Orally administered endoxifen inhibits tumor growth in melanoma-bearing mice

Abstract

Endoxifen, an active metabolite of tamoxifen, has been shown to be an effective anti-estrogenic agent in estrogen receptor-positive breast cancer patients. In melanoma, estrogen receptor expression is shown to be associated with disease progression. However, the therapeutic benefit of endoxifen in melanoma has not yet been evaluated. Here, we present the first demonstration of the anti-melanogenic activity of endoxifen in vitro and in vivo.The in vitro cytotoxic effect of endoxifen was tested using a cell viability assay. The in vivo anti-melanogenic activity was evaluated in B16F10 cell-bearing C57BL/6 mice, a mouse melanoma model. The general toxicity was tested in Swiss albino mice.Endoxifen exhibited greater activity against melanoma cell lines. Treatment of B16F10 mouse and SK-MEL-5 human melanoma cell lines with 10 μM of endoxifen for 48 h respectively resulted in 93.6 and 92.5% cell death. Orally administered endoxifen, at dose levels of 4 and 8 mg/kg body weight/day for 20 consecutive days, respectively reduced metastatic melanoma nodules in the lungs by 26.7 and 82.7%.Endoxifen was found to be a safe and effective anti-melanogenic agent in animal studies.

Female melanoma and estrogen receptors expression: an immunohistochemical pilot study

“…It has recently been demonstrated that endoxifen, a 100-times more powerful active metabolite compared to TAM, can be a promising new therapeutic agent against CM by blocking ER transcription [40]. The mechanism of action of endoxifen inhibition in CM cells has been not completely clarified, but at nanomolar concentrations, the molecule can effectively block ER transcriptional activity, resulting in anti-melanogenic activity [40]. Besides, the selective ERβ agonist LY500307 has been observed to be effective against lung metastasis from CM, both in vitro and in vivo.…”

Sex and Gender Disparities in Melanoma

“…injected with melanoma cells, decreases lung nodules [55]. Oral administration of TAM [56] and EDX [57] exert inhibitory effects on tumor metastatization into the mouse lungs. (Right) AR action is responsible for the increased number of lung metastases through the miR-539-3p/USP13/MITF/AXL axis [58], whereas AR blockade mediates an increase in the immune response [59].…”

“…Therefore, to induce melanoma cell death in vitro, endoxifen (EDX), a metabolite of TAM that is safer and has more cytostatic activity than the parent drug has been used [66]. Furthermore, EDX orally administered in mice for four weeks reduced lung metastatic nodules without any side effects [57]. Another reason for different epidemiological evidence in TAM's effectiveness could lie in its possible different and tissue-related effects on the two estrogen receptors, similarly to E2 [67,68].…”

Estrogen Receptors and Melanoma: A Review

“…It has been found to be up to 100 times more potent than TAM but with a more favorable toxicity and safety profile. For all these reasons endoxifen could be a promising new therapeutic agent for advanced melanoma [84]. Selective pharmacological activation of ERβ through its agonist LY500307 has been shown to have a potent suppressive action against lung metastasis from melanoma in vitro and in vivo.…”