Current Standards of Care in Small-Cell and Non-Small-Cell Lung Cancer

Schiller, Joan H.

doi:10.1159/000055386

Cited by 140 publications

(108 citation statements)

References 58 publications

(95 reference statements)

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“…NSCLC accounts for 80% of all lung cancer cases, with adenocarcinoma being the major subtype (3). NSCLC is less responsive to chemotherapy and as such has been the main focus of current research on investigating new drugs for its therapy (4). The prognosis of lung cancer is poor because of the late diagnosis at advanced stage (5).…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of Quercitrin-induced Apoptosis in Non-small Cell Lung Cancer

Çinçin

Unlu

Kıran

et al. 2014

Archives of Medical Research

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Background and Aims. Quercitrin (QR; quercetin-3-O-rhamnoside) has been used previously as an antibacterial agent and has been shown to inhibit the oxidation of low-density lipoproteins and prevent an allergic reaction. Furthermore, it was demonstrated that quercitrin exerts protective effects against H 2 O 2 -induced dysfunction in lung fibroblast cells. However, the mechanisms of quercitrin effects on cancer cell proliferation and apoptosis is not well understood. The aim of this study is to investigate the cytotoxic and apoptotic effects of quercitrin and the molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer (NSCLC) cell lines. Methods. Time-and dose-dependent antiproliferative and apoptotic effects of quercitrin determined by WST-1 cell proliferation assay, lactate dehydrogenase (LDH) cytotoxicity assay, determination of nucleosome enrichment factor, changes in caspase-3 activity, loss of mitochondrial membrane potential (MMP) and also the localization of phosphatidylserine in the plasma membrane. Changes in whole genome gene expression levels were examined by Illumina Human HT-12v4 beadchip microarrays.Results. There were significant increases in caspase-3 activity, loss of MMP, and increases in apoptotic cell population in response to quercitrin in A549 and NCI-H358 NSCLC cells in a time-and dose-dependent manner. Conclusion. Our results demonstrated that genes involved in leukocyte transendothelial migration, cell adhesion and phosphatidylinositol signaling system pathways were the most statistically significant pathways in NCI-H358 and A549 cells. These results revealed that quercitrin has antiproliferative and apoptotic effects on lung cancer cells by modulating the immune response. After confirming its anticarcinogenic effects in vivo, quercitrin could be a novel and strong anticancer agent against NSCLC. Ó 2014 IMSS. Published by Elsevier Inc.

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Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of Quercitrin-induced Apoptosis in Non-small Cell Lung Cancer

Çinçin

Unlu

Kıran

et al. 2014

Archives of Medical Research

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“…Mechanistically, the resistance phenomena may be explained by (i) mutation or overexpression of drug target proteins, and/or (ii) inactivation of drugs by a reduction in uptake or enhanced detoxification and removal of drugs. Currently, radiation and platinum-based drugs are the standard treatment for lung cancer (1). However, the toxicity profiles and high rate of relapse with platinum compounds limit their use and effectiveness.…”

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confidence: 99%

Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism

Ren

Villeneuve

Jiang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

559

506

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The major obstacle in cancer treatment is the resistance of cancer cells to therapies. Nrf2 is a transcription factor that regulates a cellular defense response and is ubiquitously expressed at low basal levels in normal tissues due to Keap1-dependent ubiquitination and proteasomal degradation. Recently, Nrf2 has emerged as an important contributor to chemoresistance. High constitutive expression of Nrf2 was found in many types of cancers, creating an environment conducive for cancer cell survival. Here, we report the identification of brusatol as a unique inhibitor of the Nrf2 pathway that sensitizes a broad spectrum of cancer cells and A549 xenografts to cisplatin and other chemotherapeutic drugs. Mechanistically, brusatol selectively reduces the protein level of Nrf2 through enhanced ubiquitination and degradation of Nrf2. Consequently, expression of Nrf2-downstream genes is reduced and the Nrf2-dependent protective response is suppressed. In A549 xenografts, brusatol and cisplatin cotreatment induced apoptosis, reduced cell proliferation, and inhibited tumor growth more substantially when compared with cisplatin treatment alone. Additionally, A549-K xenografts, in which Nrf2 is expressed at very low levels due to ectopic expression of Keap1, do not respond to brusatol treatment, demonstrating that brusatol-mediated sensitization to cisplatin is Nrf2 dependent. Moreover, a decrease in drug detoxification and impairment in drug removal may be the primary mechanisms by which brusatol enhances the efficacy of chemotherapeutic drugs. Taken together, these results clearly demonstrate the effectiveness of using brusatol to combat chemoresistance and suggest that brusatol can be developed into an adjuvant chemotherapeutic drug.

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“…Lung cancer can be divided into two major histopathological groups: non-small-cell lung cancer (NSCLC) (Van Zandwijk et al 1995) and small-cell lung cancer (SCLC) (Schiller 2001). About 80% of lung cancers are NSCLC, and they are subdivided into adenocarcinomas, squamous cell, bronchioalveolar, and large-cell carcinomas (Travis 2002).…”

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confidence: 99%

Mouse models for human lung cancer

Meuwissen

Berns²

2005

Genes Dev.

272

243

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In recent years several new mouse models for lung cancer have been described. These include models for both non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Tumorigenesis in these conditional mouse tumor models can be initiated in adult mice through Cre-recombinase-induced activation of oncogenic mutations in a subset of the cells. They present a marked improvement over mouse models that depend on carcinogen induction of tumors. These models permit us to study the consecutive steps involved in initiation and progression and allow us to address questions like the cell of origin, and the role of cancer stem cells in the maintenance of these tumors. They now need to be validated as suitable preclinical models for intervention studies in which questions with respect to therapy response and resistance can be addressed.During the last decades lung cancer has become the leading cause of cancer deaths in the world, accounting for even more solid tumor deaths than breast, pancreatic, prostate, and colorectal combined (Landis et al. 1999). More then 170,000 new cases are being diagnosed each year in the United States alone, of whom ∼160,000 will eventually die, representing 28% of all cancer deaths (Jemal et al. 2004). Worldwide more than a million deaths are due to lung cancer. Tobacco smoking is the major causal agent, being responsible for ∼85% of the lung cancer incidence. Other respiratory exposure to occupational or environmental carcinogens, such as asbestos or radon, and yet unknown genetic factors contribute to the remaining 15% . Although smoking cessation before the age of 30 does substantially reduce the risk of lung cancer, this is significantly less for those who stop smoking at 50 or 60 yr (Peto et al. 2000;Doll et al. 2004). Interestingly, nearly 50% of all first diagnosed lung cancers in the United States are from people who stopped smoking at least 5 or more years ago (Peto and Lopez 2001). This indicates that extensive damage to the respiratory tract can persist over many years. Indeed, recent studies (Mao 2002;Pfeifer et al. 2002;Wistuba et al. 2002) showed the presence of multiple genetic lesions, often manifested in clonal patches of cells in respiratory epithelium of current and former smokers.Lung cancer can be divided into two major histopathological groups: non-small-cell lung cancer (NSCLC) (Van Zandwijk et al. 1995) SCLC and NSCLC show major differences in histopathologic characteristics that can be explained by the distinct patterns of genetic lesions found in both tumor classes . Responsiveness to treatment with chemotherapy and/or radiation also differs significantly between NSCLC and SCLC and has a dramatic effect on clinical treatment outcome. The overall 5-yr survival rate for lung cancer is ∼14% (Travis et al. 1995); for SCLC alone it is even worse, ∼5% (Worden and Kalemkerian 2000).Spontaneous lung tumors in mice are similar in morphology, histopathology, and molecular characteristics to human adenocarcinomas. Mouse models for lung cancer can thus serve as a valua...

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Current Standards of Care in Small-Cell and Non-Small-Cell Lung Cancer

Cited by 140 publications

References 58 publications

Molecular Mechanisms of Quercitrin-induced Apoptosis in Non-small Cell Lung Cancer

Molecular Mechanisms of Quercitrin-induced Apoptosis in Non-small Cell Lung Cancer

Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism

Mouse models for human lung cancer

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