Benzopyran derivative CDRI-85/287 induces G2-M arrest in estrogen receptor-positive breast cancer cells via modulation of estrogen receptors α- and β-mediated signaling, in parallel to EGFR signaling and suppresses the growth of tumor xenograft

Saxena, Ruchi; Fatima, Iram; Chandra, Vishal; Selvanesan, Blesson Chellakkan; Kharkwal, Geetika; Hussain, Mohammad Kamil; Hussain, Mohd Kamil; Roy, Bal Gangadhar; Dwivedi, Anila

doi:10.1016/j.steroids.2013.07.004

Cited by 8 publications

(8 citation statements)

References 47 publications

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“…By contrast, although increasing evidence from in vitro and in vivo studies supports that ERβ has tumour suppressive properties by inhibiting cell proliferation and triggering cell cycle arrest, the interaction between estrogen/phytoestrogen and ERβ is uncertain [19]–. Hence, we determined the expression levels of ERβ in breast cancer cells based on calycosin-induced antiproliferative activity.…”

Section: Discussionmentioning

confidence: 97%

Calycosin Suppresses Breast Cancer Cell Growth via ERβ-Dependent Regulation of IGF-1R, p38 MAPK and PI3K/Akt Pathways

et al. 2014

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We previously reported that calycosin, a natural phytoestrogen structurally similar to estrogen, successfully triggered apoptosis of estrogen receptor (ER)-positive breast cancer cell line, MCF-7. To better understand the antitumor activities of calycosin against breast cancer, besides MCF-7 cells, another ER-positive cell line T-47D was analyzed here, with ER-negative cell lines (MDA-231, MDA-435) as control. Notably, calycosin led to inhibited cell proliferation and apoptosis only in ER-positive cells, particularly in MCF-7 cells, whereas no such effect was observed in ER-negative cells. Then we investigated whether regulation of ERβ, a subtype of ER, contributed to calycosin-induced apoptosis in breast cancer cells. The results showed that incubation of calycosin resulted in enhanced expression ERβ in MCF-7 and T-47D cells, rather than MDA-231 and MDA-435 cells. Moreover, with the upregulation of ERβ, successive changes in downstream signaling pathways were found, including inactivation of insulin-like growth factor 1 receptor (IGF-1R), then stimulation of p38 MAPK and suppression of the serine/threonine kinase (Akt), and finally poly(ADP-ribose) polymerase 1 (PARP-1) cleavage. However, the other two members of the mitogen-activated protein kinase (MAPK) family, extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK), were not consequently regulated by downregulated IGF-1R, indicating ERK 1/2 and JNK pathways were not necessary to allow proliferation inhibition by calycosin. Taken together, our results indicate that calycosin tends to inhibit growth and induce apoptosis in ER-positive breast cancer cells, which is mediated by ERβ-induced inhibition of IGF-1R, along with the selective regulation of MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways.

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Section: Discussionmentioning

confidence: 97%

Calycosin Suppresses Breast Cancer Cell Growth via ERβ-Dependent Regulation of IGF-1R, p38 MAPK and PI3K/Akt Pathways

et al. 2014

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“…2) named CDRI-85/287, an ER ligand which was previously discovered and evaluated for its potent antiestrogenic activity in the uterus and anti-implantation properties in animal models [78–81], recently has attracted great interest for its growth inhibitory activity on breast cancers [82]. CDRI-85/287 in its racemic form displayed a slight preference for ERα over ERβ, with low relative binding affinities of 0.25% for ERα and 0.15% for ERβ, although previous studies assigned a higher ER binding affinity to the L-enantiomer [83].…”

Section: Update On Chemical Classes Comprising Erα and Erβ Modulatorsmentioning

confidence: 99%

Estrogen receptors alpha (ERα) and beta (ERβ): Subtype-selective ligands and clinical potential

et al. 2014

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Estrogen receptors alpha (ERα) and beta (ERβ) are nuclear transcription factors that are involved in the regulation of many complex physiological processes in humans. Modulation of these receptors by prospective therapeutic agents is currently being considered for prevention and treatment of a wide variety of pathological conditions, such as, cancer, metabolic and cardiovascular diseases, neurodegeneration, inflammation, and osteoporosis. This review provides an overview and update of compounds that have been recently reported as modulators of ERs, with a particular focus on their potential clinical applications.

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“…Western blotting was performed following standard protocol with some modifications . Briefly, cells were washed with ice-cold PBS and then lysed in RIPA buffer.…”

Section: Methodsmentioning

confidence: 99%

Bivalent Approach for Homodimeric Estradiol Based Ligand: Synthesis and Evaluation for Targeted Theranosis of ER(+) Breast Carcinomas

et al. 2016

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The synthesis of estradiol based bivalent ligand [(EST)2DT] is reported and its potential for targeted imaging and therapy of ER(+) tumors has been evaluated. For the purpose, ethinylestradiol was functionalized with an azidoethylamine moiety via click chemistry. The resultant derivative was reacted in a bivalent mode with DTPA-dianhydride to form the multicoordinate chelating agent, (EST)2DT which displayed capability to bind (99m)Tc. The radiolabeled complex, (99m)Tc-(EST)2DT was obtained in >99% radiochemical purity and 20-48 GBq/μmol of specific activity. RBA assay revealed ∼15% binding with estrogen receptor. Evaluation of ligand on ER(+)-cell line (MCF-7) suggested enhanced and ER-mediated uptake. In vivo assays displayed early tracer accumulation in MCF-7 xenografts with tumor to muscle ratio ∼6 in 2 h and negligible uptakes in nontargeted organs. MTT assay performed on ER(+) and ER(-) cell lines displayed selective inhibition of ER(+) cancer cell growth with IC50 = 14.3 μM which was comparable to tamoxifen. The anticancer activity of the ligand is possibly due to the increase in ERβ and suppression of ERα protein levels in gene transcription. The studies reveal the potential of (EST)2DT as diagnostic imaging agent with the additional benefits in therapy.

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Benzopyran derivative CDRI-85/287 induces G2-M arrest in estrogen receptor-positive breast cancer cells via modulation of estrogen receptors α- and β-mediated signaling, in parallel to EGFR signaling and suppresses the growth of tumor xenograft

Cited by 8 publications

References 47 publications

Calycosin Suppresses Breast Cancer Cell Growth via ERβ-Dependent Regulation of IGF-1R, p38 MAPK and PI3K/Akt Pathways

Calycosin Suppresses Breast Cancer Cell Growth via ERβ-Dependent Regulation of IGF-1R, p38 MAPK and PI3K/Akt Pathways

Estrogen receptors alpha (ERα) and beta (ERβ): Subtype-selective ligands and clinical potential

Bivalent Approach for Homodimeric Estradiol Based Ligand: Synthesis and Evaluation for Targeted Theranosis of ER(+) Breast Carcinomas

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