INHIBITION OF LUNG CANCER CELL GROWTH BY QUERCETIN GLUCURONIDES VIA G<sub>2</sub>/M ARREST AND INDUCTION OF APOPTOSIS

Yang, Jen‐Hung; Hsia, Te Chun; Kuo, Hsiu Maan; Chao, Pei Dawn Lee; Chou, Chi‐Chung; Wei, Yau‐Huei; Chung, Jing Gung

doi:10.1124/dmd.105.005280

Cited by 161 publications

(127 citation statements)

References 49 publications

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“…Additionally, CHC has also been identified as an inhibitor of the anion exchanger 1 (Deuticke 1982), an important pH regulator that is responsible for Cl K /HCO 3 K membrane exchange (Kopito 1990). Different effects have been identified as mediating the antitumour activity of quercetin, including cell cycle arrest (Yang et al 2006) and apoptosis (Granado-Serrano et al 2006, Yang et al 2006, as well as inhibition of the phosphatidylinositol 3-kinase/Akt pathway Granado-Serrano et al 2006). However, we observed that quercetin only affected the MCT1-positive breast cancer cells at the metabolic level with no disturbance in the metabolic behaviour of MCT1-negative breast cancer cell lines, indicating some preference for MCT inhibition.…”

Section: Discussioncontrasting

confidence: 40%

Differential sensitivities to lactate transport inhibitors of breast cancer cell lines

Morais-Santos¹,

Miranda-Gonçalves²,

Pinheiro³

et al. 2013

Endocrine-Related Cancer

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The tumour microenvironment is known to be acidic due to high glycolytic rates of tumour cells. Monocarboxylate transporters (MCTs) play a role in extracellular acidification, which is widely known to be involved in tumour progression. Recently, we have described the upregulation of MCT1 in breast carcinomas and its association with poor prognostic variables. Thus, we aimed to evaluate the effect of lactate transport inhibition in human breast cancer cell lines. The effects of a-cyano-4-hydroxycinnamate, quercetin and lonidamine on cell viability, metabolism, proliferation, apoptosis, migration and invasion were assessed in a panel of different breast cancer cell lines. MCT1, MCT4 and CD147 were differently expressed among the breast cancer cell lines and, as expected, different sensitivities were observed for the three inhibitors. Interestingly, in the most sensitive cell lines, lactate transport inhibition induced a decrease in cell proliferation, migration and invasion, as well as an increase in cell death. Results were validated by silencing MCT1 expression using siRNA. The results obtained here support targeting of lactate transport as a strategy to treat breast cancer, with a special emphasis on the basal-like subtype, which so far does not have a specific molecular therapy.

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Section: Discussioncontrasting

confidence: 40%

Differential sensitivities to lactate transport inhibitors of breast cancer cell lines

Morais-Santos¹,

Miranda-Gonçalves²,

Pinheiro³

et al. 2013

Endocrine-Related Cancer

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“…The flavone-induced G 2 -M arrest apparent in breast cancer cells in the present study was likely mediated by p21 Waf1 , which induces such arrest in a variety of cell types [33,34,35,36]. In contrast to its effects in malignant cells, flavone induced G 0 -G 1 arrest without apoptosis in nonmalignant breast epithelial cells, suggesting that nonmalignant cells might be able to regain their proliferative capacity.…”

Section: Discussionmentioning

confidence: 44%

Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines

Ullmannova

Popescu

2007

Cancer Detection and Prevention

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Background-Dietary flavone was previously shown to increase the expression of deleted in liver cancer-1 gene (DLC-1) in HT-29 colon carcinoma cell line (Proteomics 2004;4:2455-64). DLC-1 that encodes a Rho GTPase-activating protein, functions as a tumor suppressor gene and is frequently inactivated or down-regulated in several common cancers. Restoration of DLC-1 expression suppresses in vitro tumor cells proliferation and tumorigenicity in vivo.Methods-Here, the effect of flavone was examined in several DLC-1-deficient cell lines derived from different types human cancer using assays for cell proliferation, gene expression and transfer.Results-We show that exposure to 15μM flavone increased DLC1 expression in breast but not in liver or prostate carcinoma cells or a nonmalignant breast epithelial cell line. Flavone restored the expression of DLC1 in the breast carcinoma cell lines MDA-MB-468, MDA-MB-361, and BT20 as well as in the colon carcinoma cell line HT-29 all of which are DLC-1-negative due to promoter hypermethylation. We further show that flavone inhibited cell proliferation, induced cell cycle arrest at G2-M, increased p21 Waf1 gene expression, and caused apoptosis. Microarray analysis of these aggressive and metastatic breast carcinoma cells revealed 29 flavone-responsive genes, among which the DNA damage-inducible GADD genes were up-regulated and the proto-oncogene STMN1 and IGFBP3 were down-regulated.Conclusions-Flavone-mediated alterations of genes that regulate tumor cell proliferation, cell cycle, and apoptosis contribute to chemopreventive and antitumoral effects of flavone. Alone or in combination with demethylating agents, flavone may be an effective adjunct to chemotherapy in preventing breast cancer metastasis.

