title: Luteinizing hormone-releasing hormone receptor-targeted deslorelin-docetaxel conjugate enhances efficacy of docetaxel in prostate cancer therapy.
abstract: 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. Fourier-transform 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 deslorelin-docetaxel 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 approximately 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado-Denver, 12700 East 19th Avenue, Aurora, CO 80045, USA.
authors.forename: Sneha
authors.initials: S
authors.lastname: Sundaram
authors.forename: Chandrasekar
authors.initials: C
authors.lastname: Durairaj
authors.forename: Rajendra
authors.initials: R
authors.lastname: Kadam
authors.forename: Uday B
authors.initials: UB
authors.lastname: Kompella
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002853:Chromatography, Liquid; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011966:Receptors, LHRH / Q000819:agonists / Q000378:metabolism*; D017550:Spectroscopy, Fourier Transform Infrared; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology*; D017329:Triptorelin Pamoate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011966:Receptors, LHRH; D043823:Taxoids; D017329:Triptorelin Pamoate; D000077143:Docetaxel; C066438:deslorelin