title: Alisol B, a novel inhibitor of the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase pump, induces autophagy, endoplasmic reticulum stress, and apoptosis.
abstract: Emerging evidence suggests that autophagic modulators have therapeutic potential. This study aims to identify novel autophagic inducers from traditional Chinese medicinal herbs as potential antitumor agents. Using an image-based screen and bioactivity-guided purification, we identified alisol B 23-acetate, alisol A 24-acetate, and alisol B from the rhizome of Alisma orientale as novel inducers of autophagy, with alisol B being the most potent natural product. Across several cancer cell lines, we showed that alisol B-treated cells displayed an increase of autophagic flux and formation of autophagosomes, leading to cell cycle arrest at the G(1) phase and cell death. Alisol B induced calcium mobilization from internal stores, leading to autophagy through the activation of the CaMKK-AMPK-mammalian target of rapamycin pathway. Moreover, the disruption of calcium homeostasis induces endoplasmic reticulum stress and unfolded protein responses in alisol B-treated cells, leading to apoptotic cell death. Finally, by computational virtual docking analysis and biochemical assays, we showed that the molecular target of alisol B is the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase. This study provides detailed insights into the cytotoxic mechanism of a novel antitumor compound.
authors.affiliation: Department of Chemistry, The University of Hong Kong, Hong Kong.
authors.forename: Betty Y K
authors.initials: BY
authors.lastname: Law
authors.forename: Mingfu
authors.initials: M
authors.lastname: Wang
authors.forename: Dik-Lung
authors.initials: DL
authors.lastname: Ma
authors.forename: Fawaz
authors.initials: F
authors.lastname: Al-Mousa
authors.forename: Francesco
authors.initials: F
authors.lastname: Michelangeli
authors.forename: Suk-Hang
authors.initials: SH
authors.lastname: Cheng
authors.forename: Margaret H L
authors.initials: MH
authors.lastname: Ng
authors.forename: Ka-Fai
authors.initials: KF
authors.lastname: To
authors.forename: Anthony Y F
authors.initials: AY
authors.lastname: Mok
authors.forename: Rebecca Y Y
authors.initials: RY
authors.lastname: Ko
authors.forename: Sze Kui
authors.initials: SK
authors.lastname: Lam
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Che
authors.forename: Pauline
authors.initials: P
authors.lastname: Chiu
authors.forename: Ben C B
authors.initials: BC
authors.lastname: Ko
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D002783:Cholestenones / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008954:Models, Biological; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D013312:Stress, Physiological / Q000187:drug effects*; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D002783:Cholestenones; D004791:Enzyme Inhibitors; C457232:alisol B; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases