Program Official

Principal Investigator

Rajesh
Agarwal
Awardee Organization

University Of Colorado Denver
United States

Fiscal Year
2021
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Skin Cancer Chemoprevention by Silibinin: Mechanisms and Efficacy

The most important risk factor for basal cell carcinoma (BCC), accounting for ~4 million new cases each year, is solar ultraviolet B radiation (UVB) exposure. One of the key molecular features of BCC is sustained activation of hedgehog (Hh) pathway through inactivating mutations in tumor suppressor gene Ptch or activating mutations in Smoothened (SMO). Consequently, extensive efforts have been made to target activated Hh pathway to treat BCC, though with toxic side effects and drug resistance. Due to these limitations, recent studies have also focused on chemopreventive strategies to manage BCC. In specific Aim I of the parent grant, we proposed to determine the preventive efficacy of topical application of silibinin on a) chronic UVB-induced macroscopic BCC formation as well as b) on the progression of UVB-induced microscopic BCC lesions to more advanced forms of BCCs. Notably, the outcomes from these studies (in the parent grant) have shown that topical silibinin application has significant protective effects against BCC growth and progression (pl. refer to efficacy outcomes section, B5: Fig 1-4). Given these important findings in our completed studies in the parent grant and the fact that silibinin has also shown strong chemopreventive and anti-cancer potential when given orally (by gavage and/or dietary feeding) in other cancers [including skin squamous cell carcinoma (SCC)], there is a compelling likelihood that silibinin would also prevent BCC progression when given orally. Such studies were not proposed in the parent grant, but (based on our completed studies) merit detailed investigation and forms the basis of this supplement; we expect similar protective effects using oral silibinin dosing in our proposed studies. Also, the anticipated efficacy of orally administered silibinin against BCC progression from ‘micro’ to ‘macro’ grade will highlight the tremendous potential of silibinin for its preventive and interventive applications against BCC progression. Our aims are: I) to determine the preventive efficacy of oral feeding of silibinin on the progression of UVB-induced microscopic BCC lesions to more advanced forms of BCCs; and II) to determine potential biomarkers of BCC chemopreventive efficacy of silibinin; specifically, to identify silibinin-associated gene expression biomarkers and correlate them with the observed effects. Considering that silibinin has a long history of human use as a widely consumed dietary supplement around the world and is considered exceptionally safe, this supplement proposal is highly significant as successful results from proposed aims would have strong translational implications in the prevention and intervention of BCC.

Publications

  • Paudel S, Mishra N, Agarwal R. Phytochemicals as Immunomodulatory Molecules in Cancer Therapeutics. Pharmaceuticals (Basel, Switzerland). 2023 Nov 26;16. (12). PMID: 38139779
  • Dheeraj A, Rigby CM, O'Bryant CL, Agarwal C, Singh RP, Deep G, Agarwal R. Silibinin Treatment Inhibits the Growth of Hedgehog Inhibitor-Resistant Basal Cell Carcinoma Cells via Targeting EGFR-MAPK-Akt and Hedgehog Signaling. Photochemistry and photobiology. 2017 Jul;93(4):999-1007. Epub 2017 Mar 6. PMID: 28120452
  • Narayanapillai S, Agarwal C, Deep G, Agarwal R. Silibinin inhibits ultraviolet B radiation-induced DNA-damage and apoptosis by enhancing interleukin-12 expression in JB6 cells and SKH-1 hairless mouse skin. Molecular carcinogenesis. 2014 Jun;53(6):471-9. Epub 2013 Jan 28. PMID: 23359305
  • Kumar R, Deep G, Agarwal R. An Overview of Ultraviolet B Radiation-Induced Skin Cancer Chemoprevention by Silibinin. Current pharmacology reports. 2015 Jun 1;1(3):206-215. PMID: 26097804
  • Narayanapillai S, Agarwal C, Tilley C, Agarwal R. Silibinin is a potent sensitizer of UVA radiation-induced oxidative stress and apoptosis in human keratinocyte HaCaT cells. Photochemistry and photobiology. 2012 Sep-Oct;88(5):1135-40. Epub 2012 Jan 10. PMID: 22118157
  • Tilley C, Deep G, Agarwal C, Wempe MF, Biedermann D, Valentová K, Kren V, Agarwal R. Silibinin and its 2,3-dehydro-derivative inhibit basal cell carcinoma growth via suppression of mitogenic signaling and transcription factors activation. Molecular carcinogenesis. 2016 Jan;55(1):3-14. Epub 2014 Dec 9. PMID: 25492239
  • Rigby C, Deep G, Jain A, Orlicky DJ, Agarwal C, Agarwal R. Silibinin inhibits ultraviolet B radiation-induced mast cells recruitment and bone morphogenetic protein 2 expression in the skin at early stages in Ptch(+/-) mouse model of basal cell carcinoma. Molecular carcinogenesis. 2019 Jul;58(7):1260-1271. Epub 2019 Mar 25. PMID: 30912211
  • Tyagi A, Kumar S, Raina K, Wempe MF, Maroni PD, Agarwal R, Agarwal C. Differential effect of grape seed extract and its active constituent procyanidin B2 3,3″-di-O-gallate against prostate cancer stem cells. Molecular carcinogenesis. 2019 Jul;58(7):1105-1117. Epub 2019 Mar 3. PMID: 30828884
  • Sikka A, Kaur M, Agarwal C, Deep G, Agarwal R. Metformin suppresses growth of human head and neck squamous cell carcinoma via global inhibition of protein translation. Cell cycle (Georgetown, Tex.). 2012 Apr 1;11(7):1374-82. Epub 2012 Apr 1. PMID: 22421144
  • Rigby CM, Roy S, Deep G, Guillermo-Lagae R, Jain AK, Dhar D, Orlicky DJ, Agarwal C, Agarwal R. Role of p53 in silibinin-mediated inhibition of ultraviolet B radiation-induced DNA damage, inflammation and skin carcinogenesis. Carcinogenesis. 2017 Jan;38(1):40-50. Epub 2016 Oct 11. PMID: 27729375
  • Roy S, Deep G, Agarwal C, Agarwal R. Silibinin prevents ultraviolet B radiation-induced epidermal damages in JB6 cells and mouse skin in a p53-GADD45α-dependent manner. Carcinogenesis. 2012 Mar;33(3):629-36. Epub 2011 Dec 12. PMID: 22166495
  • Paudel S, Raina K, Tiku VR, Maurya A, Orlicky DJ, You Z, Rigby CM, Deep G, Kant R, Raina B, Agarwal C, Agarwal R. Chemopreventive efficacy of silibinin against basal cell carcinoma growth and progression in UVB-irradiated Ptch+/- mice. Carcinogenesis. 2022 Jun 27;43(6):557-570. PMID: 35184170
  • Shrotriya S, Tyagi A, Deep G, Orlicky DJ, Wisell J, Wang XJ, Sclafani RA, Agarwal R, Agarwal C. Grape seed extract and resveratrol prevent 4-nitroquinoline 1-oxide induced oral tumorigenesis in mice by modulating AMPK activation and associated biological responses. Molecular carcinogenesis. 2015 Apr;54(4):291-300. Epub 2013 Nov 14. PMID: 24243690
  • Shrotriya S, Deep G, Lopert P, Patel M, Agarwal R, Agarwal C. Grape seed extract targets mitochondrial electron transport chain complex III and induces oxidative and metabolic stress leading to cytoprotective autophagy and apoptotic death in human head and neck cancer cells. Molecular carcinogenesis. 2015 Dec;54(12):1734-47. Epub 2014 Dec 31. PMID: 25557495
  • Serkova NJ, Davis DM, Steiner J, Agarwal R. Quantitative NMR-Based Metabolomics on Tissue Biomarkers and Its Translation into In Vivo Magnetic Resonance Spectroscopy. Methods in molecular biology (Clifton, N.J.). 2019;1978:369-387. PMID: 31119675
  • Guillermo-Lagae R, Deep G, Ting H, Agarwal C, Agarwal R. Silibinin enhances the repair of ultraviolet B-induced DNA damage by activating p53-dependent nucleotide excision repair mechanism in human dermal fibroblasts. Oncotarget. 2015 Nov 24;6(37):39594-606. PMID: 26447614