Abstract
Oral squamous cell carcinoma (OSCC) accounts for 5.8% of all malignancies in Taiwan and the incidence of OSCC is on the rise. OSCC is also a common malignancy worldwide and the five-year survival rate remains poor. Therefore, new and effective treatments are needed to control OSCC. In the present study we have investigated the efficacy and associated mechanisms of polyenylpyrroles and their analogs in both in vitro cell culture and in vivo nude mice xenografts. Auxarconjugatin B (compound 1a) resulted in cell cycle arrest in the G2/M phase and caspase-dependent apoptosis in OEC-M1 and HSC-3 cells by activating DNA damage and mitochondria dysfunction through the loss of mitochondrial membrane potential, release of cytochrome c, increase in B-cell lymphoma-2-associated X protein level, and decrease in B-cell lymphoma-2 level. Compound 1a-induced generation of intracellular reactive oxygen species through cytochrome P450 1A1 was identified as a major mechanism of its effect for DNA damage, mitochondria dysfunction and apoptosis, which was reversed by antioxidant N-acetylcysteine as well as cytochrome P450 1A1 inhibitor and specific siRNA. Furthermore, compound 1a-treated nude mice showed a reduction in the OEC-M1 xenograft tumor growth and an increase in the caspase-3 activation in xenograft tissue. These results provide promising insights as to how compound 1a mediates cytotoxicity and may prove to be a molecular rationale for its translation into a potential therapeutic against OSCC.
Highlights
DNA damage might activate p53dependent apoptosis through inhibiting both the G1/S and the According to the latest report from the Department of Health, Executive Yuan, Taiwan, oral cancer affects a significant number of patients in their economically productive age and approximately 2300 men in Taiwan with an average age of 58.3 years succumb to oral cancer every year
The relative tumor volume at day n (RTVn) versus day 0 was expressed according to the following formula: RTVn = TVn/TV0
Mitochondria play an important role in cell death by changing its outer and inner membrane permeability and leading to cytochrome c release and caspase activation [21]
Summary
Despite advances in clinical management, the survival rate remains poor [2,3] This strongly underlines the importance of discovering and developing new and effective treatments to improve the prognosis of oral cancer patients. Apoptosis is one of the important mechanisms of anticancer drug-mediated cell death It is induced by two major pathways: mitochondrial (intrinsic) pathway and death receptor (extrinsic) pathway. The typically small quantities that can be obtained from the isolation of natural sources (fungi or bacteria) often limit its applications To address this limitation as well as to provide access to structurally diverse analogs of these compounds, we have developed a synthetic strategy that allows conjugated polyenes to be synthesized expediently. By western blotting method: cells with or without treatment were harvested by centrifugation at 6006g for 10 min. Cytochrome c release into the cytosolic fraction for each condition was assessed by western blotting analysis
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