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“…Survivin, a member of the inhibitor of apoptosis gene family, is expressed in a cell cycle-dependent manner, increasing in the G2/M phase of the cell cycle followed by a rapid decline in the G1 phase [26,27]. Recent studies have revealed that quercetin inhibits cell proliferation by causing cell cycle arrest in G2/M phase [28,29]. Although quercetin causes cells to arrest in G2/M phase, expression of survivin is down-regulated by treatment with quercetin (Fig.…”

Section: Discussionmentioning

confidence: 99%

Quercetin augments TRAIL-induced apoptotic death: Involvement of the ERK signal transduction pathway

Kim

Lee

Jeong

et al. 2008

Biochemical Pharmacology

155

115

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Combined treatment with quercetin and TRAIL induced cytotoxicity and enhanced annexin V staining and poly (ADP-ribose) polymerase (PARP) cleavage in human prostate cancer cell lines DU-145 and PC-3. These indicators of apoptosis resulted from the activation of caspase-8, -9, and -3. Although the expression levels of FLIPs, cIAP1, cIAP2, and the Bcl-2 family were not changed in quercetin-treated cells, significant downregulation of survivin occurred. Knockdown survivin by siRNA significantly increased TRAIL-induced apoptosis. We hypothesized that quercetin-induced activation of MAPK (ERK, p38, JNK) is responsible for downregulation of survivin gene expression. To test this hypothesis, we selectively inhibited MAPK during treatment with quercetin. Our data demonstrated that inhibitor of ERK (PD98059), but not p38 MAPK (SB203580) or JNK (SP600125), significantly maintained the intracellular level of survivin during treatment with quercetin. Interestingly, PD98059 also prevented quercetin-induced deacetylation of histone H3. Data from survivin promoter activity assay suggest that the Sp1 transcription factor binds to the survivin promoter region and quercetin inhibits its binding activity through deacetylation of histone H3. Quercetin-induced activation of the ERK-MSK1 signal transduction pathway may be responsible for deacetylation of histone H3. Taken together, our findings suggest that quercetin enhances TRAIL induced apoptosis by inhibition of survivin expression, through ERK-MSK1-mediated deacetylation of H3.

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INHIBITION OF LUNG CANCER CELL GROWTH BY QUERCETIN GLUCURONIDES VIA G₂/M ARREST AND INDUCTION OF APOPTOSIS

Abstract: ABSTRACT:Lung cancer is the leading cause of cancer death in many developed countries, including Taiwan

Cited by 161 publications

References 49 publications

Differential sensitivities to lactate transport inhibitors of breast cancer cell lines

Differential sensitivities to lactate transport inhibitors of breast cancer cell lines

Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines

Quercetin augments TRAIL-induced apoptotic death: Involvement of the ERK signal transduction pathway

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INHIBITION OF LUNG CANCER CELL GROWTH BY QUERCETIN GLUCURONIDES VIA G2/M ARREST AND INDUCTION OF APOPTOSIS

Abstract: ABSTRACT:Lung cancer is the leading cause of cancer death in many developed countries, including Taiwan

Cited by 161 publications

References 49 publications

Differential sensitivities to lactate transport inhibitors of breast cancer cell lines

Differential sensitivities to lactate transport inhibitors of breast cancer cell lines

Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines

Quercetin augments TRAIL-induced apoptotic death: Involvement of the ERK signal transduction pathway

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INHIBITION OF LUNG CANCER CELL GROWTH BY QUERCETIN GLUCURONIDES VIA G₂/M ARREST AND INDUCTION OF APOPTOSIS