AbstractBackground: Cancer is one of the leading causes of morbidity and mortality globally. Cancer-associated thrombosis is well established in clinical settings, and thrombin has been found to induce angiogenesis at cancer sites. This establishes a link between cardiovascular diseases and cancer, where cancer and thrombin have been intricately associated. Various selective estrogen receptor modulators (SERMs) have been reported to exhibit anticancer activity. Therefore, we investigated estradiol-17β and SERMs dl-ormeloxifene (centchroman), raloxifene and levormeloxifene (l-centchroman) for their anticancer effects and their effect on thrombin activity.Methods: Anticancer activity was assessed against PC-3 cell line by flow cytometry following treatment with estradiol-17β and SERMs at 10 nM–1 mM concentrations. The cells were stained with propidium iodide and the percentage of cells in the sub-G0/G1 region was considered apoptotic. Thrombin inhibitory effect was evaluated by thrombin inhibition assay in vitro following incubation with 100 nM–3 mM concentrations of estradiol-17β or various SERMs. Further, the effect of estradiol-17β and SERMs on endogenous thrombin generation potential (ETP) was assessed by thrombin generation assay on rat plasma in vitro.Results: These compounds exhibited >90% cell death in PC-3 cell lines at 1 mM concentration except estradiol-17β. Neither estradiol-17β, dl-ormeloxifene and levormeloxifene showed any thrombin inhibitory or enhancing activity in thrombin inhibition assay, nor did they show any effect on ETP on rat plasma in vitro. However, raloxifene inhibited thrombin activity in a concentration-dependent manner. Raloxifene decreased ETP of the plasma at 3 and 1 mM,which is equivalent to that of 30–100 U/mL of heparin. Interestingly, raloxifene increased thrombin generation at lower concentrations and it inhibited thrombin generation at higher concentrations.Conclusions: These observations suggest that dl-ormeloxifene, estradiol-17β and levormeloxifene do not possess thrombin inhibitory activity. Raloxifene possesses thrombin modulatory effect in addition to its anticancer activity, and this observation may help us in understanding the thromboembolic complications associated with raloxifene.

01 Nov 2006·SteroidsQ4 · MEDICINE

Modulation of estrogen receptor transactivation and estrogen-induced gene expression by ormeloxifene—A triphenylethylene derivative

Q4 · MEDICINE

Article

Author: Chellakkan S. Blesson ; Smita Awasthi ; Geetika Kharkwal ; Anila Dwivedi ; Amita Daverey

The study was aimed to investigate the interaction of D,L-ormeloxifene (Orm), a triphenylethylene and its hydroxy derivative with estrogen receptor subtypes alpha and beta, its influence on ERE-driven transcriptional activation and progesterone receptor expression. In competitive binding experiments using human recombinant ERalpha and ERbeta, Orm showed interaction with both ER subtypes, with more selectivity and higher affinity towards ERalpha (8.8%) as compared to ERbeta (3%). In case of 7-hydroxy derivative, the relative binding affinity for both ERs was enhanced several folds. Orm showed lower Ki, i.e. higher affinity for ERalpha (250 nM) than for ERbeta (750 nM). It was observed that Orm promoted the formation of ER-ERE complexes in uterine tissue extract whereas its hydroxy derivative showed inhibitory effects. Transient co-transfection assay in COS-1 cells using ERE-luciferase reporter construct, revealed that Orm showed estrogenic response whereas its hydroxy-derivative was potent antiestrogen at ERalpha at transcription level. In immature rats, Orm (2 mg/kg) was associated with less increase in uterine weight and in luminal epithelial cell height than E2 or Tam. Orm also induced the expression of PR mRNA but the expression level was significantly less than estradiol treated group. These results suggest that ER-ERE complexes formed under the influence of 7-hydroxy Orm appear to be transcriptionally less effective hence antagonizing the E2-regulated gene expression in this target tissue.

01 Oct 2001·ContraceptionQ2 · MEDICINE

Interaction with anti-implantation and estrogen antagonistic activities of dl-ormeloxifene, a selective estrogen receptor modulator, by tetracycline in female Sprague-Dawley rats

Q2 · MEDICINE

Article

Author: R Ghosh ; V.P Kamboj ; M.M Singh

Among the 10 commonly used therapeutic agents investigated, concurrent oral administration of tetracycline (140 mg/kg) twice daily on Days 1-5 post-coitum (pc) interfered with the post-coital anti-implantation activity and almost completely abolished estrogen antagonistic activity of the single anti-implantation (1.5 mg/kg, orally) dose of dl-ormeloxifene administered on Day 1 pc, resulting in the occurrence of resorbed implantations in 50% of the females. However, no such interaction was evident when tetracycline was administered intramuscularly or when ormeloxifene was administered at twice its anti-implantation dose. There was no effect of ormeloxifene and/or tetracycline treatment on serum estradiol and progesterone levels, and all animals presented apparently normal corpora lutea. Ormeloxifene administered per se inhibited aminopyrine-N-demethylase (AD), glucose-6-phosphate dehydrogenase (G-6-PDH) and glutathione-S-transferase (GST) in the liver on the day of maximal endometrial receptivity, which was prevented by tetracycline co-administration. Aniline hydroxylase and AD were not detected in small intestine or uterus in vehicle control or any of the treatment groups. There was, however, no effect of ormeloxifene plus tetracycline treatment on serum total alkaline phosphatase activity. Findings suggest that interference with anti-implantation action of ormeloxifene by tetracycline might be due primarily to the almost complete abolition of its estrogen antagonistic activity at the uterine level, effected by decreased bioavailability of ormeloxifene and/or its active metabolite(s) by altered enterohepatic recirculation because of the effect on gut microflora. This might alternatively be related to an increased rate of its metabolism and elimination from the system via prevention of ormeloxifene-induced inhibition of hepatic AD, G-6-PDH, and GST, which, by effecting a decreased rate of metabolism, might be responsible for prolonged (approximately 120 h) duration of estrogen antagonistic/anti-implantation action of ormeloxifene in this species.

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Indication	Highest Phase	Country/Location	Organization	Date
Contraception	IND Approval	IN	Central Drug Research Institute	25 Aug 2023

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