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• W4200114335 endingPage "148520" @default.
• W4200114335 startingPage "148520" @default.
• W4200114335 abstract "Tamoxifen has been widely used in the treatment of estrogen receptor (ER)-positive breast cancer, whereas it also exhibits ER-independent anticancer effects in various cancer cell types. As one of the convincing mechanisms underlying the ER-independent effects, induction of apoptosis through mitochondrial dysfunction has been advocated. However, the mechanism of action of tamoxifen even at the isolated mitochondrial level is not fully understood and remains controversial. Here, we attempted to comprehensively understand tamoxifen's multiple actions in isolated rat liver mitochondria through not only revisiting the actions hitherto reported but also conducting originally designed experiments. Using submitochondrial particles, we found that tamoxifen has potential as an inhibitor of both respiratory complex I and ATP synthase. However, these inhibitory effects were not elicited in intact mitochondria, likely because penetration of tamoxifen across the inner mitochondrial membrane is highly restricted owing to its localized positive charge (-N+H(CH3)2). This restricted penetration may also explain why tamoxifen is unable to function as a protonophore-type uncoupler in mitochondria. Moreover, tamoxifen suppressed opening of the mitochondrial permeability transition pore induced by Ca2+ overload through enhancing phosphate uptake into the matrix. The photoaffinity labeling experiments using a photolabile tamoxifen derivative (pTAM1) indicated that pTAM1 specifically binds to voltage-dependent anion channels (VDACs) 1 and 3, which regulate transport of various substances into mitochondria. The binding of tamoxifen to VDAC1 and/or VDAC3 could be responsible for the enhancement of phosphate uptake. Taking all the results together, we consider the principal impairment of mitochondrial functions caused by tamoxifen." @default.
• W4200114335 created "2021-12-31" @default.
• W4200114335 creator A5011147640 @default.
• W4200114335 creator A5029297763 @default.
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• W4200114335 creator A5053139157 @default.
• W4200114335 creator A5057423168 @default.
• W4200114335 creator A5062352603 @default.
• W4200114335 creator A5084553426 @default.
• W4200114335 date "2022-02-01" @default.
• W4200114335 modified "2023-10-02" @default.
• W4200114335 title "Comprehensive understanding of multiple actions of anticancer drug tamoxifen in isolated mitochondria" @default.
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