Silibinin Inhibits Colorectal Cancer Growth by Inhibiting Tumor Cell Proliferation and Angiogenesis

Singh, Rana P.; Gu, Mallikarjuna; Agarwal, Rajesh

doi:10.1158/0008-5472.can-07-6247

Cited by 167 publications

(150 citation statements)

References 47 publications

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“…The monoclonal IgG 1 antibody, Bevacizumab (Avastin), which binds VEGF preventing receptor binding, has been evaluated in the first-and second-line treatment in patients with colorectal cancer (Willett et al, 2004(Willett et al, , 2006Chua and Cunningham, 2006;Rasheed et al, 2008). Interestingly, novel antiangiogenic compounds have been developed that decrease HIF-1a and other HIFs (Mackay et al, 2005;Zhu et al, 2007;Singh et al, 2008).…”

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confidence: 99%

Hypoxia-inducible factor-1α and -2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis

et al. 2009

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The hypoxia-mediated response of tumours is a major determining factor in growth and metastasis. Understanding tumour biology under hypoxic conditions is crucial for the development of antiangiogenic therapy. Using one of the largest cohorts of rectal adenocarcinomas to date, this study investigated hypoxia-inducible factor-1a (HIF-1a) and HIF-2a protein expression in relation to rectal cancer recurrence and cancer-specific survival. Patients (n ¼ 90) who had undergone surgery for rectal adenocarcinoma, with no prior neoadjuvant therapy or metastatic disease, and for whom adequate follow-up data were available were selected. Microvessel density (MVD), HIF-1a and HIF-2a expressions were assessed immunohistologically with the CD34 antibody for vessel identification and the NB100-131B and NB100-132D3 antibodies for HIF-1a and HIF-2a, respectively. In a multifactorial analysis, results were correlated with tumour stage, recurrence rate and long-term survival. Microvessel density was higher across T and N stages (Po0.001) and associated with poor survival (hazard ratio (HR) ¼ 8.7, Po0.005) and decreased disease-free survival (HR ¼ 4.7, Po0.005). hypoxia-inducible factor-1a and -2a were expressed in 450% of rectal cancers (HIF-1a, 54%, 48/90; HIF-2a, 64%, 58/90). HIF-1a positivity was associated with both TNM stage (Po0.05) and vascular invasion (Po0.005). In contrast, no associations were shown between HIF-2a expression and any pathological features, and HIF-1a positivity had no effect on outcome. The study showed an independent association between HIF-1a expression and advanced TNM stage with poor outcome. Our results indicate that HIF-1a, but not HIF-2a, might be used as a marker of prognosis, in addition to methods currently used, to enhance patient management.

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confidence: 99%

Hypoxia-inducible factor-1α and -2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis

et al. 2009

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“…1A). Accumulating evidence indicates that silibinin has anticancer activity in various tumor cells, including cancers of prostate (5)(6)(7)(8)(9), breast (10,11), skin (12), colon (13), lung (14), kidney (15,16), and bladder (17)(18)(19)(20). There is increasing interest in elucidating the mechanisms of action for silibinin as an effective agent for chemoprevention and chemotherapy against various types of cancers.…”

Section: Introductionmentioning

confidence: 99%

Chemopreventive and Chemotherapeutic Effects of Intravesical Silibinin against Bladder Cancer by Acting on Mitochondria

Zeng

Sun

et al. 2011

Molecular Cancer Therapeutics

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Intravesical chemotherapy is often used to prevent the recurrence of superficial bladder cancer after transurethral resection. A search for more effective and less toxic intravesical agents is urgently needed. We previously found the in vitro apoptotic effects of silibinin, a natural flavonoid, on high-risk bladder carcinoma cells. Here, we further explored the underlying mechanisms and examined the intravesical efficacy in the prevention and treatment of bladder cancer. Human bladder carcinoma cell line 5637, which has the same molecular features of high-risk superficial bladder cancer, was used as the model system in vitro and in vivo. Autochthonous rat model of bladder cancer induced by intravesical N-methyl-N-nitrosourea (MNU) was used to investigate its intravesical efficacy. Exposure of 5637 cells to silibinin resulted in growth inhibition and induction of caspase-dependent and -independent apoptosis, which was associated with disruption of mitochondrial membrane potential and selective release of cytochrome c, Omi/HtrA2, and apoptosisinducing factor (AIF) from mitochondria. Silibinin also downregulated survivin and caused nuclear translocation of AIF. Oral silibinin suppressed the growth of 5637 xenografts, which was accompanied with the activation of caspase-3, downregulation of survivin, and increased translocation of AIF. Furthermore, intravesical silibinin effectively inhibited the carcinogenesis and progression of bladder cancer in rats initiated by MNU by reducing the incidence of superficial and invasive bladder lesions without any side effects, which was accompanied with proapoptotic effects. These findings identify the in vitro and in vivo antitumor efficacy of silibinin, and suggest silibinin as an effective and novel intravesical agent for bladder cancer.

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“…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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Silibinin Inhibits Colorectal Cancer Growth by Inhibiting Tumor Cell Proliferation and Angiogenesis

Cited by 167 publications

References 47 publications

Hypoxia-inducible factor-1α and -2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis

Hypoxia-inducible factor-1α and -2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis

Chemopreventive and Chemotherapeutic Effects of Intravesical Silibinin against Bladder Cancer by Acting on Mitochondria

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

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