RRC ID 54475
Author Iwasawa T, Shinomiya T, Ota N, Shibata N, Nakata K, Shiina I, Nagahara Y.
Title Novel Ridaifen-B Structure Analog Induces Apoptosis and Autophagy Depending on Pyrrolidine Side Chain.
Journal Biol Pharm Bull
Abstract Ridaifen (RID)-B is an analog derived from tamoxifen (TAM). TAM has an antitumor effect by acting as an antagonist to estrogen receptor (ER). However, TAM is known to also induces apoptosis in cancer cells that do not have ER. We clarified that RID-B induces cell death at a lower concentration than TAM, and causes ER-independent apoptosis and autophagy. Based on the results of previous studies, we assumed that RID-B had a unique target different from ER and examined structural activity correlation to determine what kinds of structural features are related to RID-B activity. As a result, we found there was activity even without one of phenyl groups (Ar3) in RID-B and revealed that two pyrrolidine side chains peculiar to RID-B are related to the action. Furthermore, analogs with shorter alkyl side chains induced autophagy, but analogs with certain length of alkyl side chains induced apoptosis. Also, although there is no doubt that RID-B induces apoptosis by causing mitochondrial injury, our results suggested that such injury induced mitochondria-selective autophagy. We revealed that RID-B induce mitophagy and that this mitophagy is a defense mechanism against RID-B. Our results suggest that autophagy was induced against apoptosis caused by mitochondrial dysfunction in RID-B, so the combination of autophagy inhibitor and anticancer-drug can be effective for cancer treatment.
Volume 42(3)
Pages 401-410
Published 2019-1-1
DOI 10.1248/bpb.b18-00643
PMID 30828072
MeSH Actins / genetics Actins / metabolism Apoptosis / drug effects* Autophagy / drug effects* Caspase 3 / genetics Caspase 3 / metabolism Cell Line, Tumor Gene Expression Regulation / drug effects Humans Mitochondria / drug effects Mitophagy Molecular Structure Pyrrolidines / chemistry* Pyrrolidines / pharmacology* Reactive Oxygen Species / metabolism Structure-Activity Relationship Tamoxifen / analogs & derivatives* Tamoxifen / chemistry Tamoxifen / pharmacology
IF 1.54
Times Cited 0
Mice RBRC00806
Human and Animal Cells Atg5^(-/-)MEF(RCB2711) Atg5^(+/+)MEF(RCB2710)