The selective estrogen receptor (ER) modulator, tamoxifen, is the only endocrine agent with approvals for both the prevention and treatment of premenopausal and postmenopausal estrogen-receptor ...positive breast cancer as well as for the treatment of male breast cancer. Endoxifen, a secondary metabolite resulting from CYP2D6-dependent biotransformation of the primary tamoxifen metabolite, N-desmethyltamoxifen (NDT), is a more potent antiestrogen than either NDT or the parent drug, tamoxifen. However, endoxifen's antitumor effects may be related to additional molecular mechanisms of action, apart from its effects on ER. In phase 1/2 clinical studies, the efficacy of Z-endoxifen, the active isomer of endoxifen, was evaluated in patients with endocrine-refractory metastatic breast cancer as well as in patients with gynecologic, desmoid, and hormone-receptor positive solid tumors, and demonstrated substantial oral bioavailability and promising antitumor activity. Apart from its potent anticancer effects, Z-endoxifen appears to result in similar or even greater bone agonistic effects while resulting in little or no endometrial proliferative effects compared with tamoxifen. In this review, we summarize the preclinical and clinical studies evaluating endoxifen in the context of breast and other solid tumors, the potential benefits of endoxifen in bone, as well as its emerging role as an antimanic agent in bipolar disorder. In total, the summarized body of literature provides compelling arguments for the ongoing development of Z-endoxifen as a novel drug for multiple indications.
Tamoxifen (TAM) is an established endocrine treatment for all stages of oestrogen receptor (ER)-positive breast cancer. Its complex metabolism leads to the formation of multiple active and inactive ...metabolites. One of the main detoxification and elimination pathways of tamoxifen and its active metabolites, 4-hydroxytamoxifen (4-OHT) and endoxifen, is via glucuronidation catalysed by uridine 5'-diphospho-glucuronosyltransferases (UGTs). However, few studies have comprehensively examined the impact of variations in the genes encoding the major hepatic UGTs on the disposition of tamoxifen and its metabolites. In the present study, we systematically sequenced exons, exon/intron boundaries, and flanking regions of UGT1A4, UGT2B7 and UGT2B15 in 240 healthy subjects of different Asian ethnicities (Chinese, Malays and Indians) to identify haplotype tagging single nucleotide polymorphisms. Subsequently, 202 Asian breast cancer patients receiving tamoxifen were genotyped for 50 selected variants in the three UGT genes to comprehensively investigate their associations with steady-state plasma levels of tamoxifen, its active metabolites and their conjugated counterparts. The UGT1A4 haplotype (containing variant 142T>G, L48 V defining the *3 allele) was strongly associated with higher plasma levels of TAM-N-glucuronide, with a twofold higher metabolic ratio of TAM-N-glucuronide/TAM observed in carriers of this haplotype upon covariate adjustment (P < 0.0001). Variants in UGT2B7 were not associated with altered O-glucuronidation of both 4-OHT and endoxifen, while UGT2B15 haplotypes had a modest effect on (E)-endoxifen plasma levels after adjustment for CYP2D6 genotypes. Our findings highlight the influence of UGT1A4 haplotypes on tamoxifen disposition in Asian breast cancer patients, while genetic variants in UGT2B7 and UGT2B15 appear to be of minor importance.
The combination of photodynamic therapy and other cancer treatment modalities is a promising strategy to enhance therapeutic efficacy and reduce side effects. In this study, a tamoxifen–zinc(II) ...phthalocyanine conjugate linked by a triethylene glycol chain has been synthesized and characterized. Having tamoxifen as the targeting moiety, the conjugate shows high specific affinity to MCF-7 breast cancer cells overexpressed estrogen receptors (ERs) and tumor tissues, therefore leading to a cytotoxic effect in the dark due to the cytostatic tamoxifen moiety, and a high photocytotoxicity due to the photosensitizing phthalocyanine unit against the MCF-7 cancer cells. The high photodynamic activity of the conjugate can be attributed to its high cellular uptake and efficiency in generating intracellular reactive oxygen species. Upon addition of exogenous 17β-estradiol as an ER inhibitor, the cellular uptake and photocytotoxicity of the conjugate are reduced significantly. As shown by confocal microscopy, the conjugate is preferentially localized in the lysosomes of the MCF-7 cells.
Tamoxifen is the most commonly used endocrine therapy for patients with hormone receptor (HR)-positive breast cancer. Despite its initial therapeutic efficacy, many patients eventually develop drug ...resistance, which remains a serious clinical challenge. To investigate roles of circular RNAs (circRNAs) in tamoxifen resistance, a tamoxifen-resistant MCF-7 cell line was established and screened for its circRNA expression profile by RNA sequencing. hsa_circ_0025202, a circRNA that was significantly downregulated, was selected for further investigation. Using a large cohort of clinical specimens, we found that hsa_circ_0025202 exhibited low expression in cancer tissues and was negatively correlated with lymphatic metastasis and histological grade. Gain- and loss-of-function assays indicated that hsa_circ_0025202 could inhibit cell proliferation, colony formation, and migration and increase cell apoptosis and sensitivity to tamoxifen. Bioinformatics and luciferase reporter assays verified that hsa_circ_0025202 could act as a miRNA sponge for miR-182-5p and further regulate the expression and activity of FOXO3a. Functional studies revealed that tumor inhibition and tamoxifen sensitization effects of hsa_circ_0025202 were achieved via the miR-182-5p/FOXO3a axis. Moreover, in vivo experiments confirmed that hsa_circ_0025202 could suppress tumor growth and enhance tamoxifen efficacy. Taken together, hsa_circ_0025202 served an anti-oncogenic role in HR-positive breast cancer, and it could be exploited as a novel marker for tamoxifen-resistant breast cancer.
This report demonstrates a novel circular RNA, named hsa_circ_0025202, which is downregulated in tamoxifen-resistant breast cancer cells. hsa_circ_0025202 was identified as a tumor suppressor, and it could improve tamoxifen sensitivity through regulating the miR-182-5p/FOXO3a axis, suggesting it could be a potential therapeutic target and marker for patients with hormone receptor-positive breast cancer.
Recent studies have demonstrated that specific miRNAs, such as miR-221/222, may be responsible for tamoxifen resistance in breast cancer. Secreted miRNAs enclosed in exosomes can act as intercellular ...bio-messengers. Our objective is to investigate the role of secreted miR-221/222 in tamoxifen resistance of ER-positive breast cancer cells. Transmission electron microscopy analysis and nanoparticle tracking analysis were performed to determine the exosomes difference between MCF-7
TamR
(tamoxifen resistant) and MCF-7
wt
(tamoxifen sensitive) cells. PKH67 fluorescent labeling assay was used to detect exosomes derived from MCF-7
TamR
cells entering into MCF-7
wt
cells. The potential function of exosomes on tamoxifen resistance transmission was analyzed with cell viability, apoptosis ,and colony formation. MiRNA microarrays and qPCR were used to detect and compare the miRNAs expression levels in the two cells and exosomes. As the targets of miR-221/222, p27 and ERα were analyzed with western blot and qPCR. Compared with the MCF-7
wt
exosomes, there were significant differences in the concentration and size distribution of MCF-7
TamR
exosomes. MCF-7
wt
cells had an increased amount of exosomal RNA and proteins compared with MCF-7
TamR
cells. MCF-7
TamR
exosomes could enter into MCF-7
wt
cells, and then released miR-221/222. And the elevated miR-221/222 effectively reduced the target genes expression of P27 and ERα, which enhanced tamoxifen resistance in recipient cells. Our results are the first to show that secreted miR-221/222 serves as signaling molecules to mediate communication of tamoxifen resistance.
The breast cancer treatment drug tamoxifen has been widely administered for more than three decades. This small molecule competes with 17β-estradiol for binding to estrogen receptor, a hormone ...receptor upregulated in a majority of breast cancers, subsequently initiating programmed cell death. We have synthesized a thiol-PEGylated tamoxifen derivative that can be used to selectively target and deliver plasmonic gold nanoparticles to estrogen receptor positive breast cancer cells with up to 2.7-fold enhanced drug potency in vitro. Optical microscopy/spectroscopy, time-dependent dose−response data, and estrogen competition studies indicate that augmented activity is due to increased rates of intracellular tamoxifen transport by nanoparticle endocytosis, rather than by passive diffusion of the free drug. Both ligand- and receptor-dependent intracellular delivery of gold nanoparticles suggest that plasma membrane localized estrogen receptor alpha may facilitate selective uptake and retention of this and other therapeutic nanoparticle conjugates. Combined targeting selectivity and enhanced potency provides opportunities for both multimodal endocrine treatment strategies and adjunctive laser photothermal therapy.
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•Melatonin increases efficacy of tamoxifen in induction of apoptosis in MCF-7 cells.•Nano structured Lipid Carriers prepared with particle size of 71nm.•Melatonin-loaded NLCs had ...synergistic effects on cytotoxic effects of tamoxifen.•NLCs can be considered as an advanced delivery system to increase cellular uptake and bioavalibility of anti-cancer agents.
Finding advanced anti-cancer agents with selective toxicity in tumor tissues is the goal of anticancer delivery systems. This study investigated potential application of nanostructured lipid carriers (NLCs) in increasing melatonin induced cytotoxicity and apoptosis in MCF-7 breast cancer cells.
Melatonin-loaded NLCs were characterized for particle size, zeta potential, Fourier transforms infrared spectroscopy, differential scanning calorimetry, cellular uptake, and scanning electron microscope (SEM). Anti-proliferative and apoptotic effects of new formulation were evaluated by MTT and flow cytometric assays, respectively. Gene expression of apoptotic markers including survivin, Bcl-2 and Bid were examined by Real time quantitative PCR.
The optimized formulation of NLCs revealed mean particle size of 71±5nm with nearly narrow size distribution. The formulation exhibited an acceptable stability during four months in terms of size and lack of drug release. The IC50 values for melatonin and tamoxifen were 1.3±0.4mM and 30.7±5.2μM, respectively. Melatonin loaded NLCs decreased percentage of cell proliferation from 55±7.2% to 40±4.1% (p<0.05). Co-treatment of the cells with melatonin loaded nanoparticles and tamoxifen caused two fold increase in the percentage of apoptosis (p<0.05). Evaluation of gene expression profile demonstrated a marked decrease in anti-apoptotic survivin with increase in pro-apoptotic Bid mRNA levels.
Taken together, our results suggest NLC technology as a promising delivery system, which elevates the efficacy of chemotherapeutics in breast cancer cells.
Objective
We synthesized new tamoxifen derivatives as anticancer drug candidates and elaborated on convection‐enhanced delivery (CED) as a strategy for delivery.
Methods
To overcome the issue of ...their poor solubility, these ferrocenyl‐tamoxifen derivatives were esterified and encapsulated into different nanocarriers, that is lipid (LNC) and polymeric nanocapsules (PNL‐NC). We describe the chemistry, the encapsulation and the physicochemical characterization of these formulations.
Key findings
Starting compounds phthalimido‐ferrocidiphenol and succinimido‐ferrocidiphenol, esterified prodrugs and their nanocapsules formulations were characterized.
These drug candidates displayed a strong in vitro activity against breast and glioblastoma cancer cells. The ester prodrugs were toxic for glioblastoma cells (IC50 = 9.2 × 10−2 μm and 6.7 × 10−2 μm, respectively). The IC50 values for breast cancer cells were higher for these compounds. The encapsulation of the esterified compounds in LNCs (≈50 nm) or PCL‐NCs (≈300 nm) did not prevent their efficacy on glioblastoma cells. These anticancer effects were due to both blockade in the S‐phase of the cell cycle and apoptosis. Moreover, the tamoxifen derivatives‐loaded nanocapsules induced no toxicity for healthy astrocytes and showed no haemolytic properties. Loaded Lipid Nanocapsules (LNCs) presented interesting profiles for the optimal delivery of active compounds.
Conclusions
Phthalimido‐ and Succinimido‐esters represent an innovative approach to treat cancers with cerebral localizations such as glioblastoma or brain metastases from breast cancers.
The aim of this study was to assess the safety of ospemifene, a novel selective estrogen receptor modulator, for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus.
In ...this multicenter, randomized, double-blind, placebo-controlled, long-term safety extension study, nonhysterectomized women aged 40 to 80 years (n = 180) received daily oral doses of placebo, ospemifene 30 mg/day, or ospemifene 60 mg/day for 40 weeks (continued as blinded treatments from the initial 12-week pivotal efficacy study of ospemifene). The total treatment period was 52 weeks. Safety assessments included adverse events, cervical Papanicolaou tests, endometrial histology, endometrial thickness, gynecological examination, breast palpation, mammography, physical examination, and clinical safety laboratory assessments.
No clinically significant adverse changes in safety assessments were observed in any treatment group. Most treatment-emergent adverse events were mild or moderate in severity. Hot flushes, the most frequently occurring treatment-emergent adverse event related to the study drug, had a low discontinuation rate (1.6%). No study participants discontinued because of endometrial or cervical pathology; no endometrial findings were clinically meaningful. On week 52, more than 95% of endometrial biopsy samples either were classified as atrophic or inactive or had insufficient tissue for diagnosis. There were no treatment-emergent adverse events of pelvic organ prolapse or venous thromboembolism. No cases of endometrial hyperplasia or carcinoma were observed. Only three participants (1.7%) taking ospemifene experienced vaginal bleeding or spotting, which was self-limiting.
Daily doses of ospemifene 30 mg and ospemifene 60 mg yielded few treatment-emergent adverse events and demonstrated no significant endometrial changes during the 1-year treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus.
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