Abstract 7310: Dietary feeding of silibinin effectively protects against UVB-induced basal cell carcinoma

Abstract

Abstract Exposure to UVB radiation causes various malignancies, including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC is the most prevalent skin cancer type worldwide; ~3.6 million cases of BCC are diagnosed annually in the USA. Silibinin (SB) is a naturally occurring flavonolignan that is present in milk thistle seeds. It has been shown to effectively reduce BCC occurrence upon UVB radiation exposure, in both pre- and post-treatment studies, when applied topically. However, SB efficacy, when fed in diet, against UVB-induced BCC formation and growth has not been reported. We addressed this question employing Ptch+/- mice, where animals were divided into three groups. Group 1: control group, mice were fed adjusted vitamin diet (AIN-76A; TD94096) with no UVB exposure. Group 2: UVB group, mice were fed pellet control diet (semi-purified, modified AIN-76A) and exposed to UVB (240 mJ/cm2) 3 times/week (Mon, Wed, Fri). Group 3: SB group, mice were fed 1% SB (w/w)-supplemented diet and exposed to UVB similar to that in Group 2. This protocol was followed for 26 weeks; thereafter, animals were sacrificed at 14 weeks and 26 weeks post-UVB initiation, and skin samples were harvested and analyzed for BCC formation. β-galactosidase staining showed the development of BCC lesions at 26 weeks in the UVB group; however, SB-fed group had both lesser number of BCC lesions and decreased area covered by BCCs as compared to the UVB group. Non-UVB exposed control group had no BCC lesions. To address if SB feeding starts exerting its efficacy earlier than 26 weeks, we selected the early efficacy timepoint for transcriptomics analysis to determine the mechanism of SB efficacy. Skin RNA samples from the 14-week time point (n=4/group; RIN≥7; DV200>85%) were subjected to library preparation (550 ng of total RNA; Zymo-Seq RiboFree Total RNA Library Kit), ribosomal RNA-depletion RNA sequencing (80 million paired-end reads/sample), and data processing. About 16,000 unique genes were identified, of which ~65% were protein-coding genes. The samples within each group were highly correlated (mean>0.99; Pearson’s correlation). The UVB cluster was sequestered away from the other groups, indicating that the SB diet effectively mitigated the effects of UVB exposure, even at the transcriptome level. Additionally, gene ontology and pathway enrichment analysis (Ingenuity Pathway Analysis, Qiagen) of differentially expressed genes (p<0.05; fold change≤2) showed UVB-induced aberration and SB-associated enrichment in mitotic prometaphase, metaphase, and anaphase pathways, RHO GTPase signaling, and cell cycle regulation; the top functional network found to be dysregulated was lipid metabolism. Taken together, these results highlight the potential of dietary SB intake (apart from topical SB) to be an effective modality against UVB-induced BCC formation and growth and identify molecular targets that are plausibly involved in SB efficacy. Citation Format: Sandeep Paudel, Neha Mishra, Komal Raina, Chapla Agarwal, Rajesh Agarwal. Dietary feeding of silibinin effectively protects against UVB-induced basal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7310.