| Budget Amount *help |
¥3,250,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥150,000)
Fiscal Year 2007: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2006: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2005: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Research Abstract |
An investigation of the ability of morphine to induce apoptosis at its clinical concentration (10^-8M) was undertaken. Cytotoxicity was tested by3-[4, 5-dimethylthiazol-2-y1]-2, 5-diphenyltetrazolium bromide (MTT), assay, induction of early apoptosis and necrosis by fluoresxence-activated cell sorter (FACS) analysis with Annexin V and propidium iodine (PI), activation of caspase-2, -3, -8 and -9 by cleavage of specific substrates, DNA fragmentation by agarose gel electrophoresis, radical intensity and 0_2 scavenging activity by ESR spectroscopy. Millimolar concentrations of morphine showed higher cytotoxicity against human tumor cell lines (HL-60, A549, MCF7) than against normal human cells. The clinical concentration of morphine produced early apoptotic markers in HL-60 and A549 cells whereas it induced higher numbers of necrotic cells in MCF 7 cells. The clinical concentration of morphine failed to activate any caspase species and induced only trace amounts of internucleosomal DNA fr
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agmentation, in contrast to cytotoxic concentration of morphine. Abovementioned study may offer new strategies for treatment and prevention of cancer using a clinical concentration of morphine not only as an anti-nociceptive, but also as an apoptosis or necrosis inducer. In addition, the possible-inducing activity of codeinone, an oxidative metabolite of codeine, without or with anticancer drugs, was investigated. Codeinone induced internucleosomal DNA fragmentation in HL-60, but not in HSC-2. Codeinone dose-dependently activated caspase-3 in both of these cells, but to a much lesser extent than attained by actinomycine D. This property of codeinone was similar to what we have found previously in a, α, β-unsaturated ketones. Codeinone did not activate caspase-8 or caspase-9 in these cells. The cytotoxic activity of codeinone against HSC-2 cells was inhibited by N-acetyl-L-cysteine, but somewhat additively stimulated by sodium ascorbate, etc. Moreover, Whether, morphinone, an oxidative metabolite of morphine, also induced a similar type of cell death in HL-60 cells was investigated. As results, our data suggest that morphinone induces non-apoptotic cell death in HL-60 cells. Less
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