Rigby Cynthia M, Roy Srirupa, Deep Gagan, Guillermo-Lagae Ruth, Jain Anil K, Dhar Deepanshi, Orlicky David J, Agarwal Chapla, Agarwal Rajesh
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences.
Present address: Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
Carcinogenesis. 2017 Jan;38(1):40-50. doi: 10.1093/carcin/bgw106. Epub 2016 Oct 11.
Non-melanoma skin cancers (NMSC) are a growing problem given that solar ultraviolet B (UVB) radiation exposure is increasing most likely due to depletion of the atmospheric ozone layer and lack of adequate sun protection. Better preventive methods are urgently required to reduce UV-caused photodamage and NMSC incidence. Earlier, we have reported that silibinin treatment activates p53 and reduces photodamage and NMSC, both in vitro and in vivo; but whether silibinin exerts its protective effects primarily through p53 remains unknown. To address this question, we generated p53 heterozygous (p53) and p53 knockout (p53) mice on SKH-1 hairless mouse background, and assessed silibinin efficacy in both short- and long-term UVB exposure experiments. In the chronic UVB-exposed skin tumorigenesis study, compared to p53 mice, p53 mice developed skin tumors earlier and had higher tumor number, multiplicity and volume. Silibinin topical treatment significantly reduced the tumor number, multiplicity and volume in p53 mice but silibinin' protective efficacy was significantly compromised in p53 mice. Additionally, silibinin treatment failed to inhibit precursor skin cancer lesions in p53 mice but improved the survival of the mice. In short-term studies, silibinin application accelerated the removal of UVB-induced DNA damage in p53 mice while its efficacy was partially compromised in p53 mice. Interestingly, silibinin treatment also inhibited the UVB-induced inflammatory markers in skin tissue. These results further confirmed that absence of the p53 allele predisposes mice to photodamage and photocarcinogenesis, and established that silibinin mediates its protection against UVB-induced photodamage, inflammation and photocarcinogenesis partly through p53 activation.
鉴于太阳紫外线B（UVB）辐射暴露量的增加（很可能是由于大气臭氧层损耗以及缺乏足够的防晒措施），非黑色素瘤皮肤癌（NMSC）正成为一个日益严重的问题。迫切需要更好的预防方法来减少紫外线引起的光损伤和NMSC的发病率。此前，我们曾报道水飞蓟宾治疗可激活p53，并在体外和体内均能减少光损伤和NMSC；但水飞蓟宾是否主要通过p53发挥其保护作用仍不清楚。为解决这个问题，我们在SKH - 1无毛小鼠背景上培育了p53杂合（p53）和p53基因敲除（p53）小鼠，并在短期和长期UVB暴露实验中评估了水飞蓟宾的疗效。在慢性UVB暴露的皮肤肿瘤发生研究中，与p53小鼠相比，p53小鼠更早出现皮肤肿瘤，且肿瘤数量、多发性和体积更高。水飞蓟宾局部治疗显著减少了p53小鼠的肿瘤数量、多发性和体积，但水飞蓟宾在p53小鼠中的保护效果显著受损。此外，水飞蓟宾治疗未能抑制p53小鼠的皮肤癌前病变，但提高了小鼠的存活率。在短期研究中，水飞蓟宾的应用加速了p53小鼠中UVB诱导的DNA损伤的清除，而其在p53小鼠中的疗效部分受损。有趣的是，水飞蓟宾治疗还抑制了皮肤组织中UVB诱导的炎症标志物。这些结果进一步证实，p53等位基因的缺失使小鼠易发生光损伤和光致癌作用，并确定水飞蓟宾部分通过激活p53介导其对UVB诱导的光损伤、炎症和光致癌作用的保护作用。
