Anti-neoplastic activity of celastrol in experimentally-induced mammary adenocarcinoma in mice: targeting wnt/β-catenin signaling pathway

Abstract

Natural bioactive compounds with anti-neoplastic effects, such as celastrol (CLS), have attracted considerable interest in recent years. The present study aimed to investigate the effect of CLS on wnt/β-catenin signaling, and its potential combination with doxorubicin (Dox) to enhance chemotherapeutic effects. After intramuscular inoculation of Ehrlich tumor cells, tumor-bearing mice received CLS (2 mg/kg, i.p), Dox (5 mg/kg, once/week, i.p), and their combination for 21 days. Treatment with CLS showed showing antioxidant and anti-inflammatory, as evidenced by a significant increase in glutathione content and a significant decrease in the malondialdehyde, interleukin 6, and interleukin 1β concentrations. CLS also inhibited VEGF-mediated angiogenesis. The current study revealed that CLS downregulated β-catenin gene expression with subsequent downstream target genes, such as cyclin-D1, and survivin, which dampens tumor cell proliferation and triggers cell cycle arrest as well as induces apoptosis as indicated by the increased expression of p53, caspase-3. The current study concludes that CLS exerted its anti-neoplastic activity by suppressing the wnt/β-catenin signaling pathway, and opens a new perspective for combining CLS with Dox to enhance its chemotherapeutic effects and reduce the oxidative imbalance and inflammatory responses associated with Dox treatment.