Growth Inhibition With Reversible Cell Cycle Arrest of Carcinoma Cells by Flavone L86-8275

Background: Previous studies have shown that polyhydroxylated flavonoids such as quercetin and genistein can inhibit tumor cell growth in vitro, and preliminary in vivo studies of the flavone L86-8275 have shown growth inhibition of LX529 and A549 lung carcinomas. L86-8275 [(-)cis-5,7dihydroxy-2-(2-chlorophenyl)-8[4-(3hydroxy-l-methyl)-piperidinyl]-4f/-lbenzopyran-4-one] is a flavone of novel structure. Purpose: The purpose of this study was to determine in vitro whether L86-8275 is a more potent inhibitor of growth in breast carcinoma and lung carcinoma cells than quercetin or genistein. Methods: We studied the effects of L86-8275 on cell growth in seven breast carcinoma cell lines and five lung carcinoma cell lines. MDA468 breast carcinoma was then selected for further study. Cell proliferation was measured by a colorimetric dye reduction assay; synthesis of DNA, RNA, and protein by incorporation of the radioactive metabolic precursors thymidine, uridine, or leucine, respectively; adenosine triphosphate (ATP) content by a luciferase-mediated bioluminescence reaction; and cell cycle progression by the use of c e l l - s y n c h r o n i z i n g d r u g s (aphidicolin and nocodazole) and flow cytometry. Results: L86-8275 was not cytotoxic to stationary-phase cells but reversibly inhibited the growth of cells in exponential growth phase. At c o n c e n t r a t i o n s of 2 5 - 1 6 0 nM, L86-8275 inhibited growth of human

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L86-8275 [(-)m-5,7-dihydroxy-2-(2chlorophenyl)-8[4-(3-hydroxy-1 -methyl)piperidinyl]-4//-1 -benzopyran-4-one] is a flavone with a novel structure (Fig. 1), compared with that of polyhydroxylated flavones including quercetin or genistein. L86-8275 is derived by synthesis from a parent structure obtained from Dysoxylum binectariferum (7,2), a plant native to India. Preliminary studies of L86-8275 revealed that it inhibited the growth in vivo of LX529 and A549 lung carcinomas (Sedlacek H: unpublished results). We therefore undertook a detailed characterization of the antiproliferative activity of this agent in carcinoma cell lines growing in vitro. Flavonoids such as quercetin have been shown to inhibit tumor cell growth

Fig. 1. Molecular structure of L86-8275. * indicates chiral centers in the molecule; see ref. (2).

(5), aerobic glycolysis (4), adenosine triphosphatase (5), synthesis of DNA, RNA, and protein (

Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275.

Previous studies have shown that polyhydroxylated flavonoids such as quercetin and genistein can inhibit tumor cell growth in vitro, and preliminary i...
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