Browsing by Author "Badal, Simone"

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    Cycloartane-3,24,25-triol inhibits MRCKa kinase and demonstrates promising anti prostate cancer activity in vitro
    (2012-11-14) Lowe, Henry I C; Watson, Charah T; Badal, Simone; Toyang, Ngeh J; Bryant, Joseph
    Abstract Background Given the high occurrence of prostate cancer worldwide and one of the major sources of the discovery of new lead molecules being medicinal plants, this research undertook to investigate the possible anti-cancer activity of two natural cycloartanes; cycloartane-3,24,25-diol (extracted in our lab from Tillandsia recurvata) and cycloartane-3,24,25-triol (purchased). The inhibition of MRCKand#945; kinase has emerged as a potential solution to restoring the tight regulation of normal cellular growth, the loss of which leads to cancer cell formation. Methods Kinase inhibition was investigated using competition binding (to the ATP sites) assays which have been previously established and authenticated and cell proliferation was measured using the WST-1 assay. Results Cycloartane-3,24,25-triol demonstrated strong selectivity towards the MRCKand#945; kinase with a Kd50 of 0.26 and#956;M from a total of 451 kinases investigated. Cycloartane-3,24,25-triol reduced the viability of PC-3 and DU145 cell lines with IC50 values of 2.226and#8201;and#177;and#8201;0.28 and#956;M and 1.67and#8201;and#177;and#8201;0.18 and#956;M respectively. Conclusions These results will prove useful in drug discovery as Cycloartane-3,24,25-triol has shown potential for development as an anti-cancer agent against prostate cancer.
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    Cytotoxic and potent CYP1 inhibitors from the marine algae Cymopolia barbata
    (2012-06-11) Badal, Simone; Gallimore, Winklet; Huang, George; Tzeng, Tzuen-Rong J; Delgoda, Rupika
    Abstract Background Extracts from the marine algae Cymopolia barbata have previously shown promising pharmacological activity including antifungal, antitumor, antimicrobial, and antimutagenic properties. Even though extracts have demonstrated such bioactivity, isolated ingredients responsible for such bioactivity remain unspecified. In this study, we describe chemical characterization and evaluations of biological activity of prenylated bromohydroquinones (PBQ) isolated from the marine algae C. barbata for their cytotoxic and chemopreventive potential. Methods The impact of PBQs on the viability of cell lines (MCF-7, HT29, HepG, and CCD18 Co) was evaluated using the MTS assay. In addition, their inhibitory impact on the activities of heterologously expressed cytochrome P450 (CYP) enzymes (CYP1A1, CYP1A2, CYP1B1, CYP2C19, CYP2D6, and CYP3A4) was evaluated using a fluorescent assay. Results 7-Hydroxycymopochromanone (PBQ1) and 7-hydroxycymopolone (PBQ2) were isolated using liquid and column chromatography, identified using 1and#8201;H and 13and#8201;C NMR spectra and compared with the spectra of previously isolated PBQs. PBQ2 selectively impacted the viability of HT29, colon cancer cells with similar potency to the known chemotherapeutic drug, fluorouracil (IC50, 19.82and#8201;and#177;and#8201;0.46 and#956;M compared to 23.50and#8201;and#177;and#8201;1.12 and#956;M, respectively) with impact toward normal colon cells also being comparable (55.65and#8201;and#177;and#8201;3.28 compared to 55.51and#8201;and#177;and#8201;3.71 and#956;M, respectively), while PBQ1 had no impact on these cells. Both PBQs had potent inhibition against the activities of CYP1A1 and CYP1B1, the latter which is known to be a universal marker for cancer and a target for drug discovery. Inhibitors of CYP1 enzymes by virtue of the prevention of activation of carcinogens such as benzo-a-pyrene have drawn attention as potential chemopreventors. PBQ2 potently inhibited the activity of CYP1B1 (IC50 0.14and#8201;and#177;and#8201;0.04 and#956;M), while both PBQ1 and PBQ2 potently inhibited the activity of CYP1A1 (IC50s of 0.39and#8201;and#177;and#8201;0.05 and#956;M and 0.93and#8201;and#177;and#8201;0.26 and#956;M, respectively). Further characterizations showed partial noncompetitive enzyme kinetics for PBQ2 with CYP1B1 with a K i of 4.7 and#215; 10and#8211;3and#8201;and#177;and#8201;5.1 and#215; 10and#8211;4 and#956;M and uncompetitive kinetics with CYP1A1 (K i = 0.84and#8201;and#177;and#8201;0.07 and#956;M); while PBQ1 displayed partial non competitive enzyme kinetics with CYP1A1 (K i of 3.07and#8201;and#177;and#8201;0.69 and#956;M), noncompetitive kinetics with CYP1A2 (K i and#8201;=and#8201;9.16and#8201;and#177;and#8201;4.68 and#956;M) and uncompetitive kinetics with CYP1B1 (K i = 0.26and#8201;and#177;and#8201;0.03 and#956;M) . Conclusions We report for the first time, two isolated ingredients from C. barbata, PBQ1 and PBQ2, that show potential as valuable chemotherapeutic compounds. A hydroxyl moiety resident in PBQ2 appears to be critical for selectivity and potency against the cancer colon cells, HT29, in comparison to the three other malignant cell lines studied. PBQs also show potency against the activities of CYP1 enzyme which may be a lead in chemoprevention. This study, the first on isolates from these marine algae, exemplifies the value of searching within nature for unique structural motifs that can display multiple biological activities.