Chemopreventive effects of silymarin and silibinin on <i>N</i>-butyl-<i>N</i>-(4-hydroxybutyl) nitrosamine–induced urinary bladder carcinogenesis in male ICR mice

Tyagi, Alpna; Raina, Komal; Singh, Rana P.; Gu, Mallikarjuna; Agarwal, Chapla; Harrison, Gail Singer; Glodé, L. Michael; Agarwal, Rajesh

doi:10.1158/1535-7163.mct-07-2006

Cited by 65 publications

(41 citation statements)

References 31 publications

(32 reference statements)

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“…Likewise, silibinin-fed SCID mice injected with SN12K1 cells exhibited a reduction in tumor size (54). Consistent with these results, several studies have shown that silibinin inhibits growth as well as induces apoptosis in several urinary bladder cancer cell lines which were associated with an increase in p53 expression, downregulation of survivin, cyclin D1, ERK1/2 phosphorylation and nuclear phospho-p65, cleavage of caspases, PARP, and Cip1/p21, and mitochondrial release of cytochrome c, Omi/HtrA2, and apoptosis-inducing factor (55)(56)(57)(58)(59)(60). This silibinin-mediated inhibition was also observed in rat models of urinary bladder cancer reducing lesions (60).…”

Section: Broad Spectrum Cancer Chemopreventive Efficacy Of Silibininsupporting

confidence: 63%

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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Section: Broad Spectrum Cancer Chemopreventive Efficacy Of Silibininsupporting

confidence: 63%

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

Ting

Deep

Agarwal

2013

AAPS J

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“…Initiation and promotion of bladder carcinogenesis by BBN is accompanied by increased cell proliferation in rodents and this is associated with changes in the expression of genes involved in cell cycle control [49,[55][56][57]. Our data also indicate an increase in Ki-67-positive cells induced by BBN, and the reduced proliferation observed for animals treated with tamoxifen concurrent with BBN is consistent with this SERM's protective effect.…”

Section: Discussionsupporting

confidence: 85%

Chemoprevention of BBN-Induced Bladder Carcinogenesis by the Selective Estrogen Receptor Modulator Tamoxifen

George¹,

Tovar-Sepulveda²,

Shen³

et al. 2011

CLINICAL/TRANSLATIONAL - Endocrine Neoplasia

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Bladder cancer is the fifth most frequent tumor in men and ninth in women in the United States. Due to a high likelihood of recurrence, effective chemoprevention is a significant unmet need. Estrogen receptors (ERs), primarily ERβ, are expressed in normal urothelium and urothelial carcinoma, and blocking ER function with selective ER modulators such as tamoxifen inhibits bladder cancer cell proliferation in vitro. Herein, the chemoprotective potential of tamoxifen was evaluated in female mice exposed to the bladder-specific carcinogen, N -butyl-N -(4-hydroxybutyl) nitrosamine (BBN). Carcinogen treatment resulted in a 76% tumor incidence and increased mean bladder weights in comparison to controls. In contrast, mice receiving tamoxifen concurrent (8-20 weeks) or concurrent and subsequent (8-32 weeks) to BBN administration had no change in bladder weight and only 10% to 14% incidence of tumors. Non-muscle-invasive disease was present in animals treated with tamoxifen before (5-8 weeks) or after (20-32 weeks) BBN exposure, while incidence of muscle-invasive bladder carcinoma was reduced. ERβ was present in all mice and thus is a potential mediator of the tamoxifen chemoprotective effect. Surprisingly, ERα expression, which was detected in 74% of the mice exposed to BBN alone but not in any control mice, was correlated with tumor incidence, indicating a possible role for this receptor in carcinogen-induced urothelial tumorigenesis. Thus, these data argue that both ERα and ERβ play a role in modulating carcinogen-induced bladder tumorigenesis. Administration of tamoxifen should be tested as a chemopreventive strategy for patients at high risk for bladder cancer recurrence.Translational Oncology (2013) 6, 244-255 IntroductionAs the fifth most common cancer in men and ninth most common in women in the United States, urinary bladder cancer accounts for significant morbidity and mortality. There are estimated to be more than 73,000 new bladder cancer cases in 2012 [1] with urothelial carcinoma accounting for approximately 90% of these; the remainder is composed of squamous cell carcinomas, adenocarcinomas, and other rare histologies [2]. Approximately 70% of all new bladder cancer cases are classified as non-muscle-invasive (Ta, T1, Tis), while the remaining 30% are muscle-invasive (T2-T4) and generally lead to cystectomy. Bladder cancer recurs at a very high rate of 50% to 90% depending on the tumor stage, grade, and number of primary tumors, and this necessitates lifetime monitoring for tumor recur-

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“…On the other hand, it also indicates that silibinin could also be effective in p53-mutated bladder tumor cells. This hypothesis is supported by the fact that, in a recently completed study, silibinin showed apoptotic cell death of human bladder carcinoma T24 and TCC-SUP cell lines (32), which are mutated for p53 in exon 5 and exon 10, respectively (33).…”

Section: Discussionmentioning

confidence: 88%

Oral Silibinin Inhibits In vivo Human Bladder Tumor Xenograft Growth Involving Down-Regulation of Survivin

Singh

Tyagi

Sharma

et al. 2008

Clinical Cancer Research

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Purpose: Chemoprevention is an upcoming approach to control bladder cancer, which is one of the commonly diagnosed malignancies showing recurrence rate of 70% or even higher. Recently, we observed the in vitro efficacy of silibinin, a flavanolignan, in human bladder transitional cell papilloma RT4 cells. Here, we investigated the antitumor efficacy and associated mechanisms of silibinin in RT4 tumor xenograft. Experimental Design: RT4 tumor xenograft was implanted s.c. in athymic nude mice, and then animals were oral gavaged with silibinin at 100 and 200 mg/kg doses, 5 days/week for 12 weeks. Tumor growth, body weight, and diet consumption were recorded, and tumors were analyzed for proliferation, apoptosis, and angiogenesis biomarkers and molecular alterations by immunohistochemistry, immunoblot analysis, and ELISA. p53 small interfering RNA was used in cell culture to examine the role of p53 in survivin expression. Results: Silibinin feeding inhibited tumor xenograft growth without any gross signs of toxicity. Silibinin decreased tumor volume by 51% to 58% (P V 0.01) and tumor weight by 44% to 49% (P < 0.05). Silibinin moderately (P < 0.001) decreased cell proliferation and microvessel density and strongly (P < 0.001) increased apoptosis in tumors. Silibinin robustly decreased survivin protein expression and its nuclear localization, as well as tumor-secreted level in mouse plasma, but increased p53 and cleaved caspase-3 levels in tumors. Silibinin-caused decrease in survivin was independent of p53. Conclusion: These findings identified in vivo antitumor efficacy of silibinin against human bladder tumor cells involving down-regulation of survivin and an increase in p53 expression together with enhanced apoptosis.

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Chemopreventive effects of silymarin and silibinin on N-butyl-N-(4-hydroxybutyl) nitrosamine–induced urinary bladder carcinogenesis in male ICR mice

Cited by 65 publications

References 31 publications

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

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

Chemoprevention of BBN-Induced Bladder Carcinogenesis by the Selective Estrogen Receptor Modulator Tamoxifen

Oral Silibinin Inhibits In vivo Human Bladder Tumor Xenograft Growth Involving Down-Regulation of Survivin

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