title: Potentiation of the antitumor effect of 11-keto-β-boswellic acid by its 3-α-hexanoyloxy derivative.
abstract: We recently discovered that a propionyloxy derivative of 11-keto-β-boswellic acid (PKBA) showed better anticancer potential than other boswellic acids including AKBA, encompassing the importance of acyl group at the 3-α-hydroxy position of KBA. In continuation of our previous work, other higher derivatives (with increasing alkoxy chain length at 3-α-hydroxy position) including butyryloxy (BKBA) and hexanoyloxy (HKBA) derivatives of KBA were synthesized. The respective IC(50) values of BKBA and HKBA in HL-60 cells were found to be 7.7 and 4.5 μg/ml. IC(50) value of HKBA was comparatively lower than that of BKBA, and further lower than that of the previously reported derivative (PKBA, IC(50) 8.7 μg/ml). In order to compare the anticancer potential of HKBA with PKBA, detailed in vitro pro-apoptotic and in vivo anticancer studies were carried out. The induction of apoptosis by HKBA was measured using various parameters including fluorescence and scanning electron microscopy, DNA fragmentation and Annexin V-FITC binding. The extent of DNA damage was measured using neutral comet assay. HKBA was further evaluated for its effect on DNA cell cycle and mitochondria where it was found to arrest cells in G(2)/M phase and also induced loss of mitochondrial membrane potential. These events were associated with increased expression of cytosolic cytochrome c and cleavage of PARP. Target based studies showed that HKBA inhibited the enzymatic activity of topoisomerases I and II at low doses than that of PKBA. In vivo studies also revealed a low dose inhibitory effect of HKBA on ascitic and solid murine tumor models.
authors.affiliation: Pharmacology Division, Indian Institute of Integrative Medicine, canal road, Jammu, India.
authors.forename: Gousia
authors.initials: G
authors.lastname: Chashoo
authors.forename: Shashank K
authors.initials: SK
authors.lastname: Singh
authors.forename: Dilip M
authors.initials: DM
authors.lastname: Mondhe
authors.forename: Parduman R
authors.initials: PR
authors.lastname: Sharma
authors.forename: Samar S
authors.initials: SS
authors.lastname: Andotra
authors.forename: Bhahwal A
authors.initials: BA
authors.lastname: Shah
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Taneja
authors.forename: Ajit K
authors.initials: AK
authors.lastname: Saxena
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018922:HL-60 Cells; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D009336:Necrosis / Q000139:chemically induced; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology; D014315:Triterpenes / Q000737:chemistry* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C447943:11-keto-boswellic acid; D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014315:Triterpenes; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II