Apoptosis induction and inhibition of hyperplasia formation by 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b)pyran in rat uterus

Chandra, Vishal; Fatima, Iram; Saxena, Ruchi; Kitchlu, Surinder; Sharma, Sharad; Hussain, Mohammad Kamil; Hussain, Mohd Kamil; Bajpai, Preeti; Dwivedi, Anila

doi:10.1016/j.ajog.2011.05.024

Cited by 10 publications

(9 citation statements)

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“… 17 We have earlier shown that K-1 inhibits classical and non-classical estrogen signaling in uterus. 15 , 16 Because Wnt signaling pathway is known to be regulated via estrogen, we explored further whether K-1 is able to suppress the estrogen-induced Wnt signaling in human endometrial cells. Interestingly, the profound effect of K-1 on Wnt7a expression was observed in hyperplasial cells and also the phosphorylated PI3K was reduced in these cells when incubated with K-1.…”

Section: Discussionmentioning

confidence: 99%

“…In our prior studies, it has been demonstrated that benzopyrans are the class of potent antiestrogenic compounds 13 , 14 that showed antiproliferative and apoptotic activity in rat endometrial hyperplasia 15 and in human endometrial cancer cells. 16 , 17 However, the complete mechanism of action of 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo(b)pyran (K-1), responsible for inhibition of endometrial hyperplasia, remains to be explored in human endometrial hyperplasial cells.…”

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confidence: 99%

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Inhibitory effect of 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo(b)pyran (K-1) on human primary endometrial hyperplasial cells mediated via combined suppression of Wnt/β-catenin signaling and PI3K/Akt survival pathway

et al. 2014

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Endometrial hyperplasia is a precursor to the most common gynecologic cancer diagnosed in women. Apart from estrogenic induction, aberrant activation of the Wnt/β-catenin signal is well known to correlate with endometrial hyperplasia and its carcinoma. The benzopyran compound 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo (b) pyran(K-1), a potent antiestrogenic agent, has been shown to have apoptosis-inducing activity in rat uterine hyperplasia. The current study was undertaken to explore the effect of the benzopyran compound K-1 on growth and Wnt signaling in human endometrial hyperplasial cells. Primary culture of atypical endometrial hyperplasial cells was characterized by the epithelial cell marker cytokeratin-7. Results revealed that compound K-1 reduced the viability of primary endometrial hyperplasial cells and expression of ERα, PR, PCNA, Wnt7a, FZD6, pGsk3β and β-catenin without affecting the growth of the primary culture of normal endometrial cells. The β-catenin target genes CyclinD1 and c-myc were also found to be reduced, whereas the expression of axin2 and Wnt/β-catenin signaling inhibitor Dkk-1 was found to be upregulated, which caused the reduced interaction of Wnt7a and FZD6. Nuclear accumulation of β-catenin was found to be decreased by compound K-1. K-1 also suppressed the pPI3K/pAkt survival pathway and induced the cleavage of caspases and PARP, thus subsequently causing the apoptosis of endometrial hyperplasial cells. In conclusion, compound K-1 suppressed the growth of human primary endometrial hyperplasial cells through discontinued Wnt/β-catenin signaling and induced apoptosis via inhibiting the PI3K/Akt survival pathway.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inhibitory effect of 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo(b)pyran (K-1) on human primary endometrial hyperplasial cells mediated via combined suppression of Wnt/β-catenin signaling and PI3K/Akt survival pathway

et al. 2014

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“…The 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b) pyran, identified as an anti-estrogenic agent, is a nonsteroidal, triaryethylene and triarylpropenone compound which was found to inhibit uterine growth [ 148 160 161 162 ]. The ability of this compound to inhibit uterine growth is attributed to its ability to antagonize estrogen action and apoptosis-inducing activities [ 162 ]. The activity of this compound has also been validated in primary cell culture of human atypical EH cells suggesting its potential use as a new targeted therapy for EH via inhibition of Wnt signaling, as well as inhibition of cell survival pathway [ 163 ].…”

Section: Limitations Of Existing Therapies Need For Further Researchmentioning

confidence: 99%

Therapeutic options for management of endometrial hyperplasia

et al. 2016

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Endometrial hyperplasia (EH) comprises a spectrum of changes in the endometrium ranging from a slightly disordered pattern that exaggerates the alterations seen in the late proliferative phase of the menstrual cycle to irregular, hyperchromatic lesions that are similar to endometrioid adenocarcinoma. Generally, EH is caused by continuous exposure of estrogen unopposed by progesterone, polycystic ovary syndrome, tamoxifen, or hormone replacement therapy. Since it can progress, or often occur coincidentally with endometrial carcinoma, EH is of clinical importance, and the reversion of hyperplasia to normal endometrium represents the key conservative treatment for prevention of the development of adenocarcinoma. Presently, cyclic progestin or hysterectomy constitutes the major treatment option for EH without or with atypia, respectively. However, clinical trials of hormonal therapies and definitive standard treatments remain to be established for the management of EH. Moreover, therapeutic options for EH patients who wish to preserve fertility are challenging and require nonsurgical management. Therefore, future studies should focus on evaluation of new treatment strategies and novel compounds that could simultaneously target pathways involved in the pathogenesis of estradiol-induced EH. Novel therapeutic agents precisely targeting the inhibition of estrogen receptor, growth factor receptors, and signal transduction pathways are likely to constitute an optimal approach for treatment of EH.

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“…Some experimental results have indicated that abnormal apoptosis occurs in EH and the apoptotic level in endometrial epithelial cells depends on estrogen [7]. Several studies have recently demonstrated that many signaling pathways take part in regulating apoptosis [8]. Signaling pathways such as survivin/caspase-3 and Fas/FasL are important in regulating apoptosis in EH patients [9,10].…”

Section: Introductionmentioning

confidence: 99%

Apoptotic Signaling Pathways in Uteri of Rats with Endometrial Hyperplasia Induced by Ovariectomy Combined with Estrogen

He¹,

Zhang²,

Zhang³

2013

Gynecol Obstet Invest

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Aims: To explore a new reliable method inducing an animal model similar to the morphology and apoptotic signaling pathways in endometrial hyperplasia patients. Methods: After the rats were ovariectomized, estradiol benzoate (60 µg/100 g) was intramuscularly injected on alternate days for 4 weeks. The morphology in the uterus was observed under a light microscope and by electron microscopy. The expression levels of survivin/caspase-3 and Fas/FasL were checked by immunohistochemistry, Western blotting and real-time polymerase chain reaction. Results: After the models were induced, the edema and hypertrophy in uteri were observed 4 weeks later. The glands in the endometrium had increased, indented hyperplasia of glandular cells appeared, and a pseudo-stratified phenomenon occurred. Under a transmission electron microscope, free ribosomes had markedly increased and the nucleus was enlarged in the cytoplasm. Compared with the control group, the expression of survivin increased (p < 0.05) while that of caspase-3 and Fas/FasL declined (p < 0.05). Conclusions: In the rat model of endometrial hyperplasia induced by ovariectomy with pharmacological estrogen add-back treatment, survivin, caspase-3 and Fas/FasL signaling pathways play an important role in regulating the apoptosis of glandular cells in uteri.

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Apoptosis induction and inhibition of hyperplasia formation by 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b)pyran in rat uterus

Cited by 10 publications

References 45 publications

Inhibitory effect of 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo(b)pyran (K-1) on human primary endometrial hyperplasial cells mediated via combined suppression of Wnt/β-catenin signaling and PI3K/Akt survival pathway

Inhibitory effect of 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo(b)pyran (K-1) on human primary endometrial hyperplasial cells mediated via combined suppression of Wnt/β-catenin signaling and PI3K/Akt survival pathway

Therapeutic options for management of endometrial hyperplasia

Apoptotic Signaling Pathways in Uteri of Rats with Endometrial Hyperplasia Induced by Ovariectomy Combined with Estrogen

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