A Novel Angiogenesis Inhibitor Bevacizumab Induces Apoptosis in the Rat Endometriosis Model

Soysal, Didem; Kızıldağ, Servet; Saatli, Bahadır; Posacı, Cemal; Soysal, Savas D.; Koyuncuoğlu, Meral; Doğan, Ömer Erbil

doi:10.2478/bjmg-2014-0077

Cited by 32 publications

(21 citation statements)

References 35 publications

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“…The GnRH‐A‐induced reduction in anti‐apoptotic Bcl‐xL abundance (Fig. ) is in agreement with findings that GnRH‐A treatment leads to a reduction in Bcl‐xL expression and promotes apoptosis in a rat endometriosis model (Soysal et al, ). During the re‐establishment of gonadotropic support after implant removal, circulating LH may increase and re‐activate the signaling cascades that elevate CREB and ATF1 activity, leading to the direct production of Bcl‐xL—although Bcl‐xL expression, via increasing AR and testosterone levels, is also possible (Sun et al, ; Kumar et al, ).…”

Section: Discussionsupporting

confidence: 90%

Signaling events associated with gonadotropin releasing hormone‐agonist‐induced hormonal castration and its reversal in canines

Bulldan¹,

Shihan²,

Goericke-Pesch

et al. 2016

Molecular Reproduction Devel

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A gonadotropin-releasing hormone agonist (GnRH-A) implant induces hormonal castration in dogs that is associated with reduced prostate and testes size. We address the molecular events associated with hormonal castration by examining GnRH-A effects on expression and phosphorylation of a number of key signaling proteins. Male beagles were treated for 5 months with a GnRH-A implant, and then surgically castrated at 0, 3, 6, 12, and, 24 weeks after implant removal; untreated animals served as controls. GnRH-A treatment led to activation of c-Raf, Erk1/2, and, p53 in the testes. Phosphorylation of p53 occurred at Ser15, consistent with activation of the c-Raf-Erk1/2-p53 signaling cascade that triggers growth arrest or apoptosis. GnRH-A also suppressed the anti-apoptotic protein Bcl-xL; reduced phosphorylation of the transcription factors CREB and ATF1; and down-regulated expression of StAR and P450scc, proteins involved in steroidogenesis. Although androgen receptor expression was little affected by GnRH-A treatment, levels of ZIP9, a membrane-bound Zn transporter that mediates non-classical signaling of testosterone, were abrogated. All of these effects were reversed within 24 weeks after implant removal. Thus, molecular signatures of implant-dependent hormonal castration include reversible cell cycle arrest and apoptosis, loss of steroidogenesis, and reduced transcriptional activity. Mol. Reprod. Dev. 83: 1092-1101, 2016. © 2016 Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 90%

Signaling events associated with gonadotropin releasing hormone‐agonist‐induced hormonal castration and its reversal in canines

Bulldan¹,

Shihan²,

Goericke-Pesch

et al. 2016

Molecular Reproduction Devel

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“…Eleven of the 16 experiments reported outcomes related to endometriosis size (volume or area) [16, 18–23, 25–27]. Seven different anti-VEGF/VEGFR agents were used, if it is considered that Jiang [11] used a same drug from the others, there were six.…”

Section: Resultsmentioning

confidence: 99%

Efficacy of Anti-VEGF/VEGFR Agents on Animal Models of Endometriosis: A Systematic Review and Meta-Analysis

