title: Induction of mitochondria-involved apoptosis in estrogen receptor-negative cells by a novel tamoxifen derivative, ridaifen-B.
abstract: Tamoxifen is an antagonist of estrogen receptor, which is used widely as an estrogen receptor-positive breast cancer drug that blocks growth signals and provokes apoptosis. However, recent studies have revealed that tamoxifen induces apoptosis even in estrogen receptor-negative cells. In the present study, we synthesized several tamoxifen derivatives to augment the apoptosis-inducing effect of tamoxifen and evaluated the apoptosis-inducing pathway. The estrogen receptor-positive human leukemia cell line HL-60 and estrogen receptor-negative human leukemia cell line Jurkat were treated with tamoxifen and synthesized tamoxifen derivatives, and thereafter subjected to cell viability-detection assays. Tamoxifen derivatives, as well as the lead compound tamoxifen, decreased the cell viability despite the expression of estrogen receptor. Among all of the synthesized tamoxifen derivatives, ridaifen-B had more potent cancer cell-damaging activity than tamoxifen. Ridaifen-B fragmented Jurkat cell DNA and activated caspases, suggesting that the ridaifen-B-induced apoptosis pathway is estrogen receptor independent. Moreover, mitochondrial involvement during ridaifen-B-induced apoptosis was estimated. Ridaifen-B significantly reduced mitochondrial membrane potential, and overexpression of Bcl-2 inhibited ridaifen-B-induced apoptosis. These results suggest that the induction of apoptosis by ridaifen-B, a novel tamoxifen derivative, is dependent on mitochondrial perturbation without estrogen receptor involvement.
authors.affiliation: Department of Biotechnology, College of Science and Engineering, Tokyo Denki University, Hatoyama, Hiki-gun, Saitama, 350-0394, Japan. yunagahara@b.dendai.ac.jp
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Nagahara
authors.forename: Isamu
authors.initials: I
authors.lastname: Shiina
authors.forename: Kenya
authors.initials: K
authors.lastname: Nakata
authors.forename: Akane
authors.initials: A
authors.lastname: Sasaki
authors.forename: Tomomi
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Masahiko
authors.initials: M
authors.lastname: Ikekita
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; C528171:ridaifen-B; D013629:Tamoxifen