Basal cell carcinoma (BCC), a non-melanoma skin cancer (NMSC) type, is a major health problem in the United States (US); annual BCC incidences alone are higher than all other cancer incidences combined (1.67 million/year). Most BCC cases are curable by surgery/radiation, but these can be painful and highly disfiguring and are not viable treatment options for BCC patients with locally advanced and metastatic disease where chemotherapy has also not proven effective. Since Hedgehog (Hh) signaling plays a central role in BCC development and progression, recently FDA has approved GDC-0449 and LDE-225 (Hh pathway inhibitors) to treat BCC; however, acquired resistance and toxicities are limitations. Taken together, clearly there is an urgent need to develop additional non-toxic strategies towards BCC prevention and intervention. In past ~20 years, we have extensively studied and reported chemopreventive efficacy of silibinin against UVB- induced skin cancer in squamous cell carcinoma (SCC) model of NMSC; currently, we are in advanced stages of developing silibinin formulation for human skin use. Based on findings showing strong silibinin efficacy in mouse skin SCC model, in preliminary studies, we also assessed its effects against UVB-induced BCC. Using Ptch1+/? mouse model of BCC, we observed that silibinin decreases UVB-induced: cyclobutane pyrimidine dimer (CPD) positive cells in ear skin, microscopic BCC formation, dermal mast cell infiltration and bone morphogenetic protein (BMP)-2 gene and protein levels in skin. Furthermore, silibinin decreased: MC9 mast cell chemotactic-migration towards mouse BCC ASZ cells and mucosal mast cell degranulation. Silibinin also decreased proliferation of mouse BCC cells in culture and mouse allografts together with inhibition of mitogenic signaling pathways. In most recent studies, silibinin significantly increased the growth inhibitory effects of Hh pathway inhibitor drugs and reversed the resistance of BCC cells to these drugs via targeting EGFR/AKT and Hh pathway and induction of apoptosis. Based on these highly significant and encouraging findings in BCC models, our hypothesis is that by targeting UVB-induced DNA damage repair and reversal of mast cells-mediated immunosuppressive events, together with modulating signaling pathways associated with drug resistance, silibinin has the potential to be an effective agent for both prevention and adjuvant therapy of BCCs.
Our aims are to: I) establish and define the role of silibinin-mediated DNA repair in its preventive efficacy against UVB-induced BCC; II) assess and establish the link between DNA damage repair, mast cells, and reversal of UVB-induced immunosuppression by silibinin in its efficacy against BCC formation; III) further establish the therapeutic efficacy of silibinin against BCC, both alone and in combination with FDA approved anti-BCC therapeutics, and define the associated mechanisms.

Public Health Relevance

Basal cell carcinoma (BCC), a non-melanoma skin cancer type, is a major health problem in the United States. Most BCC cases are curable by surgery/radiation, but these can be painful and highly disfiguring and are not viable treatment options for BCC patients with locally advanced and metastatic disease where chemotherapy has also not proven effective. Clearly there is an urgent need to develop additional non-toxic strategies towards BCC prevention and intervention. Studies are proposed in this application to demonstrate that by targeting UVB-induced DNA damage repair and reversal of mast cells-mediated immunosuppressive events, together with modulating signaling pathways associated with drug resistance, silibinin has the potential to be an effective agent for both prevention and adjuvant therapy of BCCs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140368-07
Application #
9502926
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Seifried, Harold E
Project Start
2010-03-01
Project End
2022-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Rigby, Cynthia M; Roy, Srirupa; Deep, Gagan et al. (2017) Role of p53 in silibinin-mediated inhibition of ultraviolet B radiation-induced DNA damage, inflammation and skin carcinogenesis. Carcinogenesis 38:40-50
Dheeraj, Arpit; Rigby, Cynthia M; O'Bryant, Cindy L et al. (2017) Silibinin Treatment Inhibits the Growth of Hedgehog Inhibitor-Resistant Basal Cell Carcinoma Cells via Targeting EGFR-MAPK-Akt and Hedgehog Signaling. Photochem Photobiol 93:999-1007
Tilley, Cynthia; Deep, Gagan; Agarwal, Chapla et al. (2016) Silibinin and its 2,3-dehydro-derivative inhibit basal cell carcinoma growth via suppression of mitogenic signaling and transcription factors activation. Mol Carcinog 55:3-14
Shrotriya, Sangeeta; Tyagi, Alpna; Deep, Gagan et al. (2015) Grape seed extract and resveratrol prevent 4-nitroquinoline 1-oxide induced oral tumorigenesis in mice by modulating AMPK activation and associated biological responses. Mol Carcinog 54:291-300
Guillermo-Lagae, Ruth; Deep, Gagan; Ting, Harold et al. (2015) Silibinin enhances the repair of ultraviolet B-induced DNA damage by activating p53-dependent nucleotide excision repair mechanism in human dermal fibroblasts. Oncotarget 6:39594-606
Kumar, Rahul; Deep, Gagan; Agarwal, Rajesh (2015) An Overview of Ultraviolet B Radiation-Induced Skin Cancer Chemoprevention by Silibinin. Curr Pharmacol Rep 1:206-215
Tilley, Cynthia; Deep, Gagan; Agarwal, Rajesh (2015) Chemopreventive opportunities to control basal cell carcinoma: Current perspectives. Mol Carcinog 54:688-97
Shrotriya, Sangeeta; Deep, Gagan; Lopert, Pamela et al. (2015) 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. Mol Carcinog 54:1734-47
Narayanapillai, Sreekanth; Agarwal, Chapla; Deep, Gagan et al. (2014) Silibinin inhibits ultraviolet B radiation-induced DNA-damage and apoptosis by enhancing interleukin-12 expression in JB6 cells and SKH-1 hairless mouse skin. Mol Carcinog 53:471-9
Sikka, Arron; Kaur, Manjinder; Agarwal, Chapla et al. (2012) Metformin suppresses growth of human head and neck squamous cell carcinoma via global inhibition of protein translation. Cell Cycle 11:1374-82

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