80%-85% of all cases of lung cancer (Dempke et al 2010). Despite the advent of new drugs and therapeutic regimens, lung cancer prognosis has not changed significantly in the last two decades (Fabbri et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Reproducible combinatorial regulatory networks elucidate novel oncogenic microRNAs in non-small cell lung cancer

Mitra

Edmonds

Sun

et al. 2014

RNA

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While previous studies reported aberrant expression of microRNAs (miRNAs) in non-small cell lung cancer (NSCLC), little is known about which miRNAs play central roles in NSCLC's pathogenesis and its regulatory mechanisms. To address this issue, we presented a robust computational framework that integrated matched miRNA and mRNA expression profiles in NSCLC using feed-forward loops. The network consists of miRNAs, transcription factors (TFs), and their common predicted target genes. To discern the biological meaning of their associations, we introduced the direction of regulation. A network edge validation strategy using three independent NSCLC expression profiling data sets pinpointed reproducible biological regulations. Reproducible regulation, which may reflect the true molecular interaction, has not been applied to miRNA-TF coregulatory network analyses in cancer or other diseases yet. We revealed eight hub miRNAs that connected to a higher proportion of targets validated by independent data sets. Network analyses showed that these miRNAs might have strong oncogenic characteristics. Furthermore, we identified a novel miRNA-TF co-regulatory module that potentially suppresses the tumor suppressor activity of the TGF-β pathway by targeting a core pathway molecule (TGFBR2). Follow-up experiments showed two miRNAs (miR-9-5p and miR-130b-3p) in this module had increased expression while their target gene TGFBR2 had decreased expression in a cohort of human NSCLC. Moreover, we demonstrated these two miRNAs directly bind to the 3 ′ untranslated region of TGFBR2. This study enhanced our understanding of miRNA-TF co-regulatory mechanisms in NSCLC. The combined bioinformatics and validation approach we described can be applied to study other types of diseases.

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“…Current drugs cannot meet the therapeutic needs [6] . Previous study demonstrated that CrTX has cytotoxic effects on A549 cells, which are human lung adenocarcinoma cells with the wild type p53 gene, and shows synergistic effects when combined with Iressa, which is currently a widely-used drug for lung cancer therapy [7,8] .…”

Section: Introductionmentioning

confidence: 99%

Anti-tumor activity of CrTX in human lung adenocarcinoma cell line A549

et al. 2011

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Aim: To assess the cytotoxic effect of crotoxin (CrTX), a potent neurotoxin extracted from the venom of the pit viper Crotalus durissus terrificus, in human lung adenocarcinoma A549 cells and investigated the underlying mechanisms. Methods: A549 cells were treated with gradient concentrations of CrTX, and the cell cycle and apoptosis were analyzed using a flow cytometric assay. The changes of cellular effectors p53, caspase-3 and cleaved caspase-3, total P38MAPK and pP38MAPK were investigated using Western blot assays. A549 xenograft model was used to examine the inhibition of CrTX on tumor growth in vivo. Results: Treatment of A549 cells with CrTX (25-200 μg/mL) for 48 h significantly inhibited the cell growth in a dose-dependent manner (IC 50 =78 μg/mL). Treatment with CrTX (25 μg/mL) for 24 h caused G1 arrest and induced cell apoptosis. CrTX (25 μg/mL) significantly increased the expression of wt p53, cleaved caspase-3 and phospho-P38MAPK. Pretreatment with the specific P38MAPK inhibitor SB203580 (5 μmol/L) significantly reduced CrTX-induced apoptosis and cleaved caspase-3 level, but G 1 arrest remained unchanged and highly expressed p53 sustained. Intraperitoneal injection of CrTX (10 μg/kg, twice a week for 4 weeks) significantly inhibited A549 tumor xenograft growth, and decreased MVD and VEGF levels. Conclusion: CrTX produced significant anti-tumor effects by inducing cell apoptosis probably due to activation of P38MAPK and caspase-3, and by cell cycle arrest mediated by increased wt p53 expression. In addition, CrTX displayed anti-angiogenic effects in vivo.

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Targeted therapies for non-small cell lung cancer

Cited by 139 publications

References 137 publications

Human positive coactivator 4 is a potential novel therapeutic target in non-small cell lung cancer

Human positive coactivator 4 is a potential novel therapeutic target in non-small cell lung cancer

Reproducible combinatorial regulatory networks elucidate novel oncogenic microRNAs in non-small cell lung cancer

Anti-tumor activity of CrTX in human lung adenocarcinoma cell line A549

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