Document Detail

Boc-lysinated-betulonic acid: a potent, anti-prostate cancer agent.
MedLine Citation:
PMID:  16777417     Owner:  NLM     Status:  MEDLINE    
Betulonic acid, derived from betulinol, a pentacyclic styrene, has shown a highly specific anti-prostate cancer activity in in vitro cell cultures. However, due to the lack of solubility of betulonic acid in aqueous medium, its potent anti-cancer activity in vivo has not been determined to the fullest extent. The present study describes the chemical synthesis of hydrophilic Boc-lysinated-betulonic acid, which has improved its solubility in an aqueous biocompatible solvent. Evaluation in cytotoxicity assays, Boc-lysinated-betulonic acid dissolved in phosphate-buffered saline (PBS) containing 22% ethanol and 4% human serum albumin, has shown 95.7% inhibition of LNCaP prostate cancer cells in culture after 72 h incubation at a concentration of 100 microM, but with little effect on normally proliferating fibroblast cells. In the in vivo assay, male athymic mice transplanted with human prostate LNCaP xenografts were injected with Boc-lysinated-betulonic acid intraperitoneally at a dose of 30 mg/kg daily for 17 days. The treated mice exhibited 92% inhibition of tumor growth as compared to controls. Histological sections of the tumors showed that Boc-lysinated-betulonic acid arrested mitosis and induced apoptosis, which was confirmed by TUNEL assay, Yo-Pro-1 staining, and the release of cleaved caspase-3 from the ex vivo in tumor culture. These studies, for the first time, demonstrate that a non-toxic hydrophilic lysinated derivative of betulonic acid and its solubility in a biocompatible aqueous medium has enhanced the bioavailability of the drug and has thus unleashed its full anti-prostate cancer activity.
Brij B Saxena; Lei Zhu; Meirong Hao; Eileen Kisilis; Meena Katdare; Ozgur Oktem; Arkadiy Bomshteyn; Premila Rathnam
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Publication Detail:
Type:  Comparative Study; In Vitro; Journal Article     Date:  2006-06-13
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  14     ISSN:  0968-0896     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  2006 Sep 
Date Detail:
Created Date:  2006-08-21     Completed Date:  2006-11-07     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  6349-58     Citation Subset:  IM    
Division of Reproductive Endocrinology, Department of OB-GYN, Weill Medical College of Cornell University, New York, NY 10021, USA.
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MeSH Terms
Antineoplastic Agents / chemical synthesis,  chemistry,  pharmacology*
Apoptosis / drug effects
Caspase 3
Caspases / drug effects
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
Lysine / analogs & derivatives,  chemistry*
Mice, Nude
Mitosis / drug effects
Molecular Conformation
Oleanolic Acid / analogs & derivatives*,  chemical synthesis,  chemistry,  pharmacology
Prostatic Neoplasms / drug therapy*,  pathology
Structure-Activity Relationship
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Reg. No./Substance:
0/Antineoplastic Agents; 0/betulonic acid; 508-02-1/Oleanolic Acid; 56-87-1/Lysine; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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