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- 저자 : Owuor, Phillip Okinda (검색결과 4 건)
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Quinacrin Induces Cytochrome c-dependent Apoptotic Signaling in Human Cervical Carcinoma Cells
Fasanmade, Adedigbo A.,Owuor, Edward D.,Ee, Rachel P.L.,Qato, Dima,Heller, Mark,Kong, Ah Ng Tony The Pharmaceutical Society of Korea 2001 Archives of Pharmacal Research Vol.24 No.2
Quinacrine (QU), a phospholipase-A2 (PLA-2) inhibitor has been used clinically as a chemotherapeutic adjuvant. To understand the mechanisms leading to its chemotherapeutic effect, we have investigated QU-induced apoptotic signaling pathways in human cervical squamous carcinoma HeLa cells. In this study, we found that QU induced cytochrome c-dependent apoptotic signaling. The release of pro-apoptotic cytochrome c was QU concentration- and time-dependent, and preceded activation of caspase-9 and -3. Flow cytometric FACScan analysis using fluorescence intensities of $DiOC_6$/ demonstrated that QU-induced cytochrome c release was independent of mitochondrial permeability transition (MPT), since the concentrations of QU that induced cytochrome c release did not alter mitochondrial membrane potential (${\blacktriangle}{\Psi}_m$). Moreover, kinetic analysis of caspase activities showed that cytochrome c release led to the activation of caspase-9 and downstream death effector caspase-3, Caspase-3 inhibitor (Ac-DEVD-CHO) partially blocked QU-induced apoptosis, suggesting the importance of caspase-3 in this apoptotic signaling mechanism. Supplementation with arachidonic acid (AA) sustained caspase-3 activation induced by QU. Using inhibitors against cellular arachidonate metabolism of lipooxygenase (Nordihydroxyguaiaretic Acid, NDGA) and cyclooxygenase (5,8,11,14-Eicosatetraynoic Acid, ETYA) demonstrated that QU-induced apoptotic signaling may be dependent on its role as a PLA-2 inhibitor. Interestingly, NDCA attenuated QU-induced cytochrome c release, caspase activity as well as apoptotic cell death. The blockade of cytochrome c release by NDCA was much more effective than that attained with cyclosporin A (CsA), a MPT inhibitor. ETYA was not effective in blocking cytochrome c release, except under very high concentrations. Caspase inhibitor z-VAD blocked the release of cytochrome c suggesting that this signaling event is caspase dependent, and caspase-8 activation may be upstream of the mitochondrial events. In summary, we report that QU induced cytochrome c-dependent apoptotic signaling cascade, which may be dependent on its role as a PLA-2 inhibitor. This apoptotic mechanism induced by QU may contribute to its known chemotherapeutic effects.
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Chen, Chi,Yu, Rong,Owuor, Edward D.,Kong, A.NTony The Pharmaceutical Society of Korea 2000 Archives of Pharmacal Research Vol.23 No.6
Green tea polyphenols (GTP) have been demonstrated to suppress tumorigenesis in several chemical-induced animal carcinogenesis models, and predicted as promising chemopreventive agents in human. Recent studies of GTP extracts showed the involvement of mitogen-activated protein kinases (MAPKs) in the regulation of Phase II enzymes gene expression and induction of apoptosis. In the current work we compared the biological actions of five green tea catechins: (1) induction of ARE reporter gene, (2) activation of MAP kinases, (3) cytotoxicity in human hepatoma HepG2-C8 cells, and (4) caspase activation in human cervical squamous carcinoma HeLa cells. For the induction of phase IIgene assay, (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG) potently induced antioxidant response element (ARE)-mediated luciferase activity, with induction observed at 25 $\mu\textrm{m}$with EGCG. The induction of ARE reporter gene appears to be structurally related to the 3-gallate group. Comparing the activation of MAPK by the five polyphenols, only EGCG showed potent activation of all three MAPKs (ERK, JNK and p38) in a dose- and time-dependent manner, whereas EGC activated ERK and p38. In the concentration range of 25 $\mu\textrm{m}$ to 1 mM, EGCG and ECG strongly suppressed HepG2-ARE-C8 cell-growth. To elucidate the mechanisms of green tea polyphenol-induced apoptosis, we measured the activation of an important cell death protein, caspase-3 induced by EGCG, and found that caspase-3 was activated in a dose- and time-dependent manner. Interestingly, the activation of caspase-3 was a relatively late event (peaked at 16 h), whereas activation of MAPKs was much earlier (peaked at 2 h). It is possible, that at low concentrations of EGCG, activation of MAPK leads to ARE-mediated gene expression including phase II detoxifying enzymes. Whereas at higher concentrations of EGCG, sustained activation of MAPKs such as JNK leads to apoptosis. These mechanisms are currently under investigation in our laboratory. As the most abundant catechin in GTP extract, we found that EGCG potently induced ARE-mediated gene expression, activated MAP kinase pathway, stimulated caspase-3 activity, and induced apoptosis. These mechanisms together with others, may contribute to the overall chemopreventive function of EGCG itself as well as the GTP.
