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ABSTRACT: Multidrug resistance (MDR) in cancer is a phenomenon in which administration of a single chemotherapeutic agent causes cross-resistance of cancer cells to a variety of therapies even with different mechanisms of action. Development of MDR against standard therapies is a major challenge in the treatment of cancer. Previously we have demonstrated a unique ability of CXL017 (5) to selectively target MDR cancer cells and synergize with mitoxantrone (MX) in HL60/MX2 MDR cells. Here we expand its scope and demonstrate that 5 can synergize with both vincristine and paclitaxel in three different MDR cell lines (HL60/DNR, K562/HHT300, and CCRF-CEM/VLB100). We also demonstrate that 5 has potent cytotoxicity in the NCI-60 panel of cell lines with an average IC(50) of 1.04 μM. In addition, 5 has a unique mechanism of action in comparison with standard agents in the NCI database based on COMPARE analysis. Further structure-activity relationship study led to the development of a more potent analogue, compound 7d, with an IC(50) of 640 nM in HL60/MX2. Additionally, one enantiomer of 5 is 13-fold more active than the less active enantiomer. Taken together, our study has led to the discovery of a series of analogues that selectively target drug-resistant cancer cells with the potential for the treatment of drug-resistant cancers.
Journal of Medicinal Chemistry 08/2011; 54(16):5937-48. · 4.80 Impact Factor
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ABSTRACT: This study presents a three-layer competition-based assay for ultrasensitive detection and quantification of endoglin from unprocessed human urine samples using a giant magnetoresistive (GMR) sensor and high-moment magnetic nanoparticle-based biosensing technology. This biosensing platform detects as few as 1000 copies of endoglin at concentrations as low as 83 fM with high detection specificity and has a three-order dynamic range. The results reveal that endoglin levels in urine have the potential to predict for the presence of prostate cancer and to distinguish between prostate cancers of different grades.
Analytical Chemistry 03/2011; 83(8):2996-3002. · 5.86 Impact Factor
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ABSTRACT: Many tumor tissues are under hypoxic conditions. Activating hypoxia-inducible factor 1 (HIF-1), a transcription factor, is a major mechanism for tumor cells to survive and even to evade other tissues. Therefore inhibiting HIF-1 is a potential strategy to help improve cancer treatment. Chalcone is a promising template to develop HIF-1 inhibitor because quite a few of chalcone-based compounds reveal moderate HIF-1 inhibitory activity and many chalcone-based compounds demonstrate promising anticancer activities in various animal models. However, there are no reports about the structure-activity relationship of chalcone compounds with respect to HIF-1 inhibition. This study reports the HIF-1 inhibitory activities of a panel of chalcones, identifies a few lead candidates of single-digit micromolar potency, and determines important structural modifications.
Bioorganic & medicinal chemistry letters 01/2011; 21(1):555-7. · 2.65 Impact Factor
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ABSTRACT: The apparent density, an intrinsic physical property of polymer beads, plays an important role in the application of beads in micro-total analysis systems and separation. Here we have developed a new, facile and milligram-scale method to describe the motion of beads in aqueous solution and further detect the apparent density of beads. The motion of beads in solutions is determined by the viscosity of solutions and the density difference between beads and solutions. In this study, using various glycerol aqueous solutions with certain viscosities and densities, the motion time (i.e. floating or sedimentation time) of hybrid polymer beads was experimentally measured and theoretically deduced, and consequently, the apparent density of monodisperse beads can be quickly and easily calculated. The results indicated that the present method provided a more precise way to predict the movement of hybrid beads in aqueous solution compared with the approach for commercial use. This new method can be potentially employed in flow cytometry, suspension stability, and particle analysis systems.
Talanta 03/2010; 80(5):1681-5. · 3.79 Impact Factor
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ABSTRACT: A novel giant magnetoresistive sensor and uniform high-magnetic-moment FeCo nanoparticles (12.8 nm)-based detecting platform with minimized detecting distance was developed for rapid biomolecule quantification from body fluids. Such a system demonstrates specific, accurate, and quick detection and quantification of interleukin-6, a low-abundance protein and a potential cancer biomarker, directly in 4 muL of unprocessed human sera. This platform is expected to facilitate the identification and validation of disease biomarkers. It may eventually lead to a low-cost personal medical device for chronic disease early detection, diagnosis, and prognosis.
Journal of the American Chemical Society 03/2010; 132(12):4388-92. · 9.91 Impact Factor
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ABSTRACT: Chalcone is a privileged structure, demonstrating promising anti-inflammatory and anticancer activities. One potential mechanism is to suppress nuclear factor kappa B (NF-kappaB) activation. The structures of chalcone-based NF-kappaB inhibitors vary significantly that there is minimum information about their structure-activity relationships (SAR). This study aims to establish SAR of chalcone-based compounds to NF-kappaB inhibition, to explore the feasibility of developing simple chalcone-based potent NF-kappaB inhibitors, and to evaluate their anticancer activities. Three series of chalcones were synthesized in one to three steps with the key step being aldol condensation. These candidates demonstrated a wide range of NF-kappaB inhibitory activities, some of low micromolar potency, establishing that structural complexity is not required for NF-kappaB inhibition. Lead compounds also demonstrate potent cytotoxicity against lung cancer cells. Their cytotoxicities correlate moderately well with their NF-kappaB inhibitory activities, suggesting that suppressing NF-kappaB activation is likely responsible for at least some of the cytotoxicities. One lead compound effectively inhibits lung tumor growth with no signs of adverse side effects.
Journal of Medicinal Chemistry 11/2009; 52(22):7228-35. · 4.80 Impact Factor
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ABSTRACT: Rapid development of multiple drug resistance against current therapies is a major barrier in the treatment of cancer. Therefore, anticancer agents that can overcome acquired drug resistance in cancer cells are of great importance. Previously, we have demonstrated that ethyl 2-amino-4-(2-ethoxy-2-oxoethyl)-6-phenyl-4H-chromene-3-carboxylate (5a, sHA 14-1), a stable analogue of ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (6, HA 14-1), mitigates drug resistance and synergizes with a variety of cancer therapies in leukemia cells. Structure-activity relationship (SAR) studies of 5a guided the development of ethyl 2-amino-6-(3',5'-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (5q, CXL017), a compound with low micromolar cytotoxicity against a wide-range of hematologic and solid tumor cells. More excitingly, our studies of 5q in camptothecin (CCRF-CEM/C2) and mitoxantrone (HL-60/MX2) resistant cancer cells highlight its ability to selectively kill drug-resistant cells over parent cancer cells. 5q inhibits tumor cell growth through the induction of apoptosis, with detailed mechanism of its selectivity toward drug-resistant cancer cells under investigation. These results suggest that 5q is a promising candidate for treatment of cancers with multiple drug resistance.
Journal of Medicinal Chemistry 10/2009; 52(19):5937-49. · 4.80 Impact Factor
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David Hermanson,
Sadiya N Addo,
Anna A Bajer,
Jonathan S Marchant,
Sonia Goutam Kumar Das, Balasubramanian Srinivasan,
Fawaz Al-Mousa,
Francesco Michelangeli,
David D Thomas,
Tucker W Lebien,
Chengguo Xing
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ABSTRACT: HA 14-1 is a small-molecule Bcl-2 antagonist that promotes apoptosis in malignant cells, but its mechanism of action is not well defined. We recently reported that HA 14-1 has a half-life of only 15 min in vitro, which led us to develop a stable analog of HA 14-1 (sHA 14-1). The current study characterizes its mode of action. Because of the antiapoptotic function of Bcl-2 family proteins on the endoplasmic reticulum (ER) and mitochondria, the effect of sHA 14-1 on both organelles was evaluated. sHA 14-1 induced ER calcium release in human leukemic cells within 1 min, followed by induction of the ER stress-inducible transcription factor ATF4. Similar kinetics and stronger intensity of ER calcium release were induced by the sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor thapsigargin, accompanied by similar kinetics and intensity of ATF4 induction. sHA 14-1 directly inhibited SERCA enzymatic activity but had no effect on the inositol triphosphate receptor. Evaluation of the mitochondrial pathway showed that sHA 14-1 triggered a loss of mitochondrial transmembrane potential (Delta psi m) and weak caspase-9 activation, whereas thapsigargin had no effect. (R)-4-(3-Dimethylamino-1-phenylsulfanylmethyl-propylamino)-N-{4-[4-(4'-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzoyl}-3-nitrobenzenesulfonamide (ABT-737), a well established small-molecule Bcl-2 antagonist, rapidly induced loss of Delta psi m and caspase-9 activation but had no effect on the ER. The pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone had some protective effect on sHA 14-1-induced cell death. These collective results suggest a unique dual targeting mechanism of sHA 14-1 on the apoptotic resistance machinery of tumor cells that includes antiapoptotic Bcl-2 family proteins and SERCA proteins.
