title: Induction of apoptosis and necrosis by resistance modifiers benzazoles and benzoxazines on tumour cell line mouse lymphoma L5718 Mdr+cells.
abstract: Eighteen new fused heterocyclic compounds of benzazoles and benzoxazines were investigated for induction and inhibition of apoptosis on tumor cells (L5718, mouse lymphoma cell line containing the human mdr-1 gene). For evaluation of apoptosis, the cells were stained with FITC-labelled Annexin-V and propidium iodide and the results were analysed by flow cytometry. Nine of these substances were also checked for reversal of multidrug resistance. The reversal of multidrug resistance was determined by measuring the rhodamine-123 accumulation in the cancer cells. Rhodamine-123 shows a green fluorescence and its intracellular concentration correlates well with the inhibition of efflux pump activity. Three of the tested compounds, 5-(p-nitrobenzamido)-2-benzylbenzoxazole (BD-3), 6-methyl-2-(o-chlorophenyl) benzoxazole (A-9) and 5-(p-nitrophenoxyacetamido)-2-phenylbenzoxazole (D-30), showed an increased apoptotic effect on mouse lymphoma cells. Moreover, compounds BD-3, A-9 and 5-(2-thienylcarboxyamido)-2-phenylbenzoxazole (D-24) also amplified the apoptosis effect of 12H-benzo(a)phenothiazines (M-627). However, D-24, alone was not effective. Additionally, 2-(p-nitrobenzyl)benzoxazole (B-11), was also found to increase the apoptotic effect of M-627. On the other hand, 5-(p-nitrophenylacetamido)-2-phenylbenzoxazole (D-7) showed an anti-apoptotic effect. No positive correlation was found between the increased drug accumulation effect and the programmed cell death induced by the compounds studied.
authors.affiliation: Humboldt University Berlin, Institute of Biology, Department of Molecular Parasitology, Berlin, Germany. andrasv@aol.com
authors.forename: Andras
authors.initials: A
authors.lastname: Varga
authors.forename: Esin
authors.initials: E
authors.lastname: Aki-Sener
authors.forename: Ismail
authors.initials: I
authors.lastname: Yalcin
authors.forename: Ozlem
authors.initials: O
authors.lastname: Temiz-Arpaci
authors.forename: Betul
authors.initials: B
authors.lastname: Tekiner-Gulbas
authors.forename: Georgy
authors.initials: G
authors.lastname: Cherepnev
authors.forename: Joseph
authors.initials: J
authors.lastname: Molnar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D048588:Benzoxazines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D019450:Genes, MDR / Q000187:drug effects*; D006801:Humans; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D015394:Molecular Structure; D009336:Necrosis / Q000188:drug therapy
chemical_list: D001562:Benzimidazoles; D048588:Benzoxazines