In vitro Anti-Proliferative Activity of the Rubia tinctorum and Alkanna tinctoria Root Extracts in Panel of Human Tumor Cell Lines hasson

Cancer is a devastating disease and is considered number one killer worldwide. Herbal formulations had played a key role over the past several decades in the development of anti-cancer drugs. Medicinal plants, which are endemic in Jordan, are known for several biological activities in particular their anti-cancer activity. However, the anti-cancer efficacy of the root extracts of Jordanian Rubia tinctorum and Alkanna tinctoria is not yet reported. To address this issue, this study assessed the anti-cancer activity of some root extracts obtained from Jordanian R. tinctorum and A. tinctoria in different tumor cell lines including the tongue, bladder, colon, gastric, lungs, breast, pancreas, and renal tissue origins by modified propidium iodide (PI) based monolayer assay. Among the tested root extracts obtained by different solvent systems, A. tinctoria in 100 % ethanol and methanol showed prominent anti-cancer activity against MDA-MB-231breast cancer cells (IC50: 2.98 µg/ml, IC70: 6.03 µg/ml), and CAL-27 tongue squamous carcinoma cells (IC50: 3.86 µg/ml, IC70: 5.97 µg/ml) respectively. Different solvent root extracts of R. tinctorum exhibited a similar trend of anti-tumor activity in both CAL-27 and MDA MB-231 cells. The anti-proliferative property of the extracts on CAL-27 and MDA-MB-231 cells is unclear. However, it can be concluded that the observed anti-cancer potential can be attributed to the phenolic compounds of the extracts as high polar solvents were used for extraction. The current study forms the rationale for isolating significant amount of anti-cancer active compounds from R. tinctorum and A. tinctori

An extensible framework for multicore response time analysis

In this paper, we introduce a multicore response time analysis (MRTA) framework, which decouples response time analysis from a reliance on context independent WCET values. Instead, the analysis formulates response times directly from the demands placed on different hardware resources. The MRTA framework is extensible to different multicore architectures, with a variety of arbitration policies for the common interconnects, and different types and arrangements of local memory. We instantiate the framework for single level local data and instruction memories (cache or scratchpads), for a variety of memory bus arbitration policies, including: Round-Robin, FIFO, Fixed-Priority, Processor-Priority, and TDMA, and account for DRAM refreshes. The MRTA framework provides a general approach to timing verification for multicore systems that is parametric in the hardware configuration and so can be used at the architectural design stage to compare the guaranteed levels of real-time performance that can be obtained with different hardware configurations. We use the framework in this way to evaluate the performance of multicore systems with a variety of different architectural components and policies. These results are then used to compose a predictable architecture, which is compared against a reference architecture designed for good average-case behaviour. This comparison shows that the predictable architecture has substantially better guaranteed real-time performance, with the precision of the analysis verified using cycle-accurate simulation

Viscum album L. extracts in breast and gynaecological cancers: a systematic review of clinical and preclinical research

<p>Abstract</p> <p>Background</p> <p><it>Viscum album </it>L. extracts (VAE, European mistletoe) are a widely used medicinal plant extract in gynaecological and breast-cancer treatment.</p> <p>Methods</p> <p>Systematic review to evaluate clinical studies and preclinical research on the therapeutic effectiveness and biological effects of VAE on gynaecological and breast cancer. Search of databases, reference lists and expert consultations. Criteria-based assessment of methodological study quality.</p> <p>Results</p> <p>19 randomized (RCT), 16 non-randomized (non-RCT) controlled studies, and 11 single-arm cohort studies were identified that investigated VAE treatment of breast or gynaecological cancer. They included 2420, 6399 and 1130 patients respectively. 8 RCTs and 8 non-RCTs were embedded in the same large epidemiological cohort study. 9 RCTs and 13 non-RCTs assessed survival; 12 reported a statistically significant benefit, the others either a trend or no difference. 3 RCTs and 6 non-RCTs assessed tumour behaviour (remission or time to relapse); 3 reported statistically significant benefit, the others either a trend, no difference or mixed results. Quality of life (QoL) and tolerability of chemotherapy, radiotherapy or surgery was assessed in 15 RCTs and 9 non-RCTs. 21 reported a statistically significant positive result, the others either a trend, no difference, or mixed results. Methodological quality of the studies differed substantially; some had major limitations, especially RCTs on survival and tumour behaviour had very small sample sizes. Some recent studies, however, especially on QoL were reasonably well conducted. Single-arm cohort studies investigated tumour behaviour, QoL, pharmacokinetics and safety of VAE. Tumour remission was observed after high dosage and local application. VAE application was well tolerated. 34 animal experiments investigated VAE and isolated or recombinant compounds in various breast and gynaecological cancer models in mice and rats. VAE showed increase of survival and tumour remission especially in mice, while application in rats as well as application of VAE compounds had mixed results. <it>In vitro </it>VAE and its compounds have strong cytotoxic effects on cancer cells.</p> <p>Conclusion</p> <p>VAE shows some positive effects in breast and gynaecological cancer. More research into clinical efficacy is warranted.</p

Role of Transferrin Receptor and the ABC Transporters ABCB6 and ABCB7 for Resistance and Differentiation of Tumor Cells towards Artesunate

