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[Display omitted] • Marine sponges are a rich source of natural products that exhibit a wide range of biological activities. • Two new cytotoxic cyclic peroxides, plakortides V (1) and W (2) were isolated from the sponge Plakinastrella sp. • Structural elucidation and absolute configuration assignment is presented. • Plakortides V and W exhibited potent cytotoxic activity in the NCI-60 cell lines screen. Two cyclic peroxides, plakortides V (1) and W (2) were purified from the organic extract of the sponge Plakinastrella sp. Their planar structures were established based on extensive NMR and MS analysis and the absolute configurations of the three stereogenic centers of the 1,2-dioxane moiety were determined to be 3 R ,4 S ,6 S by comparative analysis of the 1H NMR spectral data of the R - or S -MTPA Mosher esters. Compounds 1 and 2 exhibited potent cytotoxic activity against LOX IMVI (melanoma), UO-31 (renal), and HL-60 (TB) (leukemia) cell lines in the NCI-60 cytotoxicity assay. [ABSTRACT FROM AUTHOR]

• Cancer/Testis Antigens 55 (CT55) expression in cancer is associated with poor survival. • CT55 is localized to both mitochondria and endoplasmic reticulum due to its ambiguous N-terminal targeting signal. • CT55 silencing decreases mtDNA copy number and delays mtDNA recovery after an acute depletion. Cancer/Testis Antigens (CTAs) represent a group of proteins whose expression under physiological conditions is restricted to testis but activated in many human cancers. Also, it was observed that co-expression of multiple CTAs worsens the patient prognosis. Five CTAs were reported acting in mitochondria and we recently reported 147 transcripts encoded by 67 CTAs encoding for proteins potentially targeted to mitochondria. Among them, we identified the two isoforms encoded by CT55 for whom the function is poorly understood. First, we found that patients with tumors expressing wild-type CT55 are associated with poor survival. Moreover, CT55 silencing decreases dramatically cell proliferation. Second, to investigate the role of CT55 on mitochondria, we first show that CT55 is localized to both mitochondria and endoplasmic reticulum (ER) due to the presence of an ambiguous N-terminal targeting signal. Then, we show that CT55 silencing decreases mtDNA copy number and delays mtDNA recovery after an acute depletion. Moreover, demethylation of CT55 promotor increases its expression, which in turn increases mtDNA copy number. Finally, we measured the mtDNA copy number in NCI-60 cell lines and screened for genes whose expression is strongly correlated to mtDNA amount. We identified CT55 as the second highest correlated hit. Also, we show that compared to siRNA scrambled control (siCtrl) treatment, CT55 specific siRNA (siCT55) treatment down-regulates aerobic respiration, indicating that CT55 sustains mitochondrial respiration. Altogether, these data show for first time that CT55 acts on mtDNA copy number, modulates mitochondrial activity to sustain cancer cell proliferation. [ABSTRACT FROM AUTHOR]

The synthesis and characterization of the full family of 11 pyrazoles were performed by means of UV–Vis, FTIR, 1H NMR, 13C NMR, two-dimensional NMR experiments and DFT simulations. As pyrazoles are known for showing diverse biological actions, they were also tested in the NCI-60 cancer cell line panel, showing moderate to good activity against different cell lines. Furthermore, the anti-proinflammatory activity test of a set of pyrazoles of the form (E)-4-((4-bromophenyl)diazenyl)-3,5-dimethyl-1- R -phenyl-1H-pyrazole was performed, this is based on the study of the blockage of the increase in intracellular [Ca2+ observed in response to platelet-activating factor (PAF) treatment of four pyrazoles (i.e. 6 , 8 , 9 and 10), which successfully displayed [Ca2+ channel inhibition. Therefore, the obtained intracellular [Ca2+ signal results indicate that the pyrazole family characterized in this study, in particular compounds 6 and 10 , are potent blockers of the PAF-initiated Ca2+ signaling that mediates the hyperpermeability typically observed during the development of inflammation. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Two new cassaine-type diterpenoids, namely erythrofordins D (1) and E (2), sourced from a Cameroon collection of Erythrophleum suaveolens were isolated and assessed for anti-tumor activity. In the NCI-60 cancer cell assay, erythrofordins D (1) and E (2) were found to be cytotoxic in the low micro molar ranges with a mean GI 50 value of 2.45 and 0.71 µM, mean TGI value of 9.77 and 2.29 µM, and a mean LC 50 of 26.92 and 11.48 µM for 1 and 2 respectively. Using the COMPARE algorithm, the new compounds were found to have similar NCI-60 response profiles to the known cardiac glycosides hyrcanoside and strophanthin. In addition, in an assay examining the viability and contractile function in human cardiomyocytes derived from induced pluripotent stem-cells, erythrofordins showed cardiotoxicity effects at concentrations as low as 0.03 µg/mL. [ABSTRACT FROM AUTHOR]

