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  • 1
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    MON-513 Suppressing the Growth of Human Medullary Thyroid Cancer Cells Using FDA-Approved Drug
    The Endocrine Society ; 2020
    In:  Journal of the Endocrine Society Vol. 4, No. Supplement_1 ( 2020-05-08)
    Details
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 4, No. Supplement_1 ( 2020-05-08)
    Abstract: Medullary thyroid carcinoma (MTC) is a solid tumor of the parafollicular cells in the thyroid gland. MTC has worse prognosis, when compared with other differentiated thyroid cancers, and MTC patients with distant metastases have a low survival rate unless thyroidectomy is performed at an early stage. Furthermore, conventional treatments have only marginal benefits. Therefore, there is a need to develop novel therapeutics for MTC. Several drugs that are developed and tested in preclinical trials fail in clinical trials. Therefore, repurposing the already US Food and Drug Administration (FDA)-approved drugs towards the treatment of cancers may have potential benefits, like saving the lives of cancer patients and lowering the investment cost of drug development. Here, we explored a novel precision treatment for thyroid cancers by repurposing the FDA-approved small molecule anti-parasitic drug Nitazoxanide (NTZ). In our study, we examined the anticancer effects of NTZ on human MTC cells using the TT cell line. We treated the TT cells with different concentrations of NTZ and assessed the cell proliferation by water-soluble tetrazolium salt (WST-1) assay and oxygen consumption rate (OCR) by Seahorse extracellular flux analysis (Seahorse XFe24 Analyzer). Additionally, we determined the effects of NTZ on the protein expression of key signaling molecules that regulate MTC cell growth by western blot analysis. Our results indicated that NTZ significantly suppressed the growth of TT cells at 24 h treatment. Very importantly, NTZ reduced the basal OCR demonstrating the inhibition of mitochondrial respiration. Moreover, protein expression studies revealed that NTZ markedly reduced the key Hippo signaling pathway effector molecule TAZ and the oncogene c-myc. Interestingly, NTZ decreased the expression of epidermal growth factor receptor (EGFR) that plays an important role for RET activation in MTC. Importantly, NTZ increased the expression of p53 upregulated modulator of apoptosis (Puma). Taken together, our findings demonstrate for the first time that NTZ inhibits the growth of MTC cells and decreases the cancer cell metabolism. The mechanisms by which NTZ targets the MTC cells involve the suppression of key oncogenic proteins and upregulation of tumor suppressor molecule. Thus, our study highlights that repurposing this FDA-approved currently used drug may have a greater advantage of being tested in preclinical models of MTC, and therefore, for the rapid consideration of NTZ as a potential therapeutic drug to treat MTC patients in the near future.
    Type of Medium: Online Resource
    ISSN: 2472-1972
    URL: Article
    DOI: 10.1210/jendso/bvaa046.1639
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2020
    detail.hit.zdb_id: 2881023-5
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  • 2
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    Abstract 4087: ALDH1A1 inhibitor induces cell cycle arrest and reduces cell proliferation of cisplatin-resistant ovarian cancer cells
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 4087-4087
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 4087-4087
    Abstract: Introduction: Ovarian cancer is one of the most common malignancies among women that causes severe mortality in USA and globally. Despite advances in cancer treatments in the last few decades, there is no substantial improvement in the survival rates of patients with advanced ovarian cancers. This is mainly attributed to drug resistance and tumor recurrence. Most patients develop resistance to platinum compounds, which are often used as the first-line therapy. Several studies have shown that aldehyde dehydrogenase (ALDH1A1) plays an important role in cancer stemness and confers resistance to cell death induced by platinum compounds used to treat ovarian cancers. Therefore, in this study, we determined the effect of a small-molecule inhibitor of ALDH1A1 (A37) in cisplatin-resistant ovarian cancer cells and assessed it's molecular mechanism of action. Experimental methods: The cisplatin-resistant ovarian cancer cells (A2780-CR) were exposed to various concentrations of ALDH1A1 inhibitor (A37) and then the cell proliferation by water-soluble tetrazolium salt (WST-1) assay, cell cycle analysis by flow cytometry and oxygen consumption rate (OCR) by Seahorse extracellular flux analysis (Seahorse XFe24 Analyzer) were performed. Furthermore, the protein expression of critical signaling molecules that modulate the proliferation of ovarian cancer cells was assessed by western blot analysis. Results: A37 treatment drastically decreased the proliferation of A2780-CR cells at 24 and 48 h. In addition, cell cycle analysis revealed a significant increase in G1 phase and dramatic decrease in S phase of the cell cycle upon A37 treatment. Interestingly, A37 suppressed the basal OCR, an indicator of mitochondrial respiration. Furthermore, A37 reduced the protein expression of mammalian target of rapamycin (mTOR), which plays a critical role in cancer cell cycle and proliferation. Conclusions: Our findings indicate that the ALDH1A1 inhibitor (A37) induces cell cycle arrest and suppresses the cell proliferation of cisplatin-resistant ovarian cancer cells, possibly through downregulation of mTOR signaling. Most importantly, A37 affects the cancer cell metabolism by reducing the mitochondrial respiration. Taken together, our study highlights the importance of potential therapeutic implication of ALDH1A1 inhibitor towards the treatment of chemoresistant-ovarian cancers. Citation Format: Ilangovan Ramachandran, Sivakumar Ramadoss, Selvendiran Karuppaiyah, Lauren Nathan, R. Ileng Kumaran, Gautam Chaudhuri. ALDH1A1 inhibitor induces cell cycle arrest and reduces cell proliferation of cisplatin-resistant ovarian cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4087.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-4087
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
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    Noninvasive Assessment of Coronary Microcirculatory Function in Postmenopausal Women and Effects of Short-Term and Long-Term Estrogen Administration
    Ovid Technologies (Wolters Kluwer Health) ; 2002
    In:  Circulation Vol. 105, No. 4 ( 2002-01-29), p. 425-430
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 105, No. 4 ( 2002-01-29), p. 425-430
    Abstract: Background — Estrogen improves endothelial function in the coronary conduit vessels of animals; however, its effects on the coronary microcirculation have not been studied completely in humans. Methods and Results — We measured myocardial blood flow (MBF) with a PET scan at rest, during cold pressor testing (CPT), and during dipyridamole hyperemia in 54 postmenopausal women without coronary artery disease. Of these, 23 were not and 31 women were taking long-term hormone replacement therapy (HRT) using estrogen either alone or with a progestogen. Each group was subdivided by coronary risk factors (RFs). Twelve young healthy women served as controls. In women not taking HRT, MBF measurements were repeated after 25 mg of conjugated equine estrogens IV. Neither short estrogen nor long-term HRT affected MBF at rest in women with and without RFs. Dipyridamole MBF was attenuated only in the women with RF who were not taking HRT. Short-term estrogen and long-term HRT did not reverse the abnormal response. MBF responses to CPT were abnormal in women not taking HRT, regardless of RFs (20±15% versus 32±21%) and remained unchanged after short-term estrogen administration. Long-term HRT normalized the response to CPT only in women without RF (53±22% versus 59±36% in the young women; NS). MBFs were similar for women on estrogen alone or estrogen plus a progestogen, regardless of presence or absence of RFs. Conclusion — Menopause is associated with abnormal CPT (an indirect measure of endothelial function), which can be reversed by long-term HRT only when RFs are absent. Progestogens do not antagonize this effect. Long-term HRT may therefore be useful in the primary prevention of coronary artery disease in women without RFs.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/hc0402.102860
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2002
    detail.hit.zdb_id: 1466401-X
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  • 4
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    Effects of calcitonin gene-related peptide on vascular resistance in rats: role of sex steroids
    American Physiological Society ; 1999
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 276, No. 6 ( 1999-06-01), p. H2063-H2068
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 276, No. 6 ( 1999-06-01), p. H2063-H2068
