title: Potentiating effect of the flavonolignan (-)-hydnocarpin in combination with vincristine in a sensitive and P-gp-expressing acute lymphoblastic leukemia cell line.
abstract: The potentiating action of the flavonolignan, (-)-hydnocarpin, in combination with vincristine was evaluated in the 697 acute lymphoblastic leukemia cell line and a P-gp-expressing variant, 697-R. Vincristine at 3 nM caused nearly complete growth inhibition in 697 cells versus a 17% growth inhibition in 697-R cells. When combined with (-)-hydnocarpin at concentrations of 10 and 5 μM, vincristine-mediated growth inhibition in the 697-R cells increased significantly over the sum of the individual agents to 72% (p ≤ 0.0001) and 41% (p = 0.0256), respectively. Vincristine at 1.5 nM (66% growth inhibition) and 0.75 nM (39% growth inhibition) combined with (-)-hydnocarpin at 10 μM (42% growth inhibition) in the 697 cells caused a significant increase in growth inhibition to 83% (p = 0.03) and to 61% (p < 0.0001), respectively, when compared to vincristine treatment as a single agent. To investigate the mechanism for the vincristine re-sensitization caused by (-)-hydnocarpin, the P-gp inhibitory effect of (-)-hydnocarpin was evaluated.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, United States of America.
authors.forename: Lynette
authors.initials: L
authors.lastname: Bueno Pérez
authors.forename: Li
authors.initials: L
authors.lastname: Pan
authors.forename: Ellen
authors.initials: E
authors.lastname: Sass
authors.forename: Sneha V
authors.initials: SV
authors.lastname: Gupta
authors.forename: Amy
authors.initials: A
authors.lastname: Lehman
authors.forename: A Douglas
authors.initials: AD
authors.lastname: Kinghorn
authors.forename: David M
authors.initials: DM
authors.lastname: Lucas
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D044947:Flavonolignans / Q000494:pharmacology*; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D014750:Vincristine / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D044947:Flavonolignans; C073621:hydnocarpin; D014750:Vincristine
keywords: (-)-hydnocarpin; P-glycoprotein; multidrug resistance; vincristine