Strategic targeting of curcumin to eliminate brain tumors
Item
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Title
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Strategic targeting of curcumin to eliminate brain tumors
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Identifier
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d_2009_2013:8396ceba7f26:10820
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identifier
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11074
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Creator
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Langone, Phyllis J.,
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Contributor
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Probal Banerjee
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Date
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2011
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biochemistry | Cellular biology | Oncology | Medicine | B16F10 | cancer | curcumin | GL261 | glioblastoma | melanoma
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Abstract
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Glioblastoma, the most common form of primary brain cancer, is highly aggressive and associated with very poor prognosis. Curcumin (or diferuloylmethane), a natural molecule, which is not toxic to normal tissue, has been shown to inhibit proliferation, induce apoptosis and inhibit angiogenesis and metastasis in a wide range of cancer cells. However, the effective delivery of curcumin to cancers presents a problem because curcumin is poorly soluble in water and metabolizes quickly. Our preliminary work has established that solubilized curcumin can cross the blood-brain barrier and is harmless to normal brain cells, that solubilized curcumin blocks brain tumor formation when introduced by injection into the blood or directly into the brain, and that it markedly decreases cell viability in several cell lines, including murine melanoma B16F10 and murine glioblastoma GL261. Targeted drug delivery is frequently used to deliver drugs selectively and at high concentrations to cancer tissue. Antibody-mediated targeting, in addition to delivering drugs selectively, serves to increase the water solubility of attached drugs. We postulated that antibody-mediated targeting would be an effective means of eliminating brain tumors. Nonetheless, a number of structural features had to be carefully considered. Curcumin has several functional groups, which potentially can be used to target the molecule to cancer cells; however, curcumin's functional groups have been shown to be critical for its anticancer activity. With this in mind, after weighing different options, we synthetically modified curcumin at its phenolic hydroxyl position to enable the formation of a cleavable antibody attachment. Intracellular hydrolysis of an ester bond returns curcumin to its original state after its delivery into target cells. Murine infiltrating melanoma (B16F10) and primary glioblastoma (GL261) brain tumor models were utilized. We created two adducts, curcumin-MUC18 for targeting to B16F10 cells and curcumin-CD68 for targeting to GL261 cells. Our studies show that both adducts are highly effective at eliminating B16F10 and GL261 cancer cells in vitro, and that these adducts destroy cancer cells at far lower concentrations than does free curcumin. Our molecular analyses show that, in GL261 cells, curcumin causes a dramatic increase in caspase 3/7 activity and suppression of tumor-promoting proteins NF-kappaB, Akt1, VEGF, cyclin D1, and BclXL. We show in GL261 cells that overexpressed NF-kappaB is protective against curcumin treatment. Lastly, we show that animals implanted with B16F10 or GL261 cells receiving targeted curcumin treatment live longer and have significantly reduced tumor size.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biochemistry
