Tamoxifen Never Ceases to Amaze: New Findings on Non-Estrogen Receptor Molecular Targets and Mediated Effects

Abstract

Tamoxifen is a first targeted drug that continues to be the gold standard in treatment of estrogen receptor positive breast cancer for almost 50 years. The current review is an update of the paper published in 2012. We provide the new data on the tamoxifen targets that are the key points of signaling cascades activating cellular proliferation, which determines aggressiveness of disease and chemotherapy resistance or sensitivity. Some inspiring clinical cases dealing with tamoxifen efficiency in treatment of different tumors are discussed. Additionally, the review includes data on antiviral, antibacterial, antifungal and antiparasitic activity of tamoxifen.

Tamoxifen induces toxicity, causes autophagy, and partially reverses dexamethasone resistance in Jurkat T cells

“…Of note, TAM is a highly lipophilic small molecule, which is able to modulate structure and mechanical properties of the cell membrane . One may speculate that TAM cytotoxicity in Jurkat cells is related to “off‐target” mechanisms, including PKC inhibition or direct effects on mitochondria, as it was demonstrated for some types of cells . Our present findings also pinpointed the mitochondria as an important TAM target (Section 3.4).…”

“…62 One may speculate that TAM cytotoxicity in Jurkat cells is related to "off-target" mechanisms, including PKC inhibition or direct effects on mitochondria, as it was demonstrated for some types of cells. 18,19 Our present findings also pinpointed the mitochondria as an important TAM target (Section 3.4). A synergistic effect of G-36 may be related to its capacity to prevent autophagy, which will to be addressed in future studies.…”

“…The mechanism of this form of cell death is under intense research and debates . In this regard, TAM was demonstrated to interact directly with mitochondrial membrane proteins, as well as with nonclassical TAM targets including PKC, mTOR, cannabinoid receptors, and multidrug resistance proteins . One can suggest also that the same drug may produce multitarget effects, with a complex cross‐talk between underlying mechanisms.…”

“…TAM is considered as an ERα antagonist and GPER agonist, which has been the first‐line targeted therapy for the management of ERα positive breast cancers for almost 60 years . However, several recent reports have pointed out some novel, “off‐target” or non‐ER‐related anticancer effects of TAM, independent of nuclear ER . Among these are target proteins involved in the regulation of proliferation, cell cycle progression, autophagy, and chemoresistance.…”

“…17 However, several recent reports have pointed out some novel, "off-target" or non-ER-related anticancer effects of TAM, independent of nuclear ER. 18,19 Among these are target proteins involved in the regulation of proliferation, cell cycle progression, autophagy, and chemoresistance. In this regard, TAM-induced apoptosis of breast cancer MCF-7 cells via GPER/PI3K/MAPK pathway has also been reported.…”