Chemopreventive role of β-caryophyllene in DMBA-induced skin cancer: Modulation of apoptotic pathways and PI3K/Akt signaling in Swiss albino mice.

Abstract

Background: The skin, with its robust structural integrity and advanced immune defense system, serves as a critical protective barrier against environmental toxins and carcinogenic compounds. Despite this, it remains vulnerable to the harmful effects of certain hazardous agents.

Objectives: This study aimed to investigate the chemopreventive potential of β-caryophyllene (BCP) in mitigating 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis, focusing on the modulation of apoptosis and PI3K/AKT signaling pathways.

Material and methods: Swiss albino mice were utilized to assess the preventive effects of BCP in DMBA-induced skin cancer. Skin carcinogenesis was initiated by topical DMBA application, followed by promotion using croton oil. To evaluate the chemopreventive efficacy of BCP, a 50 mg/kg oral dose was administered 3 times a week for 16 weeks.

Results: The BCP treatment in DMBA-induced skin cancer mice significantly reduced tumor incidence, tumor burden and the total number of papillomas compared to untreated DMBA-exposed mice. Notably, BCP administration (p < 0.05) resulted in a marked increase in body weight and improvement in antioxidant enzyme activity. Additionally, BCP treatment led to significant reductions in lipid peroxidation and enhanced detoxification enzyme function. Histological examination of DMBA-induced skin tissues revealed the presence of keratin pearls, well-differentiated tumor cells and neutrophil infiltration. In contrast, BCP-treated mice showed only mild hyperplasia, dysplasia and moderate keratosis, suggesting a lower degree of tissue damage. Furthermore, BCP demonstrated a protective effect on liver histology, counteracting the toxic effects of DMBA exposure. Gene expression analysis revealed that BCP treatment significantly (p < 0.05) upregulated the pro-apoptotic genes Bax, p53, caspase-3 and caspase-9, while downregulating the anti-apoptotic Bcl-2 expression. Additionally, BCP treatment led to a marked reduction in the expression of proliferating cell nuclear antigen (PCNA), cyclin D1 and PI3K/Akt signaling pathways, which are key regulators of cell proliferation and survival.

Conclusions: This study provides compelling evidence that the antioxidant and pro-apoptotic effects of β-caryophyllene contribute to its chemopreventive properties in DMBA-induced skin carcinogenesis in mice. The modulation of key apoptotic signaling pathways and the suppression of the PI3K/Akt pathway by BCP underscores its potential as a therapeutic agent for preventing skin cancer. These findings pave the way for further exploration of BCP as a promising candidate for skin cancer prevention and therapy.