Tamoxifen Inhibits Topoisomerases, Depletes Mitochondrial DNA, and Triggers Steatosis in Mouse Liver

Larosche, Isabelle; Lettéron, Philippe; Fromenty, Bernard; Vadrot, Nathalie; Abbey-Toby, Adjé; Feldmann, Gérard; Pessayre, Dominique; Mansouri, Abdellah

doi:10.1124/jpet.106.114546

Cited by 131 publications

(122 citation statements)

References 34 publications

(70 reference statements)

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“…All of the deleterious effects induced by tamoxifen were highly exacerbated in the presence of estradiol [151]. Tamoxifen-induced inhibition of topoisomerases, mitochondrial DNA depletion and also the triggering of steatosis in mouse liver was also previously demonstrated [152]. The study demonstrated that tamoxifen is electrophoretically accumulated inside hepatic mitochondria, where it acutely impairs -oxidation and respiration.…”

Section: Mitochondrial Hepatic Toxicitymentioning

confidence: 69%

Investigating Drug-induced Mitochondrial Toxicity: A Biosensor to Increase Drug Safety?

Pereira¹,

Moreira²,

Pereira³

et al. 2009

CDS

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Mitochondria are recognized as the producers of the majority of energy cells need for their normal activity. After the initial comprehension of how mitochondrial oxidative phosphorylation produces energy, mitochondrial research was not a priority for most cell biologists until novel mitochondrial functions were identified. In fact, it is now known that mitochondria are not only involved in cell calcium homeostasis, intermediate metabolism and free radical generation but are also a crucial crossroad for several cell death pathways. The notion that several clinically used drugs and other xenobiotics induce organ degeneration through damaging mitochondrial bioenergetics led to the use of the organelle as an effective and reliable bio-sensor to predict drug safety. Classic methods used to test the toxicity of a wide range of compounds on isolated mitochondrial fractions were later replaced by novel high-throughput methods to investigate the safety of a very large number of new molecules. Without surprise, the assessment of "mitochondrial safety" for new discovered molecules is of clear interest for pharmaceutical companies which can now select compounds lacking mitochondrial toxicity to undergo further trials, thus avoiding the possibility of later human toxicity due to mitochondrial liabilities.

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Section: Mitochondrial Hepatic Toxicitymentioning

confidence: 69%

Investigating Drug-induced Mitochondrial Toxicity: A Biosensor to Increase Drug Safety?

Pereira¹,

Moreira²,

Pereira³

et al. 2009

CDS

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“…27 They showed 4-OHT was preferentially accumulated in mitochondria and inhibited both mtDNA synthesis and topoisomerase. It may be possible that 4-OHT treatment also triggers mtDNA deletions by inhibiting topoisomerase which causes insufficient relaxation to complete mtDNA replication.…”

Section: Discussionmentioning

confidence: 99%

Induction of acquired resistance to antiestrogen by reversible mitochondrial DNA depletion in breast cancer cell line

Naito

Carcel-Trullols

Xie

et al. 2008

Intl Journal of Cancer

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Although the net benefits of tamoxifen in adjuvant breast cancer therapy have been proven, the recurrence of the cancer in an aggressive and hormone independent form has been highly problematic. We previously demonstrated the important role mitochondrial DNA (mtDNA) plays in hormone-independence in prostate cancer. Here, the role of mtDNA in breast cancer progression was investigated. We established hydroxytamoxifen (4-OHT) resistant HTRMCF by growing MCF-7, human breast adenocarcinoma cells, in the presence of 4-OHT. HTRMCF was cross-resistant to 4-OHT and ICI182,780 concurrent with the depletion of mtDNA. To further investigate the role of mtDNA depletion, MCF-7 was depleted of mtDNA by treatment with ethidium bromide. MCFq0 was resistant to both 4-OHT and ICI182,780. Furthermore, cybrid (MCFcyb) prepared by fusion MCFq0 with platelet to transfer mtDNA showed susceptibility to antiestrogen. Surprisingly, after withdrawal of 4-OHT for 8 weeks, HTRMCF and their clones became susceptible to both drugs concurrent with a recovery of mtDNA. Herein, our results substantiated the first evidence that the depletion of mtDNA induced by hormone therapy triggers a shift to acquired resistance to hormone therapy in breast cancer. In addition, we showed that mtDNA depletion can be reversed, rendering the cancer cells susceptible to antiestrogen. The fact that the hormone independent phenotype can be reversed should be a step toward more effective treatments for estrogen-responsive breast cancer. ' 2007 Wiley-Liss, Inc.

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“…88 Higher intra-mitochondrial accrual of drugs like amiodarone, perhexiline or tamoxifen causes progressive reduction in mitochondrial respiration. 88,89 This leads to decreased ATP production in cells.…”

Section: Acquired Mitochondrial Disorders Of Livermentioning

confidence: 99%

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Tamoxifen Inhibits Topoisomerases, Depletes Mitochondrial DNA, and Triggers Steatosis in Mouse Liver

Cited by 131 publications

References 34 publications

Investigating Drug-induced Mitochondrial Toxicity: A Biosensor to Increase Drug Safety?

Investigating Drug-induced Mitochondrial Toxicity: A Biosensor to Increase Drug Safety?

Induction of acquired resistance to antiestrogen by reversible mitochondrial DNA depletion in breast cancer cell line

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