title: 16-Hydroxycleroda-3,13-dien-15,16-olide deregulates PI3K and Aurora B activities that involve in cancer cell apoptosis.
abstract: 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 G₂/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.
authors.affiliation: Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yi-Hsiung
authors.initials: YH
authors.lastname: Lin
authors.forename: Chien-Chih
authors.initials: CC
authors.lastname: Lee
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Chan
authors.forename: Wen-Hsin
authors.initials: WH
authors.lastname: Chang
authors.forename: Yang-Chang
authors.initials: YC
authors.lastname: Wu
authors.forename: Jan-Gowth
authors.initials: JG
authors.lastname: Chang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004224:Diterpenes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C072581:16-hydroxycleroda-3,13(14)-dien-15,16-olide; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases