The Effect of Exchanging Various Substituents at the 2-Position of 2-Methoxyestradiol on Cytotoxicity in Human Cancer Cell Cultures and Inhibition of Tubulin Polymerization

Cushman, Mary; Mohanakrishnan, Arasambattu K.; Hollingshead, Melinda G.; Hamel, Ernest

doi:10.1021/jm020218r

Cited by 39 publications

(23 citation statements)

References 31 publications

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“…The dependence of the reaction on the chain length may at least partially explain why 6-shogaol reduces the content of SH groups in tubulin more than 3-nonen-2-one. Previous reports have suggested that steric effects are involved in interactions with tubulin [17][18][19]. The chain length may be important for a,b-unsaturated carbonyl compounds to penetrate the interior of tubulin.…”

Section: Resultsmentioning

confidence: 99%

Specific reaction of α,β‐unsaturated carbonyl compounds such as 6‐shogaol with sulfhydryl groups in tubulin leading to microtubule damage

et al. 2008

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6-Shogaol and 6-gingerol are ginger components with similar chemical structures. However, while 6-shogaol damages microtubules, 6-gingerol does not. We have investigated the molecular mechanism of 6-shogaol-induced microtubule damage and found that the action of 6-shogaol results from the structure of a,b-unsaturated carbonyl compounds. a,b-Unsaturated carbonyl compounds such as 6-shogaol react with sulfhydryl groups of cysteine residues in tubulin, and impair tubulin polymerization. The reaction with sulfhydryl groups depends on the chain length of a,b-unsaturated carbonyl compounds. In addition, a,b-unsaturated carbonyl compounds are more reactive with sulfhydryl groups in tubulin than in 2-mercaptoethanol, dithiothreitol, glutathione and papain, a cysteine protease.

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Section: Resultsmentioning

confidence: 99%

Specific reaction of α,β‐unsaturated carbonyl compounds such as 6‐shogaol with sulfhydryl groups in tubulin leading to microtubule damage

et al. 2008

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“…The concentration of 2MEO occupying 50% of receptors (f100 nmol/L) is in the same order of magnitude as that for significant actions on either endothelial or tumor cells (100-1000 nmol/L; see, e.g., refs. 9,19,24,35).…”

Section: Discussionmentioning

confidence: 99%

2-Methoxyestradiol Is an Estrogen Receptor Agonist That Supports Tumor Growth in Murine Xenograft Models of Breast Cancer

Sutherland

Schuliga

Harris

et al. 2005

Clinical Cancer Research

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Purpose: 2-Methoxyestradiol (2MEO) is being developed as a novel antitumor agent based on its antiangiogenic activity, tumor cell cytotoxicity, and apparent lack of toxicity. However, pharmacologic concentrations of 2MEO bind to estrogen receptors (ER). We have therefore examined the ER activity of 2MEO.Experimental Design: Estrogenic actions of 2MEO were evaluated by changes in gene expression of the ER-positive (MCF7) breast tumor cell line and, in vivo, estrogenicity was assessed in breast tumor xenograft models and by measuring endocrine responses in uterus and liver.Results: In the ER-positive breast tumor cell line (MCF7), microarray experiments revealed that 269 of 279 changes in gene expression common to 2MEO and estradiol were prevented by the ER antagonist, ICI 182,780. Changes in the expression of selected genes and their sensitivity to inhibition by ICI 182,780 were confirmed by quantitative reverse transcription-PCR measurement. Activation of ER in MCF7 cells by 2MEO was further confirmed by stimulation of an estrogen response element -dependent reporter gene that was blocked by ICI 182,780 (1 Mmol/L). Doses of 2MEO (15-150 mg/kg) that had no antitumor efficacy in either nu/nu BALB/c or severe combined immunodeficient mice bearing ER-negative MDA-MB-435 tumors had uterotropic and hepatic estrogen-like actions. In female nu/nu BALB/c mice inoculated with the estrogen-dependent MCF7 tumor cells, 2MEO (50 mg/kg/d) supported tumor growth.Conclusions: Tumor growth enhancement by 2MEO at doses generating serum levels (100-500 nmol/L) that have estrogenic activity suggests that a conservative approach to the further clinical evaluation of this agent should be adopted and that its evaluation in breast cancer is inappropriate.

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“…Interestingly, 2-methoxyestradiol, a mammalian metabolite, interacts with the colchicine binding site in b-tubulin and modulates microtubule dynamics [21], also showing taxol-like effects [22]. Tubulin-modulating effects have also been shown for other steroids like estradiol and testosterone [23].…”

Section: -Hydroxyfurost-5-en-3-yl 6-deoxy-mentioning

confidence: 99%

Cytotoxic Steroidal Saponins from the Rhizomes of Tacca integrifolia

Shwe

Aye

Sein

et al. 2010

Chemistry & Biodiversity

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Three new steroid saponins (3beta,25R)-spirost-5-en-3-yl 6-deoxy-alpha-L-mannopyranosyl-(1-->2)-[beta-D-glucopyranosyl-(1-->4)-6-deoxy-alpha-L-mannopyranosyl-(1-->3)]-beta-D-glucopyranoside (1), (3beta,22R,25R)-26-(beta-D-glucopyranosyloxy)-22-hydroxyfurost-5-en-3-yl 6-deoxy-alpha-L-mannopyranosyl-(1-->2)-[6-deoxy-alpha-L-mannopyranosyl-(1-->3)]-beta-D-glucopyranoside (3), and (3beta,22R,25R)-26-(beta-D-glucopyranosyloxy)-22-hydroxyfurost-5-en-3-yl 6-deoxy-alpha-L-mannopyranosyl-(1-->2)-[beta-D-glucopyranosyl-(1-->4)-6-deoxy-alpha-L-mannopyranosyl-(1-->3)]-beta-D-glucopyranoside (5), as well as the new pregnane glycoside (3beta,16beta)-3-{[6-deoxy-alpha-L-mannopyranosyl-(1-->2)-[6-deoxy-alpha-L-mannopyranosyl-(1-->3)]-beta-D-glucopyranosyl]oxy}-20-oxopregn-5-en-16-yl (4R)-5-(beta-D-glucopyranosyloxy)-4-methylpentanoate (6), were isolated from the rhizomes of Tacca integrifolia together with two known (25R) configurated steroid saponins (3beta,25R)-spirost-5-en-3-yl 6-deoxy-alpha-L-mannopyranosyl-(1-->2)-[6-deoxy-alpha-L-mannopyranosyl-(1-->3)]-beta-D-glucopyranoside (2) and (3beta,22R,25R)-26-(beta-D-glucopyranosyloxy)-22-methoxyfurost-5-en-3-yl 6-deoxy-alpha-L-mannopyranosyl-(1-->2)-[6-deoxy-alpha-L-mannopyranosyl-(1-->3)]-beta-D-glucopyranoside (4). The cytotoxic activity of the isolated compounds was evaluated in HeLa cells and showed the highest cytotoxicity value for compound 2 with an IC(50) of 1.2+/-0.4 muM. Intriguingly, while compounds 1-5 exhibited similar cytotoxic properties between 1.2+/-0.4 (2) and 4.0+/-0.6 muM (5), only compound 2 showed a significant microtubule-stabilizing activity in vitro.

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The Effect of Exchanging Various Substituents at the 2-Position of 2-Methoxyestradiol on Cytotoxicity in Human Cancer Cell Cultures and Inhibition of Tubulin Polymerization

Cited by 39 publications

References 31 publications

Specific reaction of α,β‐unsaturated carbonyl compounds such as 6‐shogaol with sulfhydryl groups in tubulin leading to microtubule damage

Specific reaction of α,β‐unsaturated carbonyl compounds such as 6‐shogaol with sulfhydryl groups in tubulin leading to microtubule damage

2-Methoxyestradiol Is an Estrogen Receptor Agonist That Supports Tumor Growth in Murine Xenograft Models of Breast Cancer

Cytotoxic Steroidal Saponins from the Rhizomes of Tacca integrifolia

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