The Effect of Different Ester Chain Modifications of Two Guaianolides for Inhibition of Colorectal Cancer Cell Growth.

Several sesquiterpene lactones (STLs) have been tested as lead drugs in cancer clinical trials. Salograviolide-A (Sal-A) and salograviolide-B (Sal-B) are two STLs that have been isolated from Centaurea ainetensis, an indigenous medicinal plant of the Middle Eastern region. The parent compounds Sal-A and Sal-B were modified and successfully prepared into eight novel guaianolide-type STLs (compounds 1-8) bearing ester groups of different geometries. Sal-A, Sal-B, and compounds 1-8 were tested against a human colorectal cancer cell line model with differing p53 status; HCT116 with wild-type p53 and HCT116 p53-/- null for p53, and the normal-like human colon mucosa cells with wild-type p53, NCM460. IC50 values indicated that derivatization of Sal-A and Sal-B resulted in potentiation of HCT116 cell growth inhibition by 97% and 66%, respectively. The effects of the different molecules on cancer cell growth were independent of p53 status. Interestingly, the derivatization of Sal-A and Sal-B molecules enhanced their anti-growth properties versus 5-Fluorouracil (5-FU), which is the drug of choice in colorectal cancer. Structure-activity analysis revealed that the enhanced molecule potencies were mainly attributed to the position and number of the hydroxy groups, the lipophilicity, and the superiority of ester groups over hydroxy substituents in terms of their branching and chain lengths. The favorable cytotoxicity and selectivity of the potent molecules, to cancer cells versus their normal counterparts, pointed them out as promising leads for anti-cancer drug design.

The association of urinary metabolites of polycyclic aromatic hydrocarbons with obstructive coronary artery disease: A red alert for action.

In Lebanon, previous studies have indicated an onset of cardiovascular diseases 12 years earlier than in other parts of the world, suggesting the presence of additional risk factors specific to Lebanon. Measurements of airborne particles in Lebanon surpass the recommendations of the World Health Organization by over 150%. This study examined the association between obstructive coronary artery disease (CAD), assessed by a novel marker calculated from coronary catheterization, and markers of air pollution, specifically polycyclic aromatic hydrocarbons (PAHs), in a cohort of 258 patients seen at the American University of Beirut Medical Center since 2014. The concentrations of four types of hydroxylated polycyclic aromatic hydrocarbons (OHPAHs), 2-OHNAP, 2-OHFLU, 3-OHPHE, and 1-OHPYR, were measured in the urine samples of these patients using high performance liquid chromatography coupled with fluorescence detector. Results showed that the OHPAH concentrations were higher than what was reported in high-income countries and, most notably, the levels for non-smokers in this study were higher than those of smokers and some occupational workers in other countries. This implies that patients were exposed to high levels of PAHs, which originate from combustion sources. In particular, 1-OHPYR showed a significant association with presence of obstructive CAD, even after adjusting for covariates like age, sex, and diabetes. Smokers or not, this association has implications for public health and calls for urgent need to pass regulations to reduce the emissions of PAH sources, such as cars, diesel generators, and incinerators.

Anti-proliferative and anti-inflammatory activities of the sea cucumber Holothuria polii aqueous extract.

OBJECTIVE: Sea cucumbers are considered among the most important functional foods. Following bioassay guided fractionation, we assessed the anti-proliferative and anti-inflammatory activities of Holothuria polii (H. polii) extracts. METHODS: Sea cucumber ethanolic extract and the partially purified aqueous fractions were assessed for their anti-proliferative activities. These latter bioactivities were evaluated in the highly invasive MDA-MB-231 human breast cancer cells in two-dimensional and three-dimensional cultures using trypan blue exclusion assay. The tumor-suppressive effects of sea cucumber ethanolic extract and aqueous fractions were assayed by measuring the trans-well invasion of MDA-MB-231 cells and the expression of some epithelial mesenchymal transition markers using quantitative reverse-transcription polymerase chain reaction and western blot analysis. The anti-inflammatory activity of the aqueous fraction was tested by measuring the secreted levels of interleukin-6, nitric oxide, and matrix metalloproteinase 9 in endotoxin-induced mammary epithelial SCp2 cells and interleukin-1ß in phorbol-12-myristate-13-acetate-activated human monocytic THP-1 cells. RESULTS: Sea cucumber ethanolic extract and the aqueous fraction significantly decreased the proliferation of MDA-MB-231 cells by more than 50% at similar and noncytotoxic concentrations and caused an arrest in the S-phase of the cell cycle of treated cells. In contrast, petroleum ether, chloroform, ethyl acetate, and n-butanol organic fractions did not show any significant activity. Furthermore, sea cucumber ethanolic extract and aqueous fraction reduced the proliferation of MDA-MB-231 cells in three-dimensional cultures by more than 60% at noncytotoxic concentrations. In addition, treatment with these concentrations resulted in the loss of stellate outgrowths in favor of spherical aggregates and a 30% decrease in invasive properties. Both sea cucumber ethanolic extract and aqueous decreased the transcription of vimentin and the protein expression levels of vimentin and N-cadherin in three-dimensional cultures. The aqueous fraction decreased the levels of inflammatory markers interleukin-6, nitric oxide, and matrix metalloproteinase 9 in the mouse mammary SCp2 cells, and the level of interleukin-1ß produced by phorbol-12-myristate-13-acetate-activated THP-1 human monocytic cells. CONCLUSION: The data reveal for the first time promising anti-proliferative and anti-inflammatory activities in H. polii water extract in two-dimensional and three-dimensional culture models.

Anti-Inflammatory and Cytostatic Activities of a Parthenolide-Like Sesquiterpene Lactone from Cota palaestina subsp. syriaca.

A sesquiterpene lactone 1-ß,10-Epoxy-6-hydroxy-1,10H-inunolide (K100) was isolated through "bioassay-guided fractionation" from Cota palaestina subsp. syriaca, an Eastern Mediterranean endemic plant. K100 inhibited endotoxin- (ET-) induced proinflammatory markers: IL-6, MMP-9, and NO in normal mouse mammary SCp2 Cells. Molecular docking in silico suggested that K100, having highly analogous structure as parthenolide (PTL), an anticancer compound, could bind PTL target proteins at similar positions and with comparable binding affinities. Both compounds, K100 and PTL, inhibited the proliferation and prolonged the S-phase of the cell cycle of breast adenocarcinoma MDA-MB-231 cells grown in 2D cultures. Noncytotoxic concentrations of K100 and PTL decreased the proliferation rate of MDA-MB-231 and shifted their morphology from stellate to spherical colonies in 3D cultures. This was accompanied with a significant increase in the amount of small colonies and a decrease in the amount of large colonies. Moreover, K100 and PTL decreased cellular motility and invasiveness of MDA-MB-231 cells. In summary, these results suggest that K100 exhibits PTL-analogous anti-inflammatory, cytostatic, and antimetastatic effects.

Differential growth inhibitory effects of highly oxygenated guaianolides isolated from the Middle Eastern indigenous plant Achillea falcata in HCT-116 colorectal cancer cells.

Medicinal plants play a crucial role in traditional medicine and in the maintenance of human health worldwide. Sesquiterpene lactones represent an interesting group of plant-derived compounds that are currently being tested as lead drugs in cancer clinical trials. Achillea falcata is a medicinal plant indigenous to the Middle Eastern region and belongs to the Asteraceae family, which is known to be rich in sesquiterpene lactones. We subjected Achillea falcata extracts to bioassay-guided fractionation against the growth of HCT-116 colorectal cancer cells and identified four secotanapartholides, namely 3-ß-methoxy-isosecotanapartholide (1), isosecotanapartholide (2), tanaphallin (3), and 8-hydroxy-3-methoxyisosecotanapartholide (4). Three highly oxygenated guaianolides were isolated for the first time from Achillea falcata, namely rupin A (5), chrysartemin B (6), and 1ß, 2ß-epoxy-3ß,4α,10α-trihydroxyguaian-6α,12-olide (7). These sesquiterpene lactones showed no or minor cytotoxicity while exhibiting promising anticancer effects against HCT-116 cells. Further structure-activity relationship studies related the bioactivity of the tested compounds to their skeleton, their lipophilicity, and to the type of functional groups neighboring the main alkylating center of the molecule.