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Heck products of parthenolide and melampomagnolide-B as anticancer modulators that modify cell cycle progression.

ABSTRACT: (E)-13-(Aryl/heteroaryl)parthenolides (5a-i and 6a-i) were synthesized and evaluated for their ability to modify cell cycle progression during progesterone-stimulated Xenopus oocyte maturation and screened for their anticancer activity against a panel of 60 human cancer cell lines. (E)-13-(4-aminophenyl) parthenolide (5b) caused a significant inhibition of progesterone-stimulated oocyte maturation, and was determined to function downstream of MAP kinase signaling, but upstream of the activation of the universal G2/M regulator, M-phase promoting factor (MPF), cyclin B/Cyclin-dependent kinase (CDK). The compound (E)-13-(2-bromo-phenyl)parthenolide (5c) activates oocyte maturation independently of progesterone stimulation. Compounds 5b and 5c displayed modest growth inhibition on select cancer cell lines at 10 ?M dose when tested on the panel of 60 cancer cell lines. By contrast, compounds (5f and 7) did not modulate oocyte maturation but did exhibit micromolar level growth inhibition against most of the human cancer cell lines over a range of doses. Together, our findings indicate that screening of compounds in the oocyte maturation assay may identify additional effective cell cycle regulatory compounds that do not necessarily exert overt cytotoxicity as assessed in traditional drug screening assays.

SUBMITTER: Penthala NR

PROVIDER: S-EPMC4167622 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Heck products of parthenolide and melampomagnolide-B as anticancer modulators that modify cell cycle progression.

Penthala Narsimha R NR Bommagani Shobanbabu S Janganati Venumadhav V MacNicol Kenzie B KB Cragle Chad E CE Madadi Nikhil R NR Hardy Linda L LL MacNicol Angus M AM Crooks Peter A PA

European journal of medicinal chemistry 20140807

(E)-13-(Aryl/heteroaryl)parthenolides (5a-i and 6a-i) were synthesized and evaluated for their ability to modify cell cycle progression during progesterone-stimulated Xenopus oocyte maturation and screened for their anticancer activity against a panel of 60 human cancer cell lines. (E)-13-(4-aminophenyl) parthenolide (5b) caused a significant inhibition of progesterone-stimulated oocyte maturation, and was determined to function downstream of MAP kinase signaling, but upstream of the activation ...[more]

PMID: 25117652

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Project description:The centre of the attraction of this article is inevitably associated with fucoidan polymers in terms of brown seaweed such as Turbinaria conoides. Fucoidan is a sulphated polysaccharide constitutes fucose as a major principle sugar along with other monosugars such as glucuronic acid, xylose and galactose. The core value of fucoidan in terms of various cancer types were substantially exhibited through targeting the key apoptotic molecules and subsequently mitigate the toxicity that are essentially included in the chemotherapeutic agents and radiation. The pragmatic investigation about the anti-cancer effect of fucoidan in a hepatoblastoma-derived (HepG2) cell line was thoroughly analyzed by the typical techniques such as cell viability, colony formation, cell migration, cell cycle progression, genetic damage and apoptosis along with their nuclear morphology and mitochondrial membrane potential. Following the analyzes, the cell viability was precisely evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. And hence, cell cycle arrest and apoptosis was appropriately examined staining with propidium iodide (PI) and annexin V-fluorescein isothiocyante (FITC) by flowcytometer, respectively. Primarily, genetic damage by fucoidan in HepG2 cell line was evaluated by following Trevigen's comet assay kit. In addition, alteration of nuclear content and mitochondrial membrane potential were also detected with Hoechst and mitochondrial membrane potential dye (JC-1: 5,5'6,6'-tetrachloro-1,1'3,3'tetraethylbenzimi-dazolycarbocyanine iodide) by fluorescence microscopy, respectively. The results of the present study showed that cells constituted with fucoidan/quercetin standard at 50, 100 and 200 μg/ml exhibited cell viability about 71, 60 & 40/80, 65 & 45%, respectively. The above recorded effect of fucoidan was a concentration-dependant inhibition on the basis of decline in colony forming and cell migration potential of HepG2 cancer cells. Compared with untreated control, fucoidan consituted cells were significantly (p ≤  0.05) accumulated proliferative cells in the G0/G1 phase of the cell cycle in a concentration dependent manner. Increasing concentration of fucoidan (50,100 and 200 μg/ml) was remarkably enhanced the DNA damage which reflected through tail moment value of 3.8, 7.1 & 12.8 folds with respect to the untreated control. Fucoidan induced total apoptotic cells were observed ∼20-40% at 50-200 μg/ml concentrations. The apoptotic cell formation effected by change in the nuclear content and mitochondrial membrane potential was confirmed in HepG2 cancer cells under fluorescence microscopy. It was eventually concluded that the fucoidan display promising anti-cancer activity against HepG2 cancer cells by promoting the inhibition of cell proliferation, migration and cell arrest on concentration dependent-manner that was well correlated with genetic damage and apoptosis.

