Abstract 718: Significantly strong protective efficacy of silibinin against basal cell carcinoma growth and progression
Authors: Paudel Sandeep , Raina Komal , Tiku Vasundhara R. , Maurya Akhilendra , Orlicky David J. , You Zhiying , Rigby Cindy M. , Deep Gagan , Kant Rama , Raina Bupinder , Agarwal Chapla , Agarwal Rajesh 
Published: June 2022

Abstract
Basal cell carcinoma (BCC) is the most common skin malignancy accounting for ∼80% of non-melanoma skin cancers (NMSCs). It arises in basal cells of skin that line the deepest layer of the epidermis. The most important risk factor for BCC is solar ultraviolet B (UVB) radiation that results in DNA damage (CPDs formation) in skin epidermis, which, if not repaired, leads to fixation of mutations and initiation of skin carcinogenesis. One of the key molecular features of BCC is sustained activation of Hedgehog signaling (Hh) pathway through inactivating mutations in tumor suppressor gene Patched (Ptch) or activating mutations in Smoothened (Smo). Therefore, extensive efforts have been made to target activated Hh pathway for the treatment of BCC, though with toxic side effects. With regards to chemoprevention of BCC, the agents which target the events associated with UVB-induced DNA damage repair, together with targeting promotion/progression stages, might provide more effective broad-spectrum opportunities to intervene at the earliest. Utilizing the well-established patched (Ptch)+/- mouse model of UVB radiation-induced BCC formation, our approach in this study was to target BCC development and its prevention by employing silibinin (a natural flavonolignan from milk thistle seeds). Previously, we have extensively reported the efficacy of silibinin against UVB-induced photodamage and photo-carcinogenesis, and also recently reported silibinin efficacy against BCC growth in cell culture (including anti-BCC drug-resistant cell lines) and mouse BCC allograft tumors. In this study, both male and female (Ptch)+/- mice were irradiated with 240 mJ/cm2 UVB dose, 3 times per week (M, W, F) for 26 and 46 weeks with or without silibinin. Silibinin (9 mg/200μl of acetone) was applied topically, 30 min post and pre-UVB exposure. Our study shows that chronic UVB exposure induced BCCs in Ptch+/- mice. Treatment with silibinin post and pre-UVB exposure for 26 weeks decreased BCC lesion numbers (39-65%), and cross-sectional area (45-72%) p&lt;0.001, respectively compared to UVB alone. Furthermore, continuous UVB exposure up to 46 weeks increased the BCC lesion number by ∼6 folds and cross-sectional area by ∼3.4 folds (p&lt;0.001) respectively. Notably, silibinin (irrespective of post and pre-UVB treatment) significantly halted the progression of BCC (81-94%, p&lt;0.001), even upon prolonged UVB exposure. Histological analysis showed increased dysplasia, fibro-sarcoma, and squamous cell carcinoma upon UVB exposure, which significantly decreased upon silibinin treatment. In addition, mechanistic studies revealed that silibinin significantly decreased basal cell proliferation (Ki-67) and the expression of cytokeratins (14 and 15), and Hh signaling mediators Smo and Gli1 in the BCC lesions. Together, our findings demonstrate that silibinin has the potential to prevent the growth and progression of UVB-induced BCC.
Citation Format: Sandeep Paudel, Komal Raina, Vasundhara R. Tiku, Akhilendra Maurya, David J. Orlicky, Zhiying You, Cindy M. Rigby, Gagan Deep, Rama Kant, Bupinder Raina, Chapla Agarwal, Rajesh Agarwal. Significantly strong protective efficacy of silibinin against basal cell carcinoma growth and progression [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 718.