title: Boc-lysinated-betulonic acid: a potent, anti-prostate cancer agent.
abstract: 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.
authors.affiliation: Division of Reproductive Endocrinology, Department of OB-GYN, Weill Medical College of Cornell University, New York, NY 10021, USA. brs2003@med.cornell.edu
authors.forename: Brij B
authors.initials: BB
authors.lastname: Saxena
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.forename: Meirong
authors.initials: M
authors.lastname: Hao
authors.forename: Eileen
authors.initials: E
authors.lastname: Kisilis
authors.forename: Meena
authors.initials: M
authors.lastname: Katdare
authors.forename: Ozgur
authors.initials: O
authors.lastname: Oktem
authors.forename: Arkadiy
authors.initials: A
authors.lastname: Bomshteyn
authors.forename: Premila
authors.initials: P
authors.lastname: Rathnam
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008239:Lysine / Q000031:analogs & derivatives / Q000737:chemistry*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects; D008968:Molecular Conformation; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000094062:Betulinic Acid
chemical_list: D000970:Antineoplastic Agents; D053148:Caspase 3; D020169:Caspases; D008239:Lysine; D009828:Oleanolic Acid; C118308:betulonic acid; D000094062:Betulinic Acid; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse