Delineating the molecular mechanisms of tamoxifen's oncolytic actions in estrogen receptor-negative cancers.

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Radin DP, Patel P

Delineating the molecular mechanisms of tamoxifen's oncolytic actions in estrogen receptor-negative cancers.

Eur J Pharmacol. 2016 Jun 15;781:173-80. doi: 10.1016/j.ejphar.2016.04.017. Epub 2016 Apr 12.

PubMed ID

27083550 [ View in PubMed

]

Abstract

Since its clinical inception, tamoxifen (TAM) has proved to be a powerful tool in treating estrogen receptor-positive breast cancers while exhibiting manageable side effects. Although TAM was synthesized as an estrogen receptor antagonist, reports have found that a significant fraction of women with estrogen receptor-negative cancers have benefitted from TAM treatment, suggesting the possibility of an alternate anti-cancer mechanism. In this paper, we present a review of recent and past literature in an attempt to clarify how TAM inhibits cell proliferation and induces apoptosis in cells lacking the estrogen receptor. Our analysis indicates that micromolar concentrations of TAM selectively elevate intracellular calcium concentrations in malignant cells, possibly by inversely agonizing cannabinoid receptors, producing considerable mitochondrial distress followed by the rapid production of reactive oxygen species. In response, cytoplasmic proteins such as JNK1 are activated, which mediates the activation of caspase-8. Fyn kinase auto phosphorylates in response to increased reactive oxygen species and directs the ubiquitin ligase c-Cbl to tag growth factor receptors for ubiquitination, potentially abrogating constitutively active survival pathways that are hallmarks of cancer progression. We attempt to differentiate the effect that TAM has on purified Protein Kinase C (PKC) compared to that in an intact cell, suggesting that low micromolar concentrations of TAM indirectly inhibit PKC by inducing EGFR destruction and high micromolar concentrations of TAM inhibits PKC through a direct binding mechanism.

DrugBank Data that Cites this Article

Drugs

Tamoxifen

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Tamoxifen	Mitogen-activated protein kinase 8	Protein	Humans	Unknown	Modulator	Details
Tamoxifen	Protein kinase C (Protein Group)	Protein group	Humans	Yes	Inhibitor	Details
Tamoxifen	Sex hormone-binding globulin	Protein	Humans	Yes	Inducer	Details