    Abstract: It has been demonstrated in reflex-intact animals that the sensitivity to calcitonin gene-related peptide (CGRP) is increased during pregnancy and that this action is mediated by sex steroids but not by nitric oxide (NO). We assessed the effects of CGRP in the following groups of anesthetized ganglion-blocked rats: 1) pregnant, 2) ovariectomized, and 3) ovariectomized and treated with estradiol and progesterone. Changes in mean arterial pressure (MAP) were assessed after the administration of varying doses of CGRP. Decreases in MAP after CGRP administration were significantly greater in pregnant rats and ovariectomized rats administered sex steroids than in ovariectomized controls. The CGRP antagonist CGRP 8–37 produced a pressor response of similar magnitude in both pregnant and ovariectomized rats. We also assessed the effects of CGRP and the modulating role of NO in the isolated uterine vascular bed preparation. CGRP reduced perfusion pressure to a greater degree in ovariectomized animals treated with sex steroids than in ovariectomized animals. This response was attenuated by pretreatment with an NO synthesis inhibitor. CGRP 8–37 produced a similar increase in perfusion pressure in both groups. We conclude that 1) the increased vascular sensitivity observed during pregnancy or after treatment with sex steroids is in part mediated by NO, and 2) CGRP 8–37 has a vasoconstrictor action of its own.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.1999.276.6.H2063
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1999
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 5
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    E 2 and not P 4 increases NO release from NANC nerves of the gastrointestinal tract: implications in pregnancy
    American Physiological Society ; 2001
    In:  American Journal of Physiology-Regulatory, Integrative and Comparative Physiology Vol. 280, No. 5 ( 2001-05-01), p. R1546-R1554
    Details
    In: American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, American Physiological Society, Vol. 280, No. 5 ( 2001-05-01), p. R1546-R1554
    Abstract: In women, during pregnancy, there is decreased motility of the gastrointestinal tract leading to a delay in gastric emptying and an increase in colonic transit time. Whether the rise in estradiol (E 2 ) or progesterone (P 4 ) is responsible for this effect is controversial. As the nitrergic component of the nonadrenergic, noncholinergic (NANC) nerves is responsible for modulating gastrointestinal motility in vivo, the purpose of this study was to evaluate whether the increased release of nitric oxide (NO) from the nitrergic component of the NANC nerves innervating the gastric fundus and colon that occurs during late pregnancy in rats is mediated by E 2 or P 4 . Ovariectomized rats treated with E 2 or P 4 alone or in combination were used for our studies. We also wanted to assess the cellular and molecular mechanisms involved. The NANC activity was studied by assessing changes in tone after application of electric field stimulation (EFS). The role of NO was determined by observing the effects of EFS in the presence and absence of the NO synthase (NOS) inhibitor N G -nitro-l-arginine methyl ester (l-NAME) and the reversibility of the effects ofl-NAME by l-arginine. Our studies indicated that there was increased magnitude of relaxation of isolated strips of rat gastric fundus and rat colon after application of EFS to tissues obtained from animals treated with E 2 alone or a combination of E 2 + P 4 but not from those treated with P 4 alone. l-NAME attenuated relaxation responses in E 2 - and E 2 + P 4 -treated animals. To elucidate whether the increased NO release may be due to an increase in neuronal NOS (nNOS) protein, we used both Western blot analysis and immunohistochemistry. We also used RT-PCR to determine whether there was an increase in nNOS mRNA after treatment with sex steroids. In nonpregnant animals, nNOS was detected by Western blot in the fundus and the colon and was barely detectable in the ileum. In pregnancy, there was an increase in nNOS in both the gastric fundus and the colon. The nNOS protein was also increased in ovariectomized animals treated with either E 2 alone or E 2 + P 4 but not P 4 alone when compared with ovariectomized animals receiving vehicle. Our results indicated that there was an increase in nNOS protein that was localized to the neurons of the myenteric plexus in the gastric fundus and colon in E 2 - and E 2 + P 4 -treated animals, but this increase was not observed in animals treated with P 4 alone. This increase in nNOS protein was accompanied by an increase in nNOS mRNA. These results suggest the possibility that E 2 , rather than P 4 , may be responsible for the delay in gastric emptying and increase in colonic transit time observed in pregnancy.