Molecular pharmacology 07/2009; 76(3):667-78. · 4.53 Impact Factor
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ABSTRACT: Zeptomole detector: A highly sensitive giant-magnetoresistive chip and FeCo nanoparticles can be used to linearly detect 600-4500 copies of streptavidin. Under unoptimized conditions, this system also detects human IL-6 with a sensitivity 13-times higher than that of standard ELISA techniques.
Angewandte Chemie International Edition 02/2009; 48(15):2764-7. · 13.45 Impact Factor
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ABSTRACT: In this paper, we present a ultra high sensitive (Zeptomole, 10(-21)) technique to enable the detection of any potential low abundance biomarkers. We demonstrated for the first time the detection of sub 13nm high-moment magnetic nanoparticle and the implementation of a novel magnetoresistive (GMR) biosensor concept with higher sensitivity and 10 times lower external field in real biomarker sensing schemes. A potential lung cancer biomarker, interleukin-6 (IL-6), was successfully detected with extremely low concentration (as few as only 200 pieces of IL-6). Together with other features of GMR sensor systems like low-cost, portability, easy-to-use, our demonstrated device may lead to future family-based personalized medicine for cancer prevention.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 01/2009; 2009:5432-5.
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ABSTRACT: Synthesis of N-glycans is of high current interests due to their important biological properties. A highly efficient convergent strategy based on the pre-activation method for assembly of the complex type core fucosylated bi-antennary N-glycan dodecasaccharide has been developed. Retrosynthetically, this extremely challenging target is broken down to three modules: a sialyl disaccharide, a glucosamine building block and a hexasaccharide diol acceptor. The sialyl disaccharide was easily obtained by selective activation of a new 5-N-trichloroacetyl protected sialyl donor in the presence of a thiogalactoside acceptor. The hexasaccharide diol module was produced by double mannosylation of a fucosylated tetrasaccharide acceptor, which in turn was generated by glycosylation of a alpha-fucosylated disaccharide with a beta-mannose containing disaccharide donor. The union of the three modules was performed in one-pot giving the fully protected dodecasaccharide in high yield. This synthesis is characterized by minimum protective group and aglycon adjustment on oligosaccharide intermediates, thus greatly enhancing the overall synthetic efficiency. The modular feature of this strategy suggests that this method can be readily adapted to the synthesis of a wide variety of N-glycan structures.
Chemistry 08/2008; 14(23):7072-81. · 5.93 Impact Factor
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ABSTRACT: A general method is introduced to immobilize organic molecules on magnetic nanoparticles through silanization reactions and determine the maximum loading level by UV-vis spectroscopy. Loading levels of 1.5 x 10(-3) mol per gram of nanoparticle were obtained with structurally diverse compounds such as rhodamine B and glucosamine. The length of the linker did not have a significant effect on loading as comparable maximum amounts of rhodamine B were immobilized on magnetic nanoparticles regardless of the linker length. Interestingly, rhodamine B derivatives lost conjugation during synthetic manipulations due to reversible spiroisobenzofuran formation. Full regeneration of conjugation was found to be slow with rhodamine B attached on magnetic nanoparticles. The results obtained from these studies will be useful for studying surface functionalization of MNPs in general.
Chirality 04/2008; 20(3-4):265-77. · 2.35 Impact Factor
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ABSTRACT: Early recognition and prevention of chronic disease, such as lung cancer, require a fast, accurate detection and longitudinal monitoring on potential biomarkers, which could identify the molecule change in the initial stage of the chronic disease. Here we report the realization of specific and accurate quantification of a low-abundance serum protein in unprocessed human sera, using our novel giant magnetoresistive (GMR) biosensing system with uniform high-magnetic-moment nanoparticles and a competition based detection scheme. Only one antibody is needed for such detection scheme. The quantification of interleukin-6 (IL-6, a low-abundance protein and a potential cancer biomarker), as low as 125 fM IL-6 proteins, directly in 4 muL of unprocessed human sera was demonstrated within 5 minutes by such system. The results nicely differentiate normal individuals and lung cancer patients. This platform has great potential to facilitate the identification and validation of disease biomarkers.