Project description:BackgroundThe cell cycle is at the center of cellular activities and is orchestrated by complex regulatory mechanisms, among which transcriptional regulation is one of the most important components. Alternative splicing dramatically expands the regulatory network by producing transcript isoforms of genes to exquisitely control the cell cycle. However, the patterns of transcript isoform expression in the cell cycle are unclear. Therapies targeting cell cycle checkpoints are commonly used as anticancer therapies, but none of them have been designed or evaluated at the alternative splicing transcript level. The utility of these transcripts as markers of cell cycle-related drug sensitivity is still unknown, and studies on the expression patterns of cell cycle-targeting drug-related transcripts are also rare.MethodsTo explore alternative splicing patterns during cell cycle progression, we performed sequential transcriptomic assays following cell cycle synchronization in colon cancer HCT116 and breast cancer MDA-MB-231 cell lines, using flow cytometry and reference cell cycle transcripts to confirm the cell cycle phases of samples, and we developed a new algorithm to describe the periodic patterns of transcripts fluctuating during the cell cycle. Genomics of Drug Sensitivity in Cancer (GDSC) drug sensitivity datasets and Cancer Cell Line Encyclopedia (CCLE) transcript datasets were used to assess the correlation of genes and their transcript isoforms with drug sensitivity. We identified transcripts associated with typical drugs targeting cell cycle by determining correlation coefficients. Cytotoxicity assays were used to confirm the effect of ENST00000257904 against cyclin dependent kinase 4/6 (CDK4/6) inhibitors. Finally, alternative splicing transcripts associated with mitotic (M) phase arrest were analyzed using an RNA synthesis inhibition assay and transcriptome analysis.ResultsWe established high-resolution transcriptome datasets of synchronized cell cycle samples from colon cancer HCT116 and breast cancer MDA-MB-231 cells. The results of the cell cycle assessment showed that 43,326, 41,578 and 29,244 transcripts were found to be periodically expressed in HeLa, HCT116 and MDA-MB-231 cells, respectively, among which 1280 transcripts showed this expression pattern in all three cancer cell lines. Drug sensitivity assessments showed that a large number of these transcripts displayed a higher correlation with drug sensitivity than their corresponding genes. Cell cycle-related drug screening showed that the level of the CDK4 transcript ENST00000547281 was more significantly associated with the resistance of cells to CDK4/6 inhibitors than the level of the CDK4 reference transcript ENST00000257904. The transcriptional inhibition assay following M phase arrest further confirmed the M-phase-specific expression of the splicing transcripts. Combined with the cell cycle-related drug screening, the results also showed that a set of periodic transcripts, for example, ENST00000314392 (a dolichyl-phosphate mannosyltransferase polypeptide 2 isoform transcript), was more associated with drug sensitivity than the levels of their corresponding gene transcripts.ConclusionsIn summary, we identified a panel of cell cycle-related periodic transcripts and found that the levels of transcripts of drug target genes showed different values for predicting drug sensitivity, providing novel insights into alternative splicing-related drug development and evaluation.

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Heck products of parthenolide and melampomagnolide-B as anticancer modulators that modify cell cycle progression.

Publications

Heck products of parthenolide and melampomagnolide-B as anticancer modulators that modify cell cycle progression.

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