Evidence for LHRH-Receptor Expression in Human Airway Epithelial (Calu-3) Cells and Its Role in the Transport of an LHRH Agonist

Koushik, Kavitha; Bandi, Nagesh; Sundaram, Shanthy; Kompella, Uday B.

doi:10.1023/b:pham.0000029294.70707.74

Cited by 18 publications

(16 citation statements)

References 41 publications

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“…Previous studies from our laboratory have used the AON approach to selectively reduce LHRH-R expression (29). Using this AON, previous studies have shown a decrease in the LHRH-R mRNA expression by ∼73 ± 10.2% and LHRH-R protein expression by 42 ± 4.8% in a lung cancer cell line (23). In this study, a decrease in cytotoxicity by the deslorelin-docetaxel conjugate was observed in both the LNCaP and PC-3 cells treated with AON against LHRH-R. Further, it was interesting to note that, although there is a significant decrease in cytotoxicity in the AON-treated group, the deslorelin-docetaxel conjugate is still significantly more cytotoxic compared with docetaxel alone.…”

Section: Discussionmentioning

confidence: 99%

“…Influence of Decreased LHRH-R Expression on the Efficacy of Deslorelin-Docetaxel Conjugate A previously described protocol was followed to determine the effect of decreased expression of LHRH-R on efficacy of deslorelin-docetaxel conjugate in vitro (23). Phosphorothioated antisense oligonucleotide (AON) and sense oligonucleotide (SON) directed against the LHRH-R, previously validated by Koushik et al (23) for reducing LHRH-R expression, were synthesized for this purpose (29).…”

Section: Molecular Cancer Therapeuticsmentioning

confidence: 99%

“…Deslorelin is a nonapeptide of molecular weight 1,285 Da with the amino acid sequence pGlu-His-Trp-Ser-Tyr-D-TrpLeu-Arg-ProNHEt (22,23). Deslorelin contains modifications at position 6 replacing Gly with D-Trp and at position 10 replacing Gly with ethylamide (22).…”

Section: Introductionmentioning

confidence: 99%

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Luteinizing hormone-releasing hormone receptor–targeted deslorelin-docetaxel conjugate enhances efficacy of docetaxel in prostate cancer therapy

Sundaram

Durairaj

Kadam

et al. 2009

Molecular Cancer Therapeutics

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Docetaxel, a chemotherapeutic agent currently used for improving survival of prostate cancer patients, suffers from low therapeutic index. The objective of this study was to prepare a new docetaxel derivative conjugated to deslorelin, a luteinizing hormone-releasing hormone (LHRH) superagonist, and to determine whether it enhances docetaxel potency in vitro and in vivo. Because docetaxel is not amenable for conjugation with peptides, we introduced a -COOH group in docetaxel, forming docetaxel-hemiglutarate, and subsequently conjugated this to serine in deslorelin, forming deslorelin-docetaxel. Fouriertransform IR, 1 H-nuclear magnetic resonance, and liquid chromatography-mass spectrometry analyses confirmed deslorelin-docetaxel formation. Antiproliferative efficacy in LNCaP and PC-3 cell lines over 24, 48, and 72 hours exhibited the order deslorelin-docetaxel > docetaxel, whereas deslorelin alone had no effect, with deslorelindocetaxel potency being 15-fold greater than docetaxel at 72 h. Further, cells pretreated with antisense oligonucleotide against LHRH receptor exhibited decreased deslorelin-docetaxel efficacy, without any change in docetaxel efficacy. Thus, deslorelin-docetaxel efficacy is likely mediated via LHRH receptor. Cell cycle analysis showed that docetaxel treatment led to arrest in G 2 -M phase, whereas deslorelin-docetaxel treatment allowed greater progression to apoptosis in both cell lines, with deslorelin-docetaxel exerting 5-fold greater apoptosis compared with docetaxel in prostate cancer cell lines. Antitumor efficacy studies in PC-3 prostate xenograft-bearing mice indicated the efficacy order deslorelin-docetaxel > docetaxel ≫ deslorelin > PBS, with deslorelin-docetaxel exerting 5.5-fold greater tumor growth inhibition than docetaxel alone. Thus, deslorelin-docetaxel prepared in this study retains pharmacologic effects of both docetaxel and deslorelin while enhancing the antiproliferative, apoptotic, and antitumor efficacy of docetaxel by several folds in prostate cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Molecular Cancer Therapeuticsmentioning

confidence: 99%

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Luteinizing hormone-releasing hormone receptor–targeted deslorelin-docetaxel conjugate enhances efficacy of docetaxel in prostate cancer therapy

Sundaram

Durairaj

Kadam

et al. 2009

Molecular Cancer Therapeutics

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“…Further, our earlier investigations indicated that respiratory epithelial cells internalize deslorelin, a peptide agonist of luteinizing hormone releasing hormone (LHRH) receptor (Koushik et al, 2004). To enhance nanoparticle cell affinity and uptake in ocular tissues, we investigated the potential value of conjugating transferrin or deslorelin on nanoparticle surface (nanoparticle functionalization).…”