The anti-malarial artesunate also exerts profound anti-cancer activity. The susceptibility of tumor cells to artesunate can be enhanced by ferrous iron. The transferrin receptor (TfR) is involved in iron uptake by internalization of transferrin and is over-expressed in rapidly growing tumors. The ATP-binding cassette (ABC) transporters ABCB6 and ABCB7 are also involved in iron homeostasis. To investigate whether these proteins play a role for sensitivity towards artesunate, Oncotest's 36 cell line panel was treated with artesunate or artesunate plus iron(II) glycine sulfate (Ferrosanol®). The majority of cell lines showed increased inhibition rates, for the combination of artesunate plus iron(II) glycine sulfate compared to artesunate alone. However, in 11 out of the 36 cell lines the combination treatment was not superior. Cell lines with high TfR expression significantly correlated with high degrees of modulation indicating that high TfR expressing tumor cells would be more efficiently inhibited by this combination treatment than low TfR expressing ones. Furthermore, we found a significant relationship between cellular response to artesunate and TfR expression in 55 cell lines of the National Cancer Institute (NCI), USA. A significant correlation was also found for ABCB6, but not for ABCB7 in the NCI panel. Artesunate treatment of human CCRF-CEM leukemia and MCF7 breast cancer cells induced ABCB6 expression but repressed ABCB7 expression. Finally, artesunate inhibited proliferation and differentiation of mouse erythroleukemia (MEL) cells. Down-regulation of ABCB6 by antisense oligonucleotides inhibited differentiation of MEL cells indicating that artesunate and ABCB6 may cooperate. In conclusion, our results indicate that ferrous iron improves the activity of artesunate in some but not all tumor cell lines. Several factors involved in iron homeostasis such as TfR and ABCB6 may contribute to this effect

Development of Resistance towards Artesunate in MDA-MB-231 Human Breast Cancer Cells

Breast cancer is the most common cancer and the second leading cause of cancer death in industrialized countries. Systemic treatment of breast cancer is effective at the beginning of therapy. However, after a variable period of time, progression occurs due to therapy resistance. Artesunate, clinically used as anti-malarial agent, has recently revealed remarkable anti-tumor activity offering a role as novel candidate for cancer chemotherapy. We analyzed the anti-tumor effects of artesunate in metastasizing breast carcinoma in vitro and in vivo. Unlike as expected, artesunate induced resistance in highly metastatic human breast cancer cells MDA-MB-231. Likewise acquired resistance led to abolishment of apoptosis and cytotoxicity in pre-treated MDA-MB-231 cells. In contrast, artesunate was more cytotoxic towards the less tumorigenic MDA-MB-468 cells without showing resistance. Unraveling the underlying molecular mechanisms, we found that resistance was induced due to activation of the tumor progression related transcription factors NFκB and AP-1. Thereby transcription, expression and activity of the matrix-degrading enzyme MMP-1, whose function is correlated with increased invasion and metastasis, was up-regulated upon acquisition of resistance. Additionally, activation of the apoptosis-related factor NFκB lead to increased expression of ant-apoptotic bcl2 and reduced expression of pro-apoptotic bax. Application of artesunate in vivo in a model of xenografted breast cancer showed, that tumors growth was not efficiently abolished as compared to the control drug doxorubicin. Taken together our in vitro and in vivo results correlate well showing for the first time that artesunate induces resistance in highly metastatic breast tumors

Molecular Editing and Biological Evaluation of Amphidinolide X and Y

Scarce and precious: A collection of compounds with deep-seated structural “point mutations” within the framework of the marine natural products amphidinolide X and Y was prepared by “diverted total synthesis”. The resulting products provided first insights into the cytotoxicity profile of these extremely scarce macrolides. Deliberate deviations from the previously described total syntheses of amphidinolide X (1) and Y (2) allowed a collection of seven designed analogues of these extremely scarce marine natural products to be obtained. These fully synthetic “natural product-like” compounds enabled first insights into the previously unknown structure–activity relationships governing this series. Although the average cytotoxicity is moderate, it was found that certain bladder, colon and prostate cancer cell lines are fairly sensitive, and that the best synthetic analogues are more active than the natural products themselves. The syntheses rely on the 9-MeO-9-BBN variant of the Suzuki coupling for the formation of the carbon frameworks, as well as on Yamaguchi lactonization reactions for the cyclization of the macrocyclic rings

SYNTHESIS AND ANTITUMOR ACTIVITY OF 2,5-BIS(3'-INDOLYL)-FURANS AND 3,5-BIS(3'-INDOLIY)-ISOXAZOLES, NORTOPSENTIN ANALOGUES

A series of novel 2,5-bis(3\u2032-indolyl)furans and 3,5-bis(3\u2032-indolyl)isoxazoles were synthesized as antitumor agents. The antiproliferative activity was evaluated in vitro toward diverse human tumor cell lines. Initially 5 isoxazoles and 3 furan derivatives were tested against a panel of 10 human tumor cell lines and the most active derivatives 3c and 4a were selected to be evaluated in an extended panel of 29 cell lines. By exhibiting mean IC50 values of 17.4 \u3bcg/mL (3a) and 20.5 \u3bcg/mL (4c), in particular 4c showed a high level of tumor selectivity toward the 29 cell lines

Total synthesis and cytotoxicity of the marine natural product malevamide D and a photoreactive analog

The marine natural product malevamide D from the cyanobacterium Symploca hydnoides was synthesized for the first time. The final peptide coupling linked the dolaisoleuine and dolaproine subunits. The phenyl group of malevamide D was also functionalized with a photoreactive diazirine moiety, which was carried through seven reaction steps. Comprehensive assessment of the cytotoxicity in a panel of 42 human cancer cell lines revealed a geomean IC70 value of 1.5 nM (IC50 0.7 nM) for malevamide D, whereas the photoreactive derivative proved to be less active by a factor of at least 200. COMPARE analysis indicated tubulin interaction as likely mode of action of malevamide D