Protective effects of silymarin against photocarcinogenesis in a mouse skin model

J Natl Cancer Inst. 1997 Apr 16;89(8):556-66. doi: 10.1093/jnci/89.8.556.

Abstract

Background: Nonmelanoma skin cancer is the most common cancer among humans; solar UV is its major cause. Therefore, it is important to identify agents that can offer protection against this cancer.

Purpose: We evaluated the protective effects of silymarin, a flavonoid compound isolated from the milk thistle plant, against UVB radiation-induced nonmelanoma skin cancer in mice and delineated the mechanism(s) of its action.

Methods: For long-term studies, three different protocols of treatment were employed, each evaluating protection by silymarin at a different stage of carcinogenesis. Female SKH-1 hairless mice were subjected to 1) UVB-induced tumor initiation followed by phorbol ester-mediated tumor promotion, 2) 7,12-dimethylbenz[a]anthracene-induced tumor initiation followed by UVB-mediated tumor promotion, and 3) UVB-induced complete carcinogenesis. Forty mice were used in each protocol and were divided into control and treatment groups. Silymarin was applied topically at a dose of 9 mg per application before UVB exposure, and its effects on tumor incidence (% of mice with tumors), tumor multiplicity (number of tumors per mouse), and average tumor volume per mouse were evaluated. In short-term studies, the following parameters were measured: formation of sunburn and apoptotic cells, skin edema, epidermal catalase and cyclooxygenase (COX) activities, and enzymatic activity and messenger RNA (mRNA) expression for ornithine decarboxylase (ODC), a frequently observed marker at tumor promotion stage. Fisher's exact test was used to evaluate differences in tumor incidence, two-sample Wilcoxon rank sum test was used for tumor multiplicity and tumor volume, and Student's t test was used for all other measurements. All statistical tests were two-sided.

Results: In the protocol with UVB-induced tumor initiation, silymarin treatment reduced tumor incidence from 40% to 20% (P = .30), tumor multiplicity by 67% (P = .10), and tumor volume per mouse by 66% (P = .14). In the protocol with UVB-induced tumor promotion, silymarin treatment reduced tumor incidence from 100% to 60% (P<.003), tumor multiplicity by 78% (P<.0001), and tumor volume per mouse by 90% (P<.003). The effect of silymarin was much more profound in the protocol with UVB-induced complete carcinogenesis, where tumor incidence was reduced from 100% to 25% (P<.0001), tumor multiplicity by 92% (P<.0001), and tumor volume per mouse by 97% (P<.0001). In short-term experiments, silymarin application resulted in statistically significant inhibition in UVB-caused sunburn and apoptotic cell formation, skin edema, depletion of catalase activity, and induction of COX and ODC activities and ODC mRNA expression.

Conclusions and implication: Silymarin can provide substantial protection against different stages of UVB-induced carcinogenesis, possibly via its strong antioxidant properties. Clinical testing of its usefulness is warranted.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene
  • Animals
  • Anticarcinogenic Agents / therapeutic use*
  • Catalase / drug effects
  • Catalase / metabolism
  • Disease Models, Animal
  • Epidermis / drug effects
  • Epidermis / enzymology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Mice
  • Mice, Hairless
  • Ornithine Decarboxylase / biosynthesis
  • Ornithine Decarboxylase / drug effects
  • Prostaglandin-Endoperoxide Synthases / drug effects
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Silymarin / therapeutic use*
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / etiology
  • Skin Neoplasms / prevention & control*
  • Sunburn / prevention & control
  • Ultraviolet Rays / adverse effects*

Substances

  • Anticarcinogenic Agents
  • Silymarin
  • 9,10-Dimethyl-1,2-benzanthracene
  • Catalase
  • Prostaglandin-Endoperoxide Synthases
  • Ornithine Decarboxylase