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Evaluation of the Biological Properties and the Enzymatic Stability of Glycosylated Luteinizing Hormone-Releasing Hormone Analogs.

ABSTRACT: The enzymatic stability, antitumor activity, and gonadotropin stimulatory effects of glycosylated luteinizing hormone-releasing hormone (LHRH) analogs were investigated in this study. Conjugation of carbohydrate units, including lactose (Lac), glucose (GS), and galactose (Gal) to LHRH peptide protected the peptide from proteolytic degradation and increased the peptides' half-lives in human plasma, rat kidney membrane enzymes, and liver homogenate markedly. Among all seven modified analogs, compound 1 (Lac-[Q(1)][w(6)]LHRH) and compound 6 (GS(4)-[w(6)]LHRH) were stable in human plasma during 4 h of experiment. The half-lives of compounds 1 and 6 improved significantly in kidney membrane enzymes (from 3 min for LHRH to 68 and 103 min, respectively). The major cleavage sites for most of the glycosylated compounds were found to be at Trp(3)-Ser(4) and Ser(4)-Tyr(5) in compounds 1-5. Compound 6 was hydrolyzed at Ser(4)-Tyr(5) and the sugar conjugation site. The antiproliferative activity of the glycopeptides was evaluated on LHRH receptor-positive prostate cancer cells. The glycosylated LHRH derivatives had a significant growth inhibitory effect on the LNCaP cells after a 48-h treatment. It was demonstrated that compound 1 significantly increased the release of luteinizing hormone (LH) at 5 and 10 nM concentrations and compound 5 (GS-[Q(1)]LHRH) stimulated the release of follicle-stimulating hormone (FSH) at 5 nM concentration in dispersed rat pituitary cells (p?

SUBMITTER: Moradi SV

PROVIDER: S-EPMC4540744 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Evaluation of the Biological Properties and the Enzymatic Stability of Glycosylated Luteinizing Hormone-Releasing Hormone Analogs.

Moradi Shayli Varasteh SV Varamini Pegah P Toth Istvan I

The AAPS journal 20150509 5

The enzymatic stability, antitumor activity, and gonadotropin stimulatory effects of glycosylated luteinizing hormone-releasing hormone (LHRH) analogs were investigated in this study. Conjugation of carbohydrate units, including lactose (Lac), glucose (GS), and galactose (Gal) to LHRH peptide protected the peptide from proteolytic degradation and increased the peptides' half-lives in human plasma, rat kidney membrane enzymes, and liver homogenate markedly. Among all seven modified analogs, compo ...[more]

PMID: 25956382

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Project description:Background Orchiectomy has been replaced by medication represented by luteinizing hormone-releasing hormone (LHRH) agonist as the first-line therapy for androgen deprivation therapy (ADT). After the wide application of LHRH agonist, the side-effects of long-term ADT were noticed. It is time to reconsider the role of medication and surgeries in the treatment of prostate cancer. Methods Embase, Pubmed, Web of science and Cochrane library were searched for relevant trials. Quality of the studies and risk of bias were assessed by using the Newcastle-Ottawa Scale (NOS). Therapeutic and adverse effects, as well as long-term metabolic adverse effects were extracted from the selected studies. The data synthesized in meta-analyses were performed with R software (4.2.1). Risk ratio (RR) with its 95% confidence interval (CI) was calculated by combining outcome data including complete and partial response rate, progression rate, death rate and adverse effects such as hot flash and increase in pain. Descriptive analysis was performed among the prostate specific antigen (PSA), testosterone and metabolic adverse effects due to a lack of homogeneity of frailty measures. Results 1,711 participants from 11 studies were included in our systematic review. 1,258 patients from six studies were included in the meta-analysis. Based on the meta-analysis, the therapeutic and adverse outcomes included overall response rate, complete response rate, partial response rate, stable rate, progression rate, death rate and hot flashes. No statistical significance was observed between LHRH agonists and orchiectomy. Compared with surgery, LHRH agonist elevated the risk of the increase in pain. In descriptive analysis, it was shown that the therapeutic effects between PSA and testosterone also showed no significant difference. Both groups had lipid and glucose metabolic disorders, and a few studies reported worse lipid metabolic performance in orchiectomy group and worse insulin resistance in LHRH agonist group. Conclusion We found that the therapeutic outcomes were similar between the two options. The results of lipid and glucose metabolic abnormality were controversial in existing studies. The direct comparison studies on metabolic adverse effects should be performed in the future. The therapeutic, metabolic, psychological and economical effects should be considered before applying ADT methods. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42022365891.

Project description:BackgroundLuteinizing hormone secreted by the anterior pituitary gland regulates gonadal function. Luteinizing hormone secretion is regulated both by alterations in gonadotrope responsiveness to hypothalamic gonadotropin releasing hormone and by alterations in gonadotropin releasing hormone secretion. The mechanisms that determine gonadotrope responsiveness are unknown but may involve regulators of G protein signaling (RGSs). These proteins act by antagonizing or abbreviating interaction of Galpha proteins with effectors such as phospholipase Cbeta. Previously, we reported that gonadotropin releasing hormone-stimulated second messenger inositol trisphosphate production was inhibited when RGS3 and gonadotropin releasing hormone receptor cDNAs were co-transfected into the COS cell line. Here, we present evidence for RGS3 inhibition of gonadotropin releasing hormone-induced luteinizing hormone secretion from cultured rat pituitary cells.ResultsA truncated version of RGS3 (RGS3T = RGS3 314-519) inhibited gonadotropin releasing hormone-stimulated inositol trisphosphate production more potently than did RSG3 in gonadotropin releasing hormone receptor-bearing COS cells. An RSG3/glutathione-S-transferase fusion protein bound more 35S-Gqalpha than any other member of the G protein family tested. Adenoviral-mediated RGS3 gene transfer in pituitary gonadotropes inhibited gonadotropin releasing hormone-stimulated luteinizing hormone secretion in a dose-related fashion. Adeno-RGS3 also inhibited gonadotropin releasing hormone stimulated 3H-inositol phosphate accumulation, consistent with a molecular site of action at the Gqalpha protein.ConclusionsRGS3 inhibits gonadotropin releasing hormone-stimulated second messenger production (inositol trisphosphate) as well as luteinizing hormone secretion from rat pituitary gonadotropes apparently by binding and suppressing the transduction properties of Gqalpha protein function. A version of RGS3 that is amino-terminally truncated is even more potent than intact RGS3 at inhibiting gonadotropin releasing hormone-stimulated inositol trisphosphate production.

Project description:Pancreatic ductal adenocarcinomas are invariably lethal, and developing effective treatments that have minimal side effects is a challenge. Previous studies from our laboratory have shown that conjugates of cell membrane disrupting lytic peptides and luteinizing hormone releasing hormone (LHRH) target and destroy human prostate and breast cancer cells in xenografts in the nude mouse model (Hansel et al., Mol Cell Endocrinol 2007;260-262:183-9; Hansel et al., Mol Cell Endocrinol 2007;269:26-33), which express LHRH receptors. The objectives of our study were to synthesize a bioconjugate of LHRH analog ([DLys(6)]-LHRH) and a dietary microchemical (curcumin) and test the hypothesis that [DLys(6)]-LHRH-curcumin targets and inhibits pancreatic cancer cell growth in vitro and in vivo. In in vitro studies, we determined by confocal microscopy, flow cytometry analysis and reverse transcriptase-polymerase chain reaction that MIAPaCa-2, Panc-1 and BxPC-3 pancreatic cancer cell lines express LHRH receptors. [DLys(6)]-LHRH-curcumin inhibited cell proliferation of pancreatic cancer cell lines and induced apoptotic cell death (p < 0.05). Apoptosis was induced by cleavage of polyadenosine-5'-diphosphate-ribose-polymerase and caspase-3. The activity of [DLys(6)]-LHRH-curcumin was equal to free curcumin at equimolar concentrations in vitro. Unlike curcumin itself, the [DLys(6)]-LHRH-curcumin conjugate is water soluble which allows its intravenous administration. In two in vivo studies, [DLys(6)]-LHRH-curcumin given intravenously caused a significant (p < 0.01) reduction in tumor weights and volumes, and free curcumin given by gavage at an equal dose failed to cause a significant reduction in tumor weights and volumes in the nude mouse pancreatic cancer model. [DLys(6)]-LHRH-curcumin treatment enhanced apoptosis compared to [DLys(6)]-LHRH and vehicle-treated controls in tumor tissue. In conclusion, [DLys(6)]-LHRH-curcumin may be useful in treating pancreatic cancer.

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Evaluation of the Biological Properties and the Enzymatic Stability of Glycosylated Luteinizing Hormone-Releasing Hormone Analogs.

Publications

Evaluation of the Biological Properties and the Enzymatic Stability of Glycosylated Luteinizing Hormone-Releasing Hormone Analogs.

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