Alisol B, a novel inhibitor of the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase pump, induces autophagy, endoplasmic reticulum stress, and apoptosis.
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.
Law
Betty Y K
BY
Department of Chemistry, The University of Hong Kong, Hong Kong.
Wang
Mingfu
M
Ma
Dik-Lung
DL
Al-Mousa
Fawaz
F
Michelangeli
Francesco
F
Cheng
Suk-Hang
SH
Ng
Margaret H L
MH
To
Ka-Fai
KF
Mok
Anthony Y F
AY
Ko
Rebecca Y Y
RY
Lam
Sze Kui
SK
Chen
Feng
F
Che
Chi-Ming
CM
Chiu
Pauline
P
Ko
Ben C B
BC
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
D000970:Antineoplastic Agents; D002783:Cholestenones; D004791:Enzyme Inhibitors; C457232:alisol B; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases