OBJECTIVESome selective estrogen receptor modulators (SERMs) have been associated with increased incidence of urinary incontinence and pelvic organ prolapse. This study explored the effects of five SERMs on the function and matrix components of the vagina and its supportive tissues.METHODSFifty-six rats were administered SERMs by oral gavage for 8 weeks (n = 8 for each SERM): raloxifene, tamoxifen, idoxifene, bazedoxifene at three different doses, and bazedoxifene with conjugated estrogens. Thirty-two rats were used as controls (n = 8 per group): sham operation (no ovariectomy), ovariectomy only, ovariectomy with vehicle gavage, and 17β-estradiol (subcutaneous). Vaginal supportive tissue complex was tested by uniaxial tensile testing. Total collagen content (hydroxyproline) and glycosaminoglycan content (Blyscan) were measured.RESULTSOvariectomy significantly decreased the mechanical integrity of the vagina and its supportive tissue complex, with a decrease in ultimate load and stiffness (all P < 0.05). Although 17β-estradiol supplementation maintained these properties similarly to sham operation, none of the SERMs was as effective--particularly idoxifene, bazedoxifene at higher doses, and bazedoxifene with conjugated estrogens (all P < 0.05). In addition, idoxifene and bazedoxifene induced increased total collagen content compared with sham or 17β-estradiol treatment (all P < 0.05). Glycosaminoglycan content did not change significantly.CONCLUSIONSUnlike 17β-estradiol, SERM supplementation does not fully prevent ovariectomy-induced deterioration in the biomechanical properties of the vagina and its supportive tissues, with the effects of idoxifene and bazedoxifene being the least. The paradoxically increased collagen content in these two groups may be related to increased formation of nonfunctional collagen.

28 Feb 2014·mBio

Estrogen Receptor Antagonists Are Anti-Cryptococcal Agents That Directly Bind EF Hand Proteins and Synergize with Fluconazole In Vivo

Article

Author: Butts, Arielle ; Chabrier-Roselló, Yeissa ; Semighini, Camile P. ; Tabroff, Julie ; Cardenas, Maria E. ; Annadurai, Sivakumar ; Abou-Gharbia, Magid ; Childers, Wayne E. ; Heitman, Joseph ; Krysan, Damian J. ; Koselny, Kristy ; DiDone, Louis ; Wellington, Melanie ; Wang, Xuying ; Brown, Jessica C. S. ; Madhani, Hiten D.

ABSTRACT Cryptococcosis is an infectious disease of global significance for which new therapies are needed. Repurposing previously developed drugs for new indications can expedite the translation of new therapies from bench to beside. Here, we characterized the anti-cryptococcal activity and antifungal mechanism of estrogen receptor antagonists related to the breast cancer drugs tamoxifen and toremifene. Tamoxifen and toremifene are fungicidal and synergize with fluconazole and amphotericin B in vitro . In a mouse model of disseminated cryptococcosis, tamoxifen at concentrations achievable in humans combines with fluconazole to decrease brain burden by ~1 log 10 . In addition, these drugs inhibit the growth of Cryptococcus neoformans within macrophages, a niche not accessible by current antifungal drugs. Toremifene and tamoxifen directly bind to the essential EF hand protein calmodulin, as determined by thermal shift assays with purified C. neoformans calmodulin (Cam1), prevent Cam1 from binding to its well-characterized substrate calcineurin (Cna1), and block Cna1 activation. In whole cells, toremifene and tamoxifen block the calcineurin-dependent nuclear localization of the transcription factor Crz1. A large-scale chemical genetic screen with a library of C. neoformans deletion mutants identified a second EF hand-containing protein, which we have named calmodulin-like protein 1 (CNAG_05655), as a potential target, and further analysis showed that toremifene directly binds Cml1 and modulates its ability to bind and activate Cna1. Importantly, tamoxifen analogs (idoxifene and methylene-idoxifene) with increased calmodulin antagonism display improved anti-cryptococcal activity, indicating that calmodulin inhibition can be used to guide a systematic optimization of the anti-cryptococcal activity of the triphenylethylene scaffold. IMPORTANCE Worldwide, cryptococcosis affects approximately 1 million people annually and kills more HIV/AIDS patients per year than tuberculosis. The gold standard therapy for cryptococcosis is amphotericin B plus 5-flucytosine, but this regimen is not readily available in regions where resources are limited and where the burden of disease is highest. Herein, we show that molecules related to the breast cancer drug tamoxifen are fungicidal for Cryptococcus and display a number of pharmacological properties desirable for an anti-cryptococcal drug, including synergistic fungicidal activity with fluconazole in vitro and in vivo , oral bioavailability, and activity within macrophages. We have also demonstrated that this class of molecules targets calmodulin as part of their mechanism of action and that tamoxifen analogs with increased calmodulin antagonism have improved anti-cryptococcal activity. Taken together, these results indicate that tamoxifen is a pharmacologically attractive scaffold for the development of new anti-cryptococcal drugs and provide a mechanistic basis for its further optimization.

13 Jan 2010·JAMA

Researchers Probe Targeted Agents’ Clinical Potential for Cancer Prevention

Author: Hampton, Tracy

BOSTON—Favorable results from treatment trials have brought considerable attention to targeted cancer prevention. Meanwhile, research continues to identify proteins important for cancer development and progression, expanding the list of agents that might one day be suitable for healthy individuals at high risk of developing certain types of cancer. Investigators discussed many of these agents and their targets at the recent Molecular Targets and Cancer Therapeutics International Conference, organized by the American Association for CancerResearch, theNationalCancer Institute, and the European Organisation for Research and Treatment of Cancer. The well-known successes of targeted therapies for breast cancer have revolutionized cancer care. Now researchers are looking to apply similar strategies to prevention. “Therapeutic interventions related to the estrogen receptor and HER2/neu have prepared the way for exploiting these same targets in breast cancer prevention,” said Karen A. Johnson, MD, PhD, MPH, of the National Cancer Institute in Bethesda, Md. The benefits of anti-HER2/neu therapies such as trastuzumab are linked to overexpression of HER2 in breast tissue. “It follows that HER2-positive DCIS [ductal carcinoma in situ] is an appropriate setting to study the effect of trastuzumab for a high-risk tissue abnormality short of invasive cancer,” said Johnson. Other investigators are examining the activity of lapatinib, a dual kinase inhibitor, for its effect on DCIS that overexpresses HER2, the epidermal growth factor receptor, or both. Phase 3 prevention studies have shown that drugs that target the estrogen receptor (ER)—including tamoxifen, raloxifene, and idoxifene—

100 Deals associated with Idoxifene

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KEGG	Wiki	ATC	Drug Bank
D04496	Idoxifene	-	-

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Phase 3	GB	-	-
Breast Cancer	Phase 3	US	-	-
Osteoporosis, Postmenopausal	Phase 3	-	BTG International Ltd.	-
Osteoporosis, Postmenopausal	Phase 3	-	Cancer Research UK	-
Osteoporosis, Postmenopausal	Phase 3	-	GSK Plc	-
Osteoporosis, Postmenopausal	Phase 3	GB	-	-
Osteoporosis, Postmenopausal	Phase 3	US	-	-
Osteoporosis, Postmenopausal	Discovery	-	-	-

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