Induction of mitochondria‐involved apoptosis in estrogen receptor‐negative cells by a novel tamoxifen derivative, ridaifen‐B

Abstract

Tamoxifen is an antagonist of estrogen receptor, which is used widely as an estrogen receptor-positive breast cancer drug that blocks growth signals and provokes apoptosis. However, recent studies have revealed that tamoxifen induces apoptosis even in estrogen receptor-negative cells. In the present study, we synthesized several tamoxifen derivatives to augment the apoptosis-inducing effect of tamoxifen and evaluated the apoptosis-inducing pathway. The estrogen receptor-positive human leukemia cell line HL-60 and estrogen receptor-negative human leukemia cell line Jurkat were treated with tamoxifen and synthesized tamoxifen derivatives, and thereafter subjected to cell viability-detection assays. Tamoxifen derivatives, as well as the lead compound tamoxifen, decreased the cell viability despite the expression of estrogen receptor. Among all of the synthesized tamoxifen derivatives, ridaifen-B had more potent cancer cell-damaging activity than tamoxifen. Ridaifen-B fragmented Jurkat cell DNA and activated caspases, suggesting that the ridaifen-B-induced apoptosis pathway is estrogen receptor independent. Moreover, mitochondrial involvement during ridaifen-B-induced apoptosis was estimated. Ridaifen-B significantly reduced mitochondrial membrane potential, and overexpression of Bcl-2 inhibited ridaifen-B-induced apoptosis. These results suggest that the induction of apoptosis by ridaifen-B, a novel tamoxifen derivative, is dependent on mitochondrial perturbation without estrogen receptor involvement. (Cancer Sci 2008; 99: 608-614) O ne way of enhancing the ability of cancer cells to multiply is by utilizing growth factor receptors, as well as growth hormone receptors, to effectively receive cellular growth signals. One of the hormone receptors, ER, is expressed in most breast cancer cells. ER has two subtypes, ER-α and ER-β. ER-α is a transcription factor that induces not only growth-promoting genes but also differentiation-related genes, (1,2) resulting in the mediation of reproduction, metabolism, and cancer-cell growth. Another ER subtype, ER-β, was cloned in 1996, (3) and has a ligand-binding domain identical to that of ER-α. However, the physiological effect of ER-β seems to be the opposite of that of ER-α: it inhibits proliferation.(4) The non-steroidal SERM TAM binds to ER instead of the endogenous growth hormone estrogen 17β-estradiol, leading to inhibition of breast cancer cell proliferation and resulting in apoptosis.(5) Therefore, TAM is now used widely as an ER-positive breast cancer drug. However, how TAM induces apoptosis, which is the pharmacological effect of TAM, is obscure as several reports have demonstrated that a high dose and long time treatment with TAM is able to induce apoptosis even in ER-negative cancer cells.(6,7) TAM therefore seems to induce apoptosis in both ER-positive and -negative cells, suggesting that ER is not necessary for TAM to provoke a cancer-cell decrease.Mitochondria play an important role in apoptosis. With multiple cytotoxic stimuli, including UV, X-ray, and many chemi...

Regulation of mitochondrial respiratory chain biogenesis by estrogens/estrogen receptors and physiological, pathological and pharmacological implications

“…Moreira et al [280] demonstrated that TAM interacted with the flavin mononucleotide site of complex I, leading to mitochondrial failure. Ridaifen-B, a novel TAM derivative, has been shown to induce apoptosis in ER-negative breast cancer cells by reducing mitochondrial membrane potential [281]. Pancratistatin (PST), a natural compound obtained from the Hawaiian spider lily, has been known to be specific and selective in inducing apoptosis in multiple cancer cell lines.…”

A ferrocenyl derivative of hydroxytamoxifen elicits an estrogen receptor-independent mechanism of action in breast cancer cell lines

“…Binding of OH-TAM to ERa leads to a decrease in tumor cell growth [6]. OH-TAM is also effective in the absence of ER expression in breast cancer, melanoma, glioma and pancreatic carcinoma [7][8][9]. However this non-genomic effect (i.e.…”

Anti‑proliferative effect of ridaifen‑B on hepatoma cells

“…Although the detailed mechanism for RID-B-mediated cancer cell growth inhibition and apoptosis is unknown, the following mechanism was indicated from the present findings: RID-B may activate caspase-3 to induce DNA fragmentation, and RID-B may directly bind to DNA to inhibit DNA synthesis. It has been reported that RID-B reduced mitochondrial membrane potential during the induction of apoptosis in the human lymphoid helper T-cell line Jurkat (11), and that RID-B induced microtubule-associated protein 1A/1B-light chain 3 and lysosome colocalization resulting in autophagy in Jurkat cells (12). Additionally, the current data revealed that caspase inhibitor, Z-VAD-FMK, partially suppressed RID-B-mediated growth inhibition and DNA fragmentation in Huh-7 cells.…”

“…1), and has been observed to elicit marked cellular damage against both ER-positive and -negative tumor cells (11). It has also been reported that RID-B induces autophagy in the ER-negative human leukemia Jurkat cell line (12).…”