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Bioactive carbazole alkaloids from Alysicarpus ovalifolius (Schumach)
Ochung', Angeline Atieno,Manguro, Lawrence Arot Oyango,Owuor, Phillip Okinda,Jondiko, Isaac Ogoche,Nyunja, Regina Achieng',Akala, Hosea,Mwinzi, Pauline,Opiyo, Sylvia Awino 한국응용생명화학회 2015 Applied Biological Chemistry (Appl Biol Chem) Vol.58 No.6
Phytochemical and biological evaluation of the stem bark of Alysicarpus ovalifolius led to the isolation of three carbazole alkaloids identified as mohanimbine (1), koenimbine (2) and koenidine (3) along with quercetin 3-O-glucoside (4), kaempferol 7-O-glucoside (5), orientin (6), apigenin (7), quercetin (8), plumbagin (9) and stigmasterol (10). The structures of these compounds were elucidated using physical and spectroscopic methods as well as comparison with the literature data. Compound 3 showed strong activity against chloroquine-sensitive strain I (D6) and the multi-drug resistant Indochicha I (W2) of Plasmodium falciparum with $IC_{50}$ values of $63.07{\pm}0.01$ and $54.19{\pm}0.04ng/mL$, respectively. Compound 1 on the other hand exhibited moderate larvicidal against Anopheles gambiae larvae as well as antimicrobial activities against Candida albicans and gram-positive Staphylococcus aureus, respectively.
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Bioactive carbazole alkaloids from Alysicarpus ovalifolius (Schumach)
Angeline Atieno Ochung,Lawrence Arot Oyango Manguro,Phillip Okinda Owuor,Isaac Ogoche Jondiko,Regina Achieng’ Nyunja,Hosea Akala,Pauline Mwinzi,Sylvia Awino Opiyo 한국응용생명화학회 2015 Applied Biological Chemistry (Appl Biol Chem) Vol.58 No.6
Phytochemical and biological evaluation of the stem bark of Alysicarpus ovalifolius led to the isolation of three carbazole alkaloids identified as mohanimbine (1), koenimbine (2) and koenidine (3) along with quercetin 3-O-glucoside (4), kaempferol 7-O-glucoside (5), orientin (6), apigenin (7), quercetin (8), plumbagin (9) and stigmasterol (10). The structures of these compounds were elucidated using physical and spectroscopic methods as well as comparison with the literature data. Compound 3 showed strong activity against chloroquine-sensitive strain I (D6) and the multi-drug resistant Indochicha I (W2) of Plasmodium falciparum with IC50 values of 63.07 – 0.01 and 54.19 – 0.04 ng/mL, respectively. Compound 1 on the other hand exhibited moderate larvicidal against Anopheles gambiae larvae as well as antimicrobial activities against Candida albicans and gram-positive Staphylococcus aureus, respectively.
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