title: Tumor-specific cytotoxicity and type of cell death induced by naphtho[2,3-b]furan-4,9-diones and related compounds in human tumor cell lines: relationship to electronic structure.
abstract: A total of thirty-nine naphtho[2,3-b]furan-4,9-diones and related compounds were tested for their cytotoxicity against three human normal oral cells (gingival fibroblast, HGF, pulp cell, HPC, periodontal ligament fibroblast, HPLF) and four human tumor cell lines (oral squamous cell carcinoma HSC-2, HSC-3, HSC-4, promyelocytic leukemia HL-60). 2-Acetylnaphtho[2,3-b]furan-4,9-dione [1] was highly cytotoxic to both normal and tumor cells, yielding low tumor-specificity. 2-Acetyl-4,9-dimethoxynaphtho[2,3-b]furan [4], the 2-(3-furanoyl) benzoic acids [5, 6] and the 1,4-naphthoquinones [7, 8] showed much reduced cytototoxicity and low tumor-specificity. The introduction of phenoxy [18], isopropylamino [23] or 2-methylpiperidino [33] groups to the 2-position of naphtho[2,3-b]furan-4,9-dione yielded compounds that showed the greatest tumor-specificity. These compounds, at twice or four times higher concentrations than CC50, induced the activation of caspase-3, caspase-8 and caspase-9 in the HSC-2 and HL-60 cells, but not so apparently in the HSC-4 cells. However, they did not induce internucleosomal DNA fragmentation in the HSC-2 and HSC-4 cells even after 24 hours incubation and only slightly induced DNA fragmentation in the HL-60 cells. Compound [18] induced the production of annexin-positive cells, but did not induce microtubule-associated protein light chain 3 (LC3) accumulation in autophagosomes in LC3-green fluorescent protein (GFP)-transfected HSC-2 cells. These data suggested that naphtho[2,3-b]furan-4,9-diones may induce the early apoptotic marker, without induction of caspase activation and DNA fragmentation in oral squamous cell carcinoma cell lines. Quantitative structure-activity relationship (QSAR) analysis suggests the applicability of the theoretical calculations such as frontier molecular orbital, dipole moments and hydrophobicity in predicting their cytotoxic activity.
authors.affiliation: Faculties of Science, Josai University, Sakado, Saitama, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Takano
authors.forename: Ken
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ogawa
authors.forename: Jyunichi
authors.initials: J
authors.lastname: Koyanagi
authors.forename: Teruo
authors.initials: T
authors.lastname: Kurihara
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Wakabayashi
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Noboru
authors.initials: N
authors.lastname: Motohashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakagami
authors.forename: Katsumi
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Tanaka