Abstract 716: Silibinin: A novel potential therapeutic agent against UVB-induced basal cell carcinoma

Abstract

Abstract Herein, we report silibinin (a natural flavonolignan from milk thistle seeds) efficacy against basal cell carcinoma (BCC), the major non-melanoma skin cancer. To determine the preventive/therapeutic activity of silibinin on the progression of UVB-induced microscopic BCC lesions to more advanced BCC, both male and female 8 weeks old Ptch1+/- mice were irradiated with 240 mJ/cm2 UVB dose 3 times/week (M, W, F) for 26 weeks, and thereafter, UVB irradiation was stopped. At this point (after initial UVB exposure for 26 weeks was stopped), these Ptch1+/- mice were randomized into 3 groups: Baseline group (mice euthanized for baseline data); Vehicle group: mice treated topically with acetone for 20 more weeks, and Silibinin group: mice treated topically with silibinin (9 mg in 200 µL acetone), once a day for five days/week for 20 more weeks i.e., till 54 weeks of mice age. Assessment of BCC and non-BCC lesion pathology was performed following β-galactosidase and H&E based histopathological analysis. Results indicated that compared to BCC-associated pathologies observed at baseline, acetone exposure for another 20 weeks resulted in a significant increase in the number (~2 folds, P<0.001) and area (~3.4 folds, P<0.001) covered by BCC lesions. There was also a significant increase in epidermal dysplasia, fibrosarcoma, and squamous cell carcinoma incidence. Notably, topical application of silibinin during this phase significantly decreased BCC numbers as well as area covered by BCC lesions by ~76% (P<0.001) and ~88% (P<0.001), respectively. This protective effect of silibinin was associated with decreased proliferation of basal cells and decreased expression of Hh signaling molecules (Smo and Gli1). To further delineate the changes associated with silibinin’ s protective effect at the transcriptomic level, RNA sequencing studies were performed in skin samples from all three groups as well as non-UVB exposed control mice. Clustering of mRNA profile by sparse Partial Least Squares - Discriminant Analysis (sPLS-DA) showed that UVB exposed tissues (not treated with silibinin) were significantly different from non-UVB controls; most notably, silibinin treatment (after UVB exposure) reversed this phenomenon and the transcriptomic profile of silibinin group was almost similar to non-UVB controls. This indicated that topical silibinin was not only able to protect against progression to advanced BCC but had the potential to even normalize the aberrant gene expression driving BCC formation. In addition, Gene ontology enrichment analysis as well as Pathway enrichment analysis of differentially expressed genes showed silibinin-associated enrichment in the calcium and CX3CR1-mediated signaling pathway, and TGF-β-mediated regulation of the extracellular matrix. Taken together, these results highlight the potential of silibinin to be an effective preventive and/or therapeutic modality against BCC growth and progression. Citation Format: Komal Raina, Sandeep Paudel, Neha Mishra, Sushil Kumar, David J. Orlicky, Zhiying You, Rama Kant, Chapla Agarwal, Rajesh Agarwal. Silibinin: A novel potential therapeutic agent against UVB-induced basal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 716.