Section: Applications Of Nanotechnology For Back Of the Eye Diseasesmentioning

confidence: 99%

Nanomedicines for back of the eye drug delivery, gene delivery, and imaging

Kompella

Amrite

Ravi

et al. 2013

Progress in Retinal and Eye Research

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222

123

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Treatment and management of diseases of the posterior segment of the eye such as diabetic retinopathy, retinoblastoma, retinitis pigmentosa, and choroidal neovascularization is a challenging task due to the anatomy and physiology of ocular barriers. For instance, traditional routes of drug delivery for therapeutic treatment are hindered by poor intraocular penetration and/or rapid ocular elimination. One possible approach to improve ocular therapy is to employ nanotechnology. Nanomedicines, products of nanotechnology, having at least one dimension in the nanoscale include nanoparticles, micelles, nanotubes, and dendrimers, with and without targeting ligands, are making a significant impact in the fields of ocular drug delivery, gene delivery, and imaging, the focus of this review. Key applications of nanotechnology discussed in this review include a) bioadhesive nanomedicines; b) functionalized nanomedicines that enhance target recognition and/or cell entry; c) nanomedicines capable of controlled release of the payload; d) nanomedicines capable of enhancing gene transfection and duration of transfection; f) nanomedicines responsive to stimuli including light, heat, ultrasound, electrical signals, pH, and oxidative stress; g) diversely sized and colored nanoparticles for imaging, and h) nanowires for retinal prostheses. Additionally, nanofabricated delivery systems including implants, films, microparticles, and nanoparticles are described. Although the above nanomedicines may be administered by various routes including topical, intravitreal, intravenous, transscleral, suprachoroidal, and subretinal routes, each nanomedicine should be tailored for the disease, drug, and site of administration. In addition to the nature of materials used in nanomedicine design, depending on the site of nanomedicine administration, clearance and toxicity are expected to differ.

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“…Deslorelin, a nonapeptide luteinizing hormone releasing hormone (LHRH) super-agonist has a molecular weight of 1285 Da and exerts its effects via the LHRH-receptor (LHRH-R) (8, 9). The LHRH-R, a member of the GPCR super family is expressed in various tissues including normal lung (10) and overexpressed on lung cancers cells (11, 12). We have established that deslorelin can be conjugated to docetaxel at the hydroxyl (-OH) group in the serine moiety (amino acid 4) via a glutarate linker (13).…”

Section: Introductionmentioning

confidence: 99%

Targeted Drug and Gene Delivery Systems for Lung Cancer Therapy

Sundaram

Trivedi

Durairaj

et al. 2009

Clinical Cancer Research

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Purpose: To evaluate the efficacy of a novel docetaxel derivative of deslorelin, a luteinizing hormone-releasing hormone (LHRH) agonist, and its combination in vivo with RGD peptide conjugated nanoparticles encapsulating an antiangiogenic, anti-vascular endothelial growth factor (VEGF) intraceptor (Flt23k; RGD-Flt23k-NP) in H1299 lung cancer cells and/or xenografts in athymic nude BALB/c mice. Experimental Design: The in vitro and in vivo efficacy of the deslorelin-docetaxel conjugate was evaluated in H1299 cells and xenografts in athymic nude mice. Coadministration of deslorelin-docetaxel conjugate and RGD-Flt23k-NP was tested in vivo in mice. Tumor inhibition, apoptosis, and VEGF inhibition were estimated in each of the treatment groups. Results: The conjugate enhanced in vitro docetaxel efficacy by 13-fold in H1299 cells compared with docetaxel at 24 hours, and this effect was inhibited following reduction of LHRH receptor expression by an antisense oligonucleotide. Combination of the conjugate with the RGD-Flt23k-NP in vivo resulted in an 82-and 15-fold tumor growth inhibition on day 39 following repeated weekly i.v. injections and a single intratumoral (i.t.) injection, respectively. These effects were significantly greater than individual targeted therapies or docetaxel alone. Similarly, apoptotic indices for the combination therapy were 14% and 10% in the i.v. and i.t. groups, respectively, and higher than the individual therapies. Combination therapy groups exhibited greater VEGF inhibition in both the i.v. and i.t. groups. Conclusions: Docetaxel efficacy was enhanced by LHRH receptor-targeted deslorelin conjugate and further improved by combination with targeted antiangiogenic nanoparticle gene therapy. Combination of novel targeted therapeutic approaches described here provides an attractive alternative to the current treatment options for lung cancer therapy. (Clin Cancer Res 2009;15(23):7299-308)

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Evidence for LHRH-Receptor Expression in Human Airway Epithelial (Calu-3) Cells and Its Role in the Transport of an LHRH Agonist

Abstract: Taken together, our results provide evidence that deslorelin is transported across the respiratory epithelium via the LHRH-receptor.

Cited by 18 publications

References 41 publications

Luteinizing hormone-releasing hormone receptor–targeted deslorelin-docetaxel conjugate enhances efficacy of docetaxel in prostate cancer therapy

Luteinizing hormone-releasing hormone receptor–targeted deslorelin-docetaxel conjugate enhances efficacy of docetaxel in prostate cancer therapy

Nanomedicines for back of the eye drug delivery, gene delivery, and imaging

Targeted Drug and Gene Delivery Systems for Lung Cancer Therapy

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