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.

journal_name

Mol Cancer Ther

authors

Law BY,Wang M,Ma DL,Al-Mousa F,Michelangeli F,Cheng SH,Ng MH,To KF,Mok AY,Ko RY,Lam SK,Chen F,Che CM,Chiu P,Ko BC

doi

10.1158/1535-7163.MCT-09-0700

subject

Has Abstract

pub_date

2010-03-01 00:00:00

pages

718-30

issue

3

eissn

1535-7163

issn

1538-8514

pii

1535-7163.MCT-09-0700

journal_volume

9

pub_type

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