    Type of Medium: Online Resource
    ISSN: 0363-6119 , 1522-1490
    URL: Article
    DOI: 10.1152/ajpregu.2001.280.5.R1546
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2001
    detail.hit.zdb_id: 1477297-8
    SSG: 12
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  • 6
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    Serum levels of soluble vascular cell adhesion molecule-1 are decreased in women receiving oral contraceptives compared with normally menstruating women: Implications in atherosclerosis
    Elsevier BV ; 2005
    In:  Fertility and Sterility Vol. 83, No. 5 ( 2005-05), p. 1480-1488
    Details
    In: Fertility and Sterility, Elsevier BV, Vol. 83, No. 5 ( 2005-05), p. 1480-1488
    Type of Medium: Online Resource
    ISSN: 0015-0282
    URL: Article
    DOI: 10.1016/j.fertnstert.2004.11.048
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2005
    detail.hit.zdb_id: 1500469-7
    SSG: 12
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  • 7
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    17-Epiestriol, an Estrogen Metabolite, Is More Potent Than Estradiol in Inhibiting Vascular Cell Adhesion Molecule 1 (VCAM-1) mRNA Expression
    Elsevier BV ; 2003
    In:  Journal of Biological Chemistry Vol. 278, No. 14 ( 2003-04), p. 11746-11752
    Details
    In: Journal of Biological Chemistry, Elsevier BV, Vol. 278, No. 14 ( 2003-04), p. 11746-11752
    Type of Medium: Online Resource
    ISSN: 0021-9258
    URL: Article
    DOI: 10.1074/jbc.M207800200
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2003
    detail.hit.zdb_id: 2141744-1
    detail.hit.zdb_id: 1474604-9
    SSG: 12
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  • 8
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    Testosterone inhibits early atherogenesis by conversion to estradiol: Critical role of aromatase
    Proceedings of the National Academy of Sciences ; 2001
    In:  Proceedings of the National Academy of Sciences Vol. 98, No. 6 ( 2001-03-13), p. 3589-3593
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 98, No. 6 ( 2001-03-13), p. 3589-3593
    Abstract: The effects of testosterone on early atherogenesis and the role of aromatase, an enzyme that converts testosterone to estrogens, were assessed in low density lipoprotein receptor-deficient male mice fed a Western diet. Castration of male mice increased the extent of fatty streak lesion formation in the aortic origin compared with testes-intact animals. Administration of anastrazole, a selective aromatase inhibitor, to testes-intact males increased lesion formation to the same extent as that observed with orchidectomized animals. Testosterone supplementation of orchidectomized animals reduced lesion formation when compared with orchidectomized animals receiving the placebo. This attenuating effect of testosterone was not observed when the animals were treated simultaneously with the aromatase inhibitor. The beneficial effects of testosterone on early atherogenesis were not explained by changes in lipid levels. Estradiol administration to orchidectomized males attenuated lesion formation to the same extent as testosterone administration. Aromatase was expressed in the aorta of these animals as assessed by reverse transcription–PCR and immunohistochemistry. These results indicate that testosterone attenuates early atherogenesis most likely by being converted to estrogens by the enzyme aromatase expressed in the vessel wall.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.051003698
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2001
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 9
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    Testosterone attenuates expression of vascular cell adhesion molecule-1 by conversion to estradiol by aromatase in endothelial cells: Implications in atherosclerosis
    Proceedings of the National Academy of Sciences ; 2002
    In:  Proceedings of the National Academy of Sciences Vol. 99, No. 6 ( 2002-03-19), p. 4055-4060
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 99, No. 6 ( 2002-03-19), p. 4055-4060
