A series of N-heterocyclic indolyl glyoxylamides were synthesized and evaluated for in vitro and in vivo anticancer activities. They exhibited a broad spectrum of anticancer activity not only in murine leukemic cancer cells but also in human gastric, breast, and uterus cancer cells as well as their multidrug resistant sublines with a wide range of IC(50) values. They also induced apoptosis and caused DNA fragmentation in human gastric cancer cells. Among the compounds studied, 7 showed the most potent activity of growth inhibition (IC(50) = 17-1711 nM) in several human cancer cells. Given orally, compounds 7 and 13 dose-dependently prolonged the survival of animals inoculated with P388 leukemic cancer cells. N-Heterocyclic indolyl glyoxylamides may be useful as orally active chemotherapeutic agents against cancer and refractory cancerous diseases of multidrug resistance phenotype.

The cyclic calcium release and uptake during calcium oscillation are thought to result from calcium-induced calcium release (CICR); however, it is unclear, especially in nonexcitable cells, how the initial calcium mobilization that triggers CICR occurs. We report here a novel mechanism, other than conventional calcium channels or the phopholipase C-inositol trisphosphate system, for initiating calcium oscillation downstream of integrin signaling. Upon integrin ␣ IIb ␤ 3 binding to fibrinogen ligand or the disintegrin rhodostomin, sodium-proton exchanger NHE1 and sodiumcalcium exchanger NCX1 are actively transported to the plasma membrane, and they become physically coupled to integrin ␣ IIb ␤ 3 . Lipid raft-dependent mechanisms modulate the membrane targeting and formation of the NHE1-integrin ␣ IIb ␤ 3 -NCX1 protein complex. NHE1 and NCX1 within such protein complex are functionally coupled, such that a local increase of sodium concentration caused by NHE1 can drive NCX1 to generate sodium efflux in exchange for calcium influx. The resulting calcium increase inside the cell can then trigger CICR as a prelude to calcium oscillation downstream of integrin ␣ IIb ␤ 3 signaling. Fluorescence resonance energy transfer based on fluorescence lifetime measurements is employed here to monitor the intermolecular interactions among NHE1-integrin ␣ IIb ␤ 3 -NCX1, which could not be properly detected using conventional biochemical assays.In many excitable or nonexcitable cells, the concentration of free intracellular calcium oscillates with a period ranging from a few seconds to a few minutes. Such calcium oscillations are involved in a wide variety of cellular functions (1, 2). It is generally believed that, except for minor variations, the cyclic increase and decrease of calcium results from an autocatalytic release of calcium in a process called calcium-induced calcium release (CICR), 2 followed by a slow negative feedback that terminates calcium release. The cytoplasmic free calcium is then taken up into the organelles to reset the cycle. Despite a general agreement on how calcium oscillation proceeds once the system has been turned on, various different mechanisms have been proposed to explain how the initial calcium mobilization is generated that triggers CICR.As a general rule, calcium entry through voltage-gated channels in electrically excitable cells (3) or through agonist-receptor interactions in nonexcitable cells, such as epithelial cells, hepatocytes, or oocytes (4), is thought to initiate the CICR process (1, 2). Typically, in nonexcitable cells, the binding of an agonist, such as a hormone, a growth factor, or an extracellular matrix, to the corresponding cell surface receptor initiates a series of reactions that end in the activation of phopholipase C (PLC) and the production of the secondary messenger inositol trisphosphate (IP 3 ) (1, 2, 4). IP 3 is thought to induce calcium release from the internal endoplasmic reticulum or mitochondria store, and governs the CICR mechanisms that modulate calcium oscillat...

2-Amino-1-arylidenaminoimidazoles, a novel class of orally (po) active microtubule-destabilizing anticancer agents, were synthesized. The compounds were designed from a hit compound identified in a drug discovery platform by using cancer cell-based high throughput screening assay. Selective synthesized compounds exerted cell cytotoxicity against human cancer cells. The underlying mechanisms for the anticancer activity were demonstrated as interacting with the tubulins and inhibiting microtubule assembly, leading to proliferation inhibition and apoptosis induction in the human tumor cells. Furthermore, two compounds showed in vivo anticancer activities in both po and intravenously (iv) administered routes and prolonged the life spans of murine leukemic P388 cells-inoculated mice. These new po active antimitotic anticancer agents are to be further examined in preclinical studies and developed for clinical uses.

Membrane fusions that occur during vesicle transport, virus infection, and tissue development, involve receptors that mediate membrane contact and initiate fusion and effectors that execute membrane reorganization and fusion pore formation. Some of these fusogenic receptors/effectors are preferentially recruited to lipid raft membrane microdomains. Therefore, major constituents of lipid rafts, such as stomatin, may be involved in the regulation of cell-cell fusion. Stomatin produced in cells can be released to the extracellular environment, either through protein refolding to pass across lipid bilayer or through exosome trafficking. We report that cells expressing more stomatin or exposed to exogenous stomatin are more prone to undergoing cell fusion. During osteoclastogenesis, depletion of stomatin inhibited cell fusion but had little effect on tartrate-resistant acid phosphatase production. Moreover, in stomatin transgenic mice, increased cell fusion leading to enhanced bone resorption and subsequent osteoporosis were observed. With its unique molecular topology, stomatin forms molecular assembly within lipid rafts or on the appositional plasma membranes, and promotes membrane fusion by modulating fusogenic protein engagement.-Lee, J.-H., Hsieh, C.-F., Liu, H.-W., Chen, C.-Y., Wu, S.-C., Chen, T.-W., Hsu, C.-S., Liao, Y.-H., Yang, C.-Y., Shyu, J.-F., Fischer, W. B., Lin, C.-H. Lipid raft-associated stomatin enhances cell fusion.

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