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ABSTRACT: A previous study demonstrated that local application of levonorgestrel-loaded polylactic acid microspheres (LNG microspheres) resulted in significant regression of endometriotic cysts in a rabbit model for 6 months without disturbing the metabolic parameters or ovarian function. In order to investigate the feasibility of local application of LNG microspheres as a long-term maintenance treatment for endometriosis, the suppressive effect of a single intra-cystic injection of LNG microspheres was studied for 1 year in a rat model.
Twenty four rats with experimental endometriotic cysts were randomized to be treated with a single intra-cystic injection of LNG microspheres (n = 8); 6-month GnRH agonist (GnRHa, n = 8) or control (n = 8). Intra-cystic injection of LNG microspheres and GnRHa treatment caused comparable regression and atrophy in endometriotic cysts in the first 6 months. Compared with the control, the wet weight of the endometriotic cysts was significantly lower in both groups at Month 6 but by Month 12 only remained low in the LNG microspheres group (P < 0.01). The immunostaining of estrogen receptors (ERs) in both the epithelium and stroma and progesterone receptors (PRs) in the stroma was significantly weakened in the LNG microspheres group at Month 6 and was not fully restored at Month 12 (P < 0.01). Metabolic parameters and estrous cycle were not disturbed by local application of LNG microspheres.
In a rat endometriosis model, the suppressive effect of a single intra-cystic injection of LNG microspheres was comparable to that of GnRHa, and was maintained for 1 year. The down-regulation of ERs and PRs might serve as possible mechanism of long-term effectiveness.
Human Reproduction 05/2012; 27(7):2089-95. · 4.47 Impact Factor
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ABSTRACT: NF-E2-related factor 2 (Nrf2) is a key transcription regulator for cellular response to oxidative stress in normal cells. In cancer cells, development of chemoresistance is associated with the constitutive activation of the Nrf2-mediated antioxidant defense system. Here, we investigated the role of Nrf2 in terms of cervical cancer cell proliferation and drug resistance.
To investigate whether cancer cells activate the Nrf2 system, we examined 40 surgical cervical cancer samples and 12 normal control tissues. Plasmids containing Nrf2-small hairpin RNA (shRNA) or non-targeting vector-control shRNA were transfected into CaSki cells. Using Western blots and RT-PCR assays, the expression levels of Nrf2 mediated-target genes were measured in CaSki cells stably expressing Nrf2-shRNA. To evaluate how the Nrf2 knockdown affected susceptibility to chemotherapeutic drugs, MTT and flow cytometry assays were done in vitro and confirmed by a mouse xenograft model in vivo.
The Nrf2-dependent defensive system was likely fully activated in cervical tumor tissues. Genetic knockdown of endogenous Nrf2 caused a global decrease in expression of Nrf2-regulated genes. This decrease in expression levels enhanced chemotherapeutic drug-induced apoptotic death in CaSki cells with a reduced cellular glutathione level. Additionally, the combination of cisplatin treatment and Nrf2 knockdown significantly suppressed tumor growth in vivo.
Our findings provide evidence that the inhibition of Nrf2 activity by shRNA might be a promising therapeutic strategy to enhance the efficacy of anticancer drugs and thus can be applied further during the course of chemotherapy in the treatment of cervical cancer.
Cancer Chemotherapy and Pharmacology 08/2011; 69(2):485-94. · 2.83 Impact Factor
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ABSTRACT: The CASP8 gene plays a central role in the apoptotic pathway and is therefore a plausible cancer susceptibility gene. However, the precise role of the CASP8 gene in epithelial ovarian cancer carcinogenesis is unclear. Therefore, we analyzed the correlation between single nucleotide polymorphisms (SNPs) and haplotypes in CASP8 and the risk and clinical characteristics of epithelial ovarian cancer (EOC) in the Chinese population.
Eight tag SNPs were identified using the MassARRAY system to genotype 37 genetic polymorphisms around and in the CASP8 gene in 100 unrelated, healthy females. Then, a case-control study of 218 EOC patients and 285 controls who were matched on residence, age and race was conducted using these 8 tag SNPs.
The risk of developing EOC was significantly decreased in association with CASP8 rs3834129 ins>del (odds ratio (OR)(del/del)=0.129, 95% confidence interval (95% CI): 0.038-0.439; OR(ins/del)=0.769, 95% CI, 0.534-1.108), rs3769827 T>C (OR(C/C)=0.187, 95% CI: 0.070-0.500; OR(T/C)=0.729, 95% CI: 0.505-1.052), rs6704688 C>T (OR(T/T)=0.344, 95% CI, 0.168-0.707; OR(C/T)=0.802, 95% CI, 0.552-1.166), and with the del-C-T haplotype of these 3 SNPs (OR=0.615, 95% CI: 0.453-0.8363). Moreover, a notably later onset was significantly associated with the rs3834129 ins/del+del/del and the rs3769827 T/C+C/C genotypes (p<0.0001).
Genetic variants of the CASP8 gene protect against EOC carcinogenesis and delay the age of EOC onset. Furthermore, these protective effects may be due to the dysfunctional expression of caspase-8 caused by the -652 6N del variant in the promoter.
Gynecologic Oncology 06/2011; 122(3):554-9. · 3.89 Impact Factor
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ABSTRACT: Endometriosis is a chronic disease that responds to systemic pseudo-pregnancy therapy. However, side effects limit their long-term use, and recurrence often occurs after cessation of medication. Reducing side effects whereas improving therapeutic efficacy of pseudo-pregnancy therapy seems contradictory, but appealing. In order to address this dilemma, the efficacy and side effects of local pseudo-pregnancy therapy were investigated for the first time in an endometriosis animal model.
Levonorgestrel-loaded polylactic acid microspheres (LNG-microspheres) were prepared by using an oil-in-water emulsification-solvent evaporation method. Rabbits with experimental endometriosis were randomized to treatment with local pseudo-pregnancy therapy, local blank microspheres, systemic pseudo-pregnancy therapy, ovariectomy or the control. Local pseudo-pregnancy was induced by injection of LNG-microspheres directly into endometrial cysts. Compared with the systemic pseudo-pregnancy group, significantly higher intra-cystic drug levels were maintained for at least 6 months with much lower serum levels in the local pseudo-pregnancy group (P < 0.01). The high intra-cystic levonorgestrel simulated a state of potent pregnancy, which induced size reductions and endometrial atrophy comparable to those of ovariectomy. Moreover, major metabolic parameters and ovarian function were not disturbed by local pseudo-pregnancy therapy.
Induction of a local pseudo-pregnancy could achieve therapeutic efficacy comparable to that of ovariectomy without provoking any marked side effects in a rabbit endometriosis model. Thus it may be a preferable option for patients with endometriosis.
Human Reproduction 11/2009; 25(2):462-9. · 4.47 Impact Factor
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ABSTRACT: As a common cause of chronic pelvic pain, endometriosis affects 10% of women of reproductive age. The most popular strategy for treating endometriosis is pseudo-pregnancy therapy. However, the efficacy of common systemic pseudo-pregnancy therapy is significantly attenuated by poor compliance because of so many side effects. While levonorgestrel-releasing intrauterine systems (LNG-IUS) successfully localize the effect of pseudo-pregnancy to the genital tract in treating endometriosis, it seemed to be insufficient to suppress the ovarian and extragenital endometriosis. We postulate that induction of a local pseudo-pregnancy via progestogen-loaded microsphere in the lesions of endometriosis may provide a more effective treatment with fewer side effects.
Medical Hypotheses 09/2009; 74(1):56-8. · 1.39 Impact Factor
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ABSTRACT: Clusterin (CLU) is a multivalent glycoprotein with ubiquitous tissue distribution. To address the possible differential functional roles assumed by different isoforms of CLU in the progression of human ovarian cancer, we constructed 2 human ovarian cancer cell models that represent examples of contradistinctive CLU expression levels. One is constitutively overexpressing different clusterin isoforms in SKOV3 cells by transfection of the 3 different expression vectors, another is silencing the intrinsically expressing clusterin in cisplatin-resistant human A2780-cis(CP70) tumor cells with the usage of shRNA-mediated CLU gene silencing. Then, the different cellular localization, biological effects, and functional roles played in tumor progression and drug resistances were studied. We found that (i) in the distinct cellular contexts of human ovarian carcinoma SKOV3 and CP70 cells assayed, sCLU is a central molecule in cell homeostasis that functions as a cytoprotective protein, whereas nCLU is proapoptotic; (ii) In SKOV3 cells, nuclear localization of the truncated CLU is NLS dependent, without which the pnCLU protein was sequestrated in cytoplasm to prevent cytotoxicity. (iii) sCLU plays a significant role in the development of the chemoresistance phenotype in ovarian cancer cells. Moreover, with the CLU-specific shRNA oligonucleotides, we successfully sensitized cells for chemotherapy, and inhibited cells' proliferation, migration and invasion. Collectively, our results reveal that, CLU gene expression might play a crucial role in ovarian cancer progression, adaptation and eventual resistance to chemotherapy through differential processing of CLU isoforms. Specifically, sCLU as an antiapoptotic protein, upregulated in an adaptive cell-survival manner by chemotherapy, confers resistance to various cell-death triggers. © 2009 UICC
International Journal of Cancer 02/2009; 125(4):791 - 806. · 5.44 Impact Factor
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ABSTRACT: To investigate the relationship between changes of serotonin metabolism and hot flushes in climacteric women.
Ninety seven climacteric women, aged 40 - 60 were enrolled and divided into 4 groups, group A: early menopausal transition 20 cases, group B: late menopausal transition, 26 cases with skip of periods 3 - 12 months, group C: early postmenopause (1 - 3 years) 28 cases, group D: late postmenopause (> 3 - 6 years) 24 cases. Twelve normal women of reproductive age were served as young controls. Fifty two postmenopausal women were subdivided into 3 groups according to presence or absence of hot flushes. (1) postmenopausal controls without hot flush, 17 cases, (2) mild hot flushes group fewer < or = 5 times/day. (3) severe hot flushes group more than 5 times/day. Plasma concentrations of tryptophan (TP), 5-hydroxytryptophane (5-HTP), 5-hydroxytryptamine (5-HT or serotonin) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in all participants by high pressure liquid chromatography-fluorescence spectrophotometer. Plasma level luteinizing hormone (LH) was measured in postmenopausal women by radioimmuno assay. The relationship between serotonin metabolic parameters and menopause, hot flushes and LH level were analysed.
(1) Mean 5-HT and 5-HIAA concentrations in plasma were significantly higher in climacteric women than those in young controls, especially in the group B. Mean 5-HTP and 5-HT levels were higher and 5-HIAA lower in group D as compared with those of young controls. (2) Plasma 5-HT levels was positively correlated to luteinizing hormone concentration in postmenopausal women (P < 0.001). (3) In the mild hot flushes group, only plasma 5-HTP levels was significantly higher than that in the postmenopausal control group. In severe hot flushes group, plasma 5-HT and 5-HTP contents were significantly higher and 5-HIAA/5-HT ratio lower than those in the postmenopausal control groups.
Our results suggest that the catabolic disorder of serotonin may involve in the underlying mechanism of hot flushes in postmenopausal women.
Zhonghua fu chan ke za zhi 01/2003; 37(12):726-8.
