Silibinin Impairs Constitutively Active TGFα-EGFR Autocrine Loop in Advanced Human Prostate Carcinoma Cells

Tyagi, Alpna; Sharma, Yogesh Kumar; Agarwal, Chapla; Agarwal, Rajesh

doi:10.1007/s11095-008-9545-z

Cited by 29 publications

(22 citation statements)

References 29 publications

(44 reference statements)

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“…Previous studies showed that silibinin could inhibit EGFR activity through various mechanisms such as suppression of ligand binding (30) or reduction of ligand expression (31). The present observations show that the inhibitory effect of silibinin on EGFR and Akt activity can also be observed in lung cancer cells.…”

Section: Discussionsupporting

confidence: 71%

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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Section: Discussionsupporting

confidence: 71%

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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“…Treatment of prostate cancer cells with silibinin abrogated constitutive activation of STAT-3 in DU145 cells (99), disrupted EGFR signaling in LNCaP and DU145 cells (100,101), targeted IGFR signaling in PC3 cells (102), the Wnt/β-catenin pathway in PC3 and DU145 cells (103), and AR signaling in LNCaP cells both directly by reducing nuclear localization of the receptor (104) and indirectly through downregulation of a co-activator, prostate epitheliumderived Ets transcription factor (105,106). Disruption of EGF signaling by silibinin in prostate cancer cells was associated with a decrease in secreted transforming growth factor-α and modulation of MAPK activity of both ERK1/2 and JNK1/2 (101). Disruption of the Wnt/β-catenin pathway involved modulation of a co-receptor, the low-density lipoprotein receptor-related protein-6 (LRP6) (103).…”

Section: Silibinin Effects On Cell Signaling In Prostate Cancer Cellsmentioning

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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“…Based on the inhibitory effect of silibinin on EGFR transactivation in response to hypertrophic stimuli [Hannay and Yu, 2003;Tyagi et al, 2008], we further assessed its effect on the downstream signaling targets such as MAPK and PI3K/Akt/GSK3b pathways. Our data showed that ERK1/2, JNK1/2, and p38 were significantly phosphorylated both in Ang II-treated cardiomyocytes and in AB mice.…”

Section: Effects Of Silibinin On Mapks and Pi3k/akt/gsk3b Signaling Imentioning

confidence: 99%

“…However, the effect of silibinin on cardiac hypertrophy and the related signaling mechanisms still remain unclear. Although silibinin has been shown to inhibit EGFR activation, very little is known about whether this inhibitory effect is related to the protective role in cardiac hypertrophy Tyagi et al, 2008]. Therefore, we aimed to determine whether silibinin attenuates cardiac hypertrophy in vitro and in vivo by interfering EGFR-dependent pathways.…”

mentioning

confidence: 99%

Silibinin attenuates cardiac hypertrophy and fibrosis through blocking EGFR‐dependent signaling

Zhang

Tang

et al. 2010

J of Cellular Biochemistry

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Cardiac hypertrophy is a major determinant of heart failure. The epidermal growth factor receptor (EGFR) plays an important role in cardiac hypertrophy. Since silibinin suppresses EGFR in vitro and in vivo, we hypothesized that silibinin would attenuate cardiac hypertrophy through disrupting EGFR signaling. In this study, we examined this hypothesis using neonatal cardiac myocytes and fibroblasts induced by angiotensin II (Ang II) and animal model by aortic banding (AB) mice. Our data revealed that silibinin obviously blocked cardiac hypertrophic responses induced by pressure overload. Meanwhile, silibinin markedly reduced the increased generation of EGFR. Moreover, these beneficial effects were associated with attenuation of the EGFR-dependent ERK1/2, PI3K/Akt signaling cascade. We further demonstrated silibinin decreased inflammation and fibrosis by blocking the activation of NF-kappaB and TGF-beta1/Smad signaling pathways in vitro and in vivo. Our results indicate that silibinin has the potential to protect against cardiac hypertrophy, inflammation, and fibrosis through blocking EGFR activity and EGFR-dependent different intracellular signaling pathways.

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Silibinin Impairs Constitutively Active TGFα-EGFR Autocrine Loop in Advanced Human Prostate Carcinoma Cells

Cited by 29 publications

References 29 publications

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

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

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

Silibinin attenuates cardiac hypertrophy and fibrosis through blocking EGFR‐dependent signaling

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