    Abstract: We previously reported that testosterone attenuated atherogenesis in LDLR −/− male mice, and that this effect of testosterone was most likely caused by its conversion to estradiol. Estradiol inhibits vascular cell adhesion molecule-1 (VCAM-1) expression, and expression of VCAM-1 is one of the early events in atherogenesis. We assessed the cellular mechanism(s) involved by which testosterone attenuates atherogenesis. We evaluated whether testosterone inhibited TNFα-induced VCAM-1 expression via its conversion to estradiol by the enzyme aromatase in human umbilical vein endothelial cells (HUVEC). Aromatase mRNA was dedected by reverse transcription–PCR in these cells. Testosterone (30 nM–1 μM) attenuated VCAM-1 mRNA expression in a concentration-dependent manner. The non aromatizable androgen, dihydrotestosterone, had no effect on VCAM-1 mRNA expression. Testosterone was less effective in attenuating VCAM-1 expression in the presence of anastrozole, an inhibitor of aromatase, indicating that testosterone inhibited VCAM-1 via conversion to estradiol. Estradiol also attenuated VCAM-1 mRNA expression, but this action was not abolished in the presence of anastrozole, indicating that anastrozole itself did not modulate VCAM-1 mRNA expression. The effect of testosterone on VCAM-1 mRNA expression was inhibited in the presence of the estrogen receptor antagonist, ICI-182780. Testosterone also attenuated TNFα-induced VCAM-1 protein expression, and this attenuation was abolished in the presence of anastrozole. In conclusion, testosterone inhibited VCAM-1 mRNA and protein expression in HUVEC by its conversion to estradiol via the enzyme aromatase present in the endothelial cells. Results from our study may help explain the mechanism by which testosterone may have beneficial effects on the cardiovascular system.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.052703199
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2002
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 10
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    Estradiol Inhibits Leukocyte Adhesion and Transendothelial Migration in Rabbits In Vivo : Possible Mechanisms for Gender Differences in Atherosclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 1999
    In:  Circulation Research Vol. 85, No. 4 ( 1999-08-20), p. 377-385
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 85, No. 4 ( 1999-08-20), p. 377-385
    Abstract: Abstract —The mechanism by which estrogens protect against atherosclerosis is not known. We evaluated in vivo whether there is a gender difference in monocyte adhesion and subendothelial migration in hypercholesterolemic rabbits and whether any gender differences observed are due to estradiol. Monocyte adhesion and subendothelial migration were assessed in a blinded fashion by analyzing a standardized segment of aorta using a scanning electron microscope. We also assessed whether estradiol modulates induction of vascular cell adhesion molecule-1 (VCAM-1) protein using Western blot and flow cytometric analyses. We observed that male rabbits develop more monocyte adhesion and subendothelial migration than do female rabbits during hypercholesterolemia. We also observed that oophorectomized rabbits given physiological estradiol supplementation demonstrate fewer adherent and subendothelial monocytes than do oophorectomized rabbits given placebo. VCAM-1 protein expression was increased in aortae obtained from hypercholesterolemic, oophorectomized animals supplemented with placebo, and this increase was attenuated by estradiol. Finally, in cultured rabbit aortic endothelial cells stimulated with lysophosphatidylcholine, we observed an increase in VCAM-1 protein that was inhibited in a concentration-dependent fashion by estradiol. We have demonstrated in vivo that there is a gender difference in monocyte adhesion to endothelial cells and transendothelial migration after hypercholesterolemia and that this gender difference is due in part to estradiol. Our results also suggest that estradiol inhibits monocyte adhesion by inhibiting expression of VCAM-1.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/01.RES.85.4.377
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1999
    detail.hit.zdb_id: 1467838-X
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