著者:所属(別形式) | Josai University, Faculty of Science, Department of Chemistry / Josai University, Faculty of Science, Department of Chemistry / Josai University, Faculty of Science, Department of Chemistry / Meikai University School of Dentistry, Department of Diagnostic and Therapeutic Sciences, Division of Pharmacology |
抄録 | We have recently reported that out of twentybenzo[b]cyclohept[e][1,4]oxazines and their S-analogs, and2-aminotropone derivatives, 7-bromo-2-(4-hydroxyanilino)tropone and 4-isopropyl-2-(2-hydroxyanilino)tropone showedthe highest tumor-specificity in human oral squamous cellcarcinoma cell lines. To gain more insight into the anti-tumoractions of these compounds, whether they induce the growthstimulation effect observed at low concentrations, known ashormesis, was investigated using a total of ten human normaland tumor cultured cells. The tumor-specificity of bothcompounds became apparent 48 hours after the start oftreatment of the cells with these compounds and reached amaximum level at 72 and 96 hours. On the other hand, theirgrowth stimulatory effects were most prominent at 24 hours,especially in normal skin and lung fibroblasts, but rapidlydisappeared with prolonged incubation time (48-96 hours).These data suggest the occurrence of a hormetic responseonly at restricted times and concentrations as has beenpreviously reported, although the biological significance isyet to be elucidated.We have recently reported that 7-bromo-2-(4-hydroxyanilino)tropone [16] and 4-isopropyl-2-(2-hydroxyanilino)tropone[20] (Figure 1), out of twenty benzo[b]cyclohept[e][1,4]oxazines and their S-analogs and 2-aminotropone derivatives,showed the highest tumor specificity (TS=4.0 and 4.4,respectively), inducing few or no apoptotic markers such asDNA fragmentation and caspase activation in human oralsquamous cell carcinoma HSC-2 cells (1). 7-Bromo-2-(4-hydroxyanilino)tropone [16] also inhibited the production ofpro-inflammatory substances such as nitric oxide (NO) by lipopolysaccharide-activated mouse macrophage-likeRAW264.7 cells at concentrations that do not affect thecellular viability (selectivity index=54), and this was mostlydue to the inhibition of inducible NO synthase andcyclooxygenase-2 expressions at both protein and mRNAlevels (2).It has been reported that many toxic substances,environmental hormones, inorganic compounds and evenirradiation modulate the growth of cultured cells in a biphasicfashion, stimulating or inhibiting the growth at lower andhigher concentrations, respectively. The growth-stimulatingeffect at low concentrations is known as hormesis (3, 4).However, we have recently found that three Chinese herbalextracts (Drynaria baronii, Angelica sinensis and Cornusofficinalis Sieb. et Zucc) failed to induce hormesis in humanoral carcinoma cell lines (5). This suggested the possibilitythat the experimental conditions used may not have beenoptimal for detecting hormesis. To confirm the generality ofthe occurrence of hormesis, whether or not these compoundsinduce hormesis was investigated in seven normal human cells(gingival fibroblast HGF, pulp cell HPC, periodontal ligamentfibroblast HPLF, skin fibroblasts NB1RGB and 305M andlung fibroblasts WI-38 and MRC-5) and three human oralsquamous cell carcinoma cell lines (HSC-2, HSC-3, HSC-4),after incubating the cells with a wide range of concentrationsof these compounds for various lengths of times. |