The small GTPase Rap1 is highly expressed in human neutrophils, but its function is largely unknown. Using the Rap1-binding domain of RalGDS (RalGDS-RBD) as an activation-specific probe for Rap1, we have investigated the regulation of Rap1 activity in primary human neutrophils. We found that a variety of stimuli involved in neutrophil activation, including fMet-Leu-Phe (fMLP), platelet-activating factor (PAF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IgG-coated particles, induce a rapid and transient Rap1 activation. In addition, we found that Rap1 is normally activated in neutrophils from chronic granulomatous disease patients that lack cytochrome b558 or p47phox and have a defective NADPH oxidase system. From these results we conclude that in neutrophils Rap1 is activated independently of respiratory burst induction. Finally, we found that Rap1 is activated by both the Ca2+ ionophore ionomycin and the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), indicating that phospholipase C (PLC) activation leading to elevated levels of intracellular free Ca2+ and diacylglycerol (DAG) can mediate Rap1 activation. However, inhibition of PLC and Ca2+ depletion only marginally affected fMLP-induced Rap1 activation, suggesting that additional pathways may control Rap1 activation.

Activation of the small GTPase Rap1 in human neutrophils

Restoration of p53 pathway by nutlin-3 induces cell cycle arrest and apoptosis in human rhabdomyosarcoma cells

Enhancement of sensitivity to tumor necrosis factor α in non-small cell lung cancer cells with acquired resistance to gefitinib

/pdf/cell-cycle-synchronization-reverses-taxol-resistance-of-3ik4i80ov2.pdf

Cell-cycle synchronization reverses Taxol resistance of human ovarian cancer cell lines

Examining the Role of the Deubiquitylating Enzyme, USP9X, in Squamous Cell Carcinoma

β-2-himachalen-6-ol (HC) is a major sesquiterpene that was isolated from the
Lebanese Daucus carota ssp. carota and was shown to possess potent anticancer activity
against various cancer cell lines. The aim of the present study was to explore the in vitro
and in vivo anticancer activities of HC and to investigate the possible mechanisms of
action involved.
Lebanese Daucus carota spp. carota plant oil was extracted from dried mature
umbels with methanol/acetone (1/1) and HC was purified using silica gel column
chromatography to 92% purity as confirmed by GC-MS and NMR.
The in vitro effect of HC on cell viability was tested against a panel of colon
cancer cell lines (Caco-2, HT-29, SK-Co, LoVo, SW-1116 and T-84), a normal colon cell
line CCD-33Co, the HaCaT-ras II-4 epidermal squamous carcinoma and the 4T1 breast
cancer cell lines. HC displayed potent cytotoxic activity as measured by the WST-1 cell
proliferation assay against all cancer cell lines with an IC50 ranging between 8-14.5μg/ml
and an IC90 between 19-36μg/ml. No significant cytotoxic effect was observed on the
normal colon cell line at the concentrations used.
Upon treatment with HC, flow cytometry and western blot analyses showed
similar results for both the SW1116 and HaCaT-ras II-4 cell lines, with an observed
accumulation of cells in the sub-G1 apoptotic phase and decreased cell population in S
and G2/M phases indicating cell cycle arrest at sub-G1phase. A decrease in the p-Erk, p-
Akt, anti-apoptotic protein (Bcl-2) and an increase in pro-apoptotic proteins (p53, Bax,
p21, cleaved Caspase-3 and PARP) was also observed.
The in vivo anticancer effect of HC was investigated using DMH-induced colon,
DMBA/TPA-induced skin carcinogenesis and 4T1 breast metastatic murine models of
cancer. HC proved to be effective in reducing cancer incidence and size in all the
experiments with a relatively low hepato-toxicity.
The present study established that HC is a potent and relatively safe anticancer
compound that induces apoptosis through the inhibition of the MAPK/Erk and PI3K/ Akt
pathways.

The in vitro and in vivo anticancer effect of β-2-himachalen-6-ol isolated from the Lebanese Daucus carota spp. carota.

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Hamid E. Daaboul

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The in vitro and in vivo anticancer effect of β-2-himachalen-6-ol isolated from the Lebanese Daucus carota spp. carota.