Toxicology, 2011, Vol.285(1), pp.72-80
► Natural product PL3 induced cancer cell apoptosis and cell cycle arrest. ► PL3 targeted and de-regulated PI3K pathway activities. ► De-activated PI3K pathway caused Aurora B degradation and spindle dysfunction. ► PL3 could reverse the drug-resistance of Bcr-ABL T315I-positive cells to Imatinib. The PI3K-AKT pathway and Aurora kinase play essential roles in such cellular processes as cell survival, angiogenesis, and differentiation, and are usually expressed at maximum levels during cancer cell proliferation. The present study investigated the effect of the natural compound, 16-hydroxycleroda-3,13-dien-15,16-olide (PL3), on regulating the PI3K-AKT pathway and Aurora B, which led to cancer cell apoptosis. PL3 acts as a PI3K inhibitor by influencing cell survival, signaling transduction, and cell cycle progression. It was observed that PL3 targeted and induced dephosphorylation of the PI3K pathway, degradation of Aurora B and mitotic-related gene expressions, and sequentially shut down the cell cycle. This eventually resulted in cell death. As Aurora B was downregulated, spindle dysfunction and destruction of the G /M phase checkpoint resulted in DNA-damaged cells undergoing apoptosis. Moreover, PL3 also resensitized T315I-mutated Bcr-ABL BA/F3 cells to improve the cytotoxicity of Imatinib in Imatinib-resistant cell line. Taken together, PL3 can perturb the PI3K-AKT pathway and Aurora B resulting in gene silencing and cell cycle disturbance. It was demonstrated that PL3 acted like a novel small-molecule PI3K modulator, thereby potentially contributing to cancer chemotherapy and combination medication.
16-Hydroxycleroda-3,13-Dien-15,16-Olide ; Aurora B ; Pi3k ; Mitotic Block ; Apoptosis ; Pharmacy, Therapeutics, & Pharmacology ; Public Health
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