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ABSTRACT: The differentiation of stem-like tumor cells may contribute to the cellular heterogeneity of breast cancers. We report the propagation of highly enriched mouse mammary cancer stem cells that retain the potential to differentiate both in vivo and in culture and their use to identify chemical compounds that influence both self-renewal and differentiation. We identify epithelial tumor initiating cells (ETICs) that express lineage markers of both basal and luminal mammary cell lineages and retain the potential, from even single cells, to generate heterogeneous tumors similar to the tumor of origin. ETICs can progress through a Rho associated coiled-coil containing protein kinase 1 (ROCK1) dependent, epithelial to mesenchymal transition to generate mesenchymal tumor initiating cells (MTICs) capable of initiating tumors of limited heterogeneity. The propagation of ETICs may allow for the identification of new therapeutic compounds that may inhibit or prevent progression of some types of breast cancer.
Stem Cells 09/2012; · 7.78 Impact Factor
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ABSTRACT: The parent phenol of adapalene and its (E)-cinnamic acid analogue were found to induce cancer cell apoptosis but cause adverse systemic effects when administered to mice. In contrast, their respective 5-Cl- and 3-Cl-substituted analogues had their adverse effects mitigated without a comparable loss of cancer cell inhibitory activity. As a result, pharmacologic space in this region of the cinnamic phenyl ring scaffold was explored. Various substituents were introduced, and their effects on cancer cell proliferation and viability were evaluated. Cinnamic acids having 3-Br, CN, NO(2), NH(2), OMe, and N(3) groups had activity comparable to that of 4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid. A comparative molecular field analysis study indicated that introduction of an H-bond acceptor at position 3 of the central phenyl ring would favor inhibition of leukemia cell viability, and docking suggested its hydrogen bonding with a polar group in a small heterodimer partner homology model. The 3-CN, NO(2), NH(2), and OH analogues also inhibited MMTV-Wnt1 murine mammary stem cell viability.
Journal of Medicinal Chemistry 12/2011; 55(1):233-49. · 4.80 Impact Factor
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ABSTRACT: (E)-4-[3'-(1-Adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces the cell cycle arrest and apoptosis of cancer cells. Because its pharmacologic properties-solubility, bioavailability, and toxicity-required improvement for translation, structural modifications were made by introducing nitrogen atoms into the cinnamyl ring and replacing its E-double bond with XCH(2) (X = O, N, and S) with the objective of enhancing these properties without impacting apoptosis-inducing activity. Analogues having nitrogen atoms in heterocyclic rings corresponding to the cinnamyl phenyl ring displayed equal or higher biological activities. The pyrimidine and pyridine analogues were more soluble in both phosphate-buffered saline and water. While the 2,5-disubstituted pyridine analogue was the most potent inducer of KG-1 acute myeloid leukemia cell apoptosis, on the basis of apoptotic activity in KG-1 cells and solubility, the 2,5-disubstituted pyrimidine proved to be the more promising candidate for treatment of acute myeloid leukemia.
Journal of Medicinal Chemistry 06/2011; 54(11):3793-816. · 4.80 Impact Factor
