Epidermal Growth Factor Receptor Mediates Silibinin-Induced Cytotoxicity in a Rat Glioma Cell Line

Lin, Qi; Singh, Rana P.; Lu, Yingnian; Agarwal, Rajesh; Harrison, Gail Singer; Franzusoff, Alex; Glode, L. Michael

doi:10.4161/cbt.2.5.452

Cited by 29 publications

(19 citation statements)

References 11 publications

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“…Recently, silibinin, a flavonoid antioxidant derived from milk thistle, has been shown to up-regulate IGFBP-3 to inhibit proliferation of prostate cancer cells (49). Interestingly, EGFR appeared to mediate the cytotoxic effect of silibinin on rat glioma cells (50).…”

Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Receptor Regulates Aberrant Expression of Insulin-Like Growth Factor-Binding Protein 3

et al. 2004

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Epidermal growth factor receptor (EGFR) is frequently overexpressed in esophageal carcinoma and its precursor lesions. To gain insights into how EGFR overexpression affects cellular functions in primary human esophageal cells, we performed gene expression profiling and identified insulin-like growth factor-binding protein (IGFBP)-3 as the most upregulated gene. IGFBP-3 regulates cell proliferation through both insulinlike growth factor-dependent and independent mechanisms. We found that IGFBP-3 mRNA and protein expression was increased in EGFRoverexpressing primary and immortalized human esophageal cells. IG-FBP-3 was also up-regulated in EGFR-overexpressing cells in organotypic culture and in EGFR transgenic mice. Furthermore, IGFBP-3 mRNA was overexpressed in 80% of primary esophageal squamous cell carcinomas and 60% of primary esophageal adenocarcinomas. Concomitant upregulation of EGFR and IGFBP-3 was observed in 60% of primary esophageal squamous cell carcinomas. Immunohistochemistry revealed cytoplasmic localization of IGFBP-3 in the preponderance of preneoplastic and neoplastic esophageal lesions. IGFBP-3 was also overexpressed in esophageal cancer cell lines at both mRNA (60%) and protein (40%) levels. IGFBP-3 secreted by cancer cells was capable of binding to insulinlike growth factor I. Functionally, epidermal growth factor appeared to regulate IGFBP-3 expression in esophageal cancer cell lines. Finally, suppression of IGFBP-3 by small interfering RNA augmented cell proliferation, suggesting that IGFBP-3 may inhibit tumor cell proliferation as a negative feedback mechanism. In aggregate, we have identified for the first time that IGFBP-3 is an aberrantly regulated gene through the EGFR signaling pathway and it may modulate EGFR effects during carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Receptor Regulates Aberrant Expression of Insulin-Like Growth Factor-Binding Protein 3

et al. 2004

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“…In glioblastoma models, silibinin was shown to inhibit growth and invasiveness and induce apoptosis (73,74). Silibinin was also reported to inhibit EGFR activation in a rat glioma cell line stably expressing human EGFR (75). NF-κB-mediated stimulation of MMP-9 in glioblastoma U87 cells was found to be abrogated by silibinin treatment which served to attenuate invasiveness (74).…”

Section: Broad Spectrum Cancer Chemopreventive Efficacy Of Silibininmentioning

confidence: 99%

Molecular Mechanisms of Silibinin-Mediated Cancer Chemoprevention with Major Emphasis on Prostate Cancer

Ting

Deep

Agarwal

2013

AAPS J

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Abstract. Despite advances in early detection, prostate cancer remains the second highest cancer mortality in American men, and even successful interventions are associated with enormous health care costs as well as prolonged deleterious effects on quality of patient life. Prostate cancer chemoprevention is one potential avenue to alleviate these burdens. It is a regime whereby long-term treatments are intended to prevent or arrest cancer development, in contrast to more direct intervention upon disease diagnosis. Based on this intention, cancer chemoprevention generally focuses on the use of nontoxic chemical agents which are well-tolerated for prolonged usage that is necessary to address prostate cancer's multistage and lengthy period of progression. One such nontoxic natural agent is the flavonoid silibinin, derived from the milk thistle plant (Silybum marianum), which has ancient medicinal usage and potent antioxidant activity. Based on these properties, silibinin has been investigated in a host of cancer models where it exhibits broad-spectrum efficacy against cancer progression both in vitro and in vivo without noticeable toxicity. Specifically in prostate cancer models, silibinin has shown the ability to modulate cell signaling, proliferation, apoptosis, epithelial to mesenchymal transition, invasion, metastasis, and angiogenesis, which taken together provides strong support for silibinin as a candidate prostate cancer chemopreventive agent.

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“…It was previously shown that silibinin is able to inhibit EGF binding to EGFR in vitro (14). Silibinin can inhibit EGFR activity through alternative mechanisms in cells with EGFR mutations because kinase domain mutations in the EGFR gene lead to constitutive ligand-independent stimulation of the tyrosine kinase activity (24).…”

Section: Silibinin Inhibits Homo-and Heterodimerization Of Egfr In Cementioning

confidence: 99%

“…The anticancer efficacy of silibinin is associated with cell cycle arrest, apoptosis, and antiangiogenesis (13). It also inhibits a variety of growth signal receptors including EGFR (14), insulin-like growth factor receptor 1 (IGFR-1; 15) and vascular endothelial growth factor receptor 1 (16). Thus, it is reasonable to think that silibinin would enhance the activity of EGFR-TKIs leading to apoptosis and growth inhibition of resistant cells in which EGFR-TKIs have failed to completely abolish EGFR activity.…”

Section: Introductionmentioning

confidence: 99%

Combined Treatment with Silibinin and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Overcomes Drug Resistance Caused by T790M Mutation

Rho

Choi

Jeon

et al. 2010

Molecular Cancer Therapeutics

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Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) produce an initially dramatic response in lung cancer patients harboring a mutation in the EGFR gene, development of acquired resistance is almost inevitable. A secondary mutation of threonine 790 (T790M) is associated with approximately half of the cases of acquired resistance. This study investigated whether the addition of silibinin to therapy with gefitinib or erlotinib could overcome T790M-mediated drug resistance considering that silibinin has various antitumor effects, including EGFR modulation. Silibinin selectively reduced the activity of the EGFR family (EGFR, ErbB2, and ErbB3) through the inhibition of receptor dimerization in lung cancer cells with EGFR mutations, but not in those harboring the wild type. In primary and acquired resistant cells with T790M, addition of silibinin enhanced the ability of EGFR-TKIs to downregulate EGFR signals and to inhibit cell growth. Similarly, the combination of silibinin and erlotinib effectively suppressed tumor growth in erlotinib resistance-bearing PC-9 xenografts. The results indicate that the addition of silibinin to EGFR-TKIs is a promising strategy to overcome T790M-mediated drug resistance. Mol Cancer Ther; 9(12); 3233-43. Ó2010 AACR.

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Epidermal Growth Factor Receptor Mediates Silibinin-Induced Cytotoxicity in a Rat Glioma Cell Line

Cited by 29 publications

References 11 publications

Epidermal Growth Factor Receptor Regulates Aberrant Expression of Insulin-Like Growth Factor-Binding Protein 3

Epidermal Growth Factor Receptor Regulates Aberrant Expression of Insulin-Like Growth Factor-Binding Protein 3

Molecular Mechanisms of Silibinin-Mediated Cancer Chemoprevention with Major Emphasis on Prostate Cancer

Combined Treatment with Silibinin and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Overcomes Drug Resistance Caused by T790M Mutation

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