Role of p53 in silibinin-mediated inhibition of ultraviolet B radiation-induced DNA damage, inflammation and skin carcinogenesis.

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.

Rigby CM ，Roy S ，Deep G ，Guillermo-Lagae R ，Jain AK ，Dhar D ，Orlicky DJ ，Agarwal C ，Agarwal R ... -  《-》

Dietary feeding of silibinin prevents early biomarkers of UVB radiation-induced carcinogenesis in SKH-1 hairless mouse epidermis.

Gu M ，Dhanalakshmi S ，Singh RP ，Agarwal R ... -  《CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION》

Silibinin prevents ultraviolet B radiation-induced epidermal damages in JB6 cells and mouse skin in a p53-GADD45α-dependent manner.

Roy S ，Deep G ，Agarwal C ，Agarwal R ... -  《-》

Silibinin inhibits inflammatory and angiogenic attributes in photocarcinogenesis in SKH-1 hairless mice.

Gu M ，Singh RP ，Dhanalakshmi S ，Agarwal C ，Agarwal R ... -  《CANCER RESEARCH》

Silibinin prevents ultraviolet radiation-caused skin damages in SKH-1 hairless mice via a decrease in thymine dimer positive cells and an up-regulation of p53-p21/Cip1 in epidermis.

Dhanalakshmi S ，Mallikarjuna GU ，Singh RP ，Agarwal R ... -  《CARCINOGENESIS》