et al. 2016

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Background/ObjectiveVascular endothelial growth factor (VEGF) is the most important promotor of angiogenesis. Some studies indicate that anti-angiogenic agents that interfere with VEGF and its receptor (VEGFR), i.e., anti-VEGF/VEGFR agents, may be applied to treat endometriosis. This meta-analysis investigated the efficacy of anti-VEGF/VEGFR agents in animal models of endometriosis.MethodsA systematic literature search was performed for animal studies published in English or Chinese from January 1995 to June 2016, which evaluated the effect of anti-VEGF/VEGFR agents on endometriosis. The databases were: PubMed, Web of Science, BIOSIS, Embase, and CNKI. The quality of included studies was assessed using the SYRCLE tool. The random-effect models were used to combine the results of selected studies. Heterogeneity was assessed using H2statistic and I2 statistic. Subgroup analyses were performed to determine the source of heterogeneity in endometriosis scores and follicle numbers.ResultsWe identified 13 studies that used anti-VEGF/VEGFR agents in various animal models. The meta-analysis showed that anti-VEGF/VEGFR agents were associated with smaller size (standardized mean difference (SMD) –0.96, 95% CI –1.31 to –0.62; P < 0.0001) and weight (SMD –1.70, 95% CI –2.75 to –0.65; P = 0.002) of endometriosis lesions, relative to the untreated controls, as well as a lower incidence rate of endometriosis (risk ratio 0.26, 95% CI 0.07 to 0.93; P = 0.038) and endometriosis score (SMD –1.17, 95% CI –1.65 to –0.69; P < 0.0001); the number of follicles were similar (SMD –0.78, 95% CI –1.65 to 0.09; P = 0.08).ConclusionsAnti-VEGF/VEGFR agents appeared to inhibit the growth of endometriosis, with no effect on ovarian function. Anti-angiogenic therapy may be a novel strategy in treating endometriosis.

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“…In mouse models, rapamycin clearly reduced endometriotic implants, along with diminished VEGF expression and decreased MVD [271]; in the nude mouse model endostatin affected expression of VEGFR2 and/or VEGF isoforms and decreased HIF-1a expression [272], while angiostatin showed a complex mechanism of the inhibition of blood vessel development [273,274]; anginex demonstrated anti-angiogenic activity in mouse model of endometriosis [274]. In a rat endometriosis model, bevacizumab, VEGF-neutralizing monoclonal antibody, was shown to increase apoptosis [275]. Other drugs with anti-angiogenic effects confirmed in experimental endometriosis are celecoxib, a COX-2 inhibitor [276], and non-toxic fumagillin analogs, semisynthetic derivatives of a natural antibiotic, Aspergillus fumigatus [274].…”

Section: Novel Approaches and Therapeutic Agents In Endometriosismentioning

confidence: 99%

Endometriosis — insights into a multifaceted entity

Amălinei

Păvăleanu

Lozneanu

et al. 2018

Folia Histochem Cytobiol.

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Firstly described at the end of nineteenth century, endometriosis remains an enigmatic disease, from etio-pathogenesis to specific markers of diagnosis and its ability to associate with malignancies. Our review has been designed from a historical perspective and steps up to an updated understanding of the disease, facilitated by relatively recent molecular and genetic progresses. Although the histopathological diagnosis is relatively simple, the therapy is difficult or ineffective. Experimental models have been extremely useful as they reproduce the human disease and allow the testing of different potential modulators or treatment options. Due to molecular resemblance to carcinogenesis, applications of anti-cancer agents are currently under scrutiny. The desired goal of an efficient therapy against symptomatic disease, along with associated infertility and malignancies, needs a deeper insight into the complex mechanisms involved in endometriosis initiation, development, and progres-sion. Current trends in genomic and proteomic approaches are useful for a more accurate classification and for the identification of new therapeutic targets.

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A Novel Angiogenesis Inhibitor Bevacizumab Induces Apoptosis in the Rat Endometriosis Model

Cited by 32 publications

References 35 publications

Signaling events associated with gonadotropin releasing hormone‐agonist‐induced hormonal castration and its reversal in canines

Signaling events associated with gonadotropin releasing hormone‐agonist‐induced hormonal castration and its reversal in canines

Efficacy of Anti-VEGF/VEGFR Agents on Animal Models of Endometriosis: A Systematic Review and Meta-Analysis

Endometriosis — insights into a multifaceted entity

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