Loss of function of DNA repair (DNAR) genes is associated with genomic instability and cancer predisposition; it also makes cancer cells reliant on a reduced set of DNAR pathways to resist DNA-targeted therapy, which remains the core of the anticancer armamentarium. Because the landscape of DNAR defects across numerous types of cancers and its relation with drug activity have not been systematically examined, we took advantage of the unique drug and genomic databases of the US National Cancer Institute cancer cell lines (the NCI-60) to characterize 260 DNAR genes with respect to deleterious mutations and expression down-regulation; 169 genes exhibited a total of 549 function-affecting alterations, with 39 of them scoring as putative knockouts across 31 cell lines. Those mutations were compared to tumor samples from 12 studies of The Cancer Genome Atlas (TCGA) and The Cancer Cell Line Encyclopedia (CCLE). Based on this compendium of alterations, we determined which DNAR genomic alterations predicted drug response for 20,195 compounds present in the NCI-60 drug database. Among 242 DNA damaging agents, 202 showed associations with at least one DNAR genomic signature. In addition to SLFN11, the Fanconi anemia-scaffolding gene SLX4 (FANCP/BTBD12) stood out among the genes most significantly related with DNA synthesis and topoisomerase inhibitors. Depletion and complementation experiments validated the causal relationship between SLX4 defects and sensitivity to raltitrexed and cytarabine in addition to camptothecin. Therefore, we propose new rational uses for existing anticancer drugs based on a comprehensive analysis of DNAR genomic parameters. [ABSTRACT FROM AUTHOR]

Abstract: Protein kinases play several pertinent roles in cell proliferation, and targeting these proteins has been shown to be a successful strategy toward controlling different malignancies. Despite the great discovery stories during the last two decades, there is still a demand for anticancer small molecules with the potential of being selective on both the protein kinase and/or the cellular level. A series of novel piperazinylpyrimidine compounds were synthesized and tested for their potential to selectively inhibit the growth of certain tumor cell lines included within the NCI-60 cell line panel. MDA-MB-468, a triple-negative/basal-like breast carcinoma, cell line was among the most sensitive cell lines towards compounds 4 and 15. The three most interesting compounds identified in cellular screens (4, 15, and 16) were subjected to kinase profiling and found to have an interesting selective tendency to target certain kinase subfamily members; PDGFR, CK1, RAF and others. Compound 4 showed a selective tendency to bind to and/or inhibit the function of certain KIT and PDGFRA mutants compared to their wild-type isoforms. Piperazinylpyrimidine based derivatives represent a new class of selective kinase inhibitors. Significantly 4 is more potent at inhibiting oncogenic mutant forms of PDGFR family kinases, which is relevant in terms of its potential use in treating tumors that have become resistant to treatment or driven by such mutations. The clinical demand for agents useful in the control of triple-negative/basal-like breast cancer justifies our interest in compound 15 which is a potent growth inhibitor of MDA-MB-468 cell line. [Copyright &y& Elsevier]

Abstract: Artemisinin and its derivatives (ARTs) are effective antimalarial drugs and also possess profound anticancer activity. However, the mechanism accounted for its distinctive activity in tumor cells remains unelucidated. We computed Pair wise Pearson correlation coefficients to identify genes that show significant correlation with ARTs activity in NCI-55 cell lines using data obtained from studies with HG-U133A Affymetrix chip. We found c-myc is one of the genes that showed the highest positive correlation coefficients among the probe sets analyzed (r =0.585, P <0.001). Dihydroartemisinin (DHA), the main active metabolite of ARTs, induced significant apoptosis in HL-60 and HCT116 cells that express high levels of c-MYC. Stable knockdown of c-myc abrogated DHA-induced apoptosis in HCT116 cells. Conversely, forced expression of c-myc in NIH3T3 cells sensitized these cells to DHA-induced apoptosis. Interestingly, DHA irreversibly down-regulated the protein level of c-MYC in DHA-sensitive HCT116 cells, which is consistent to persistent G1 phase arrest induced by DHA. Further studies demonstrated that DHA accelerated the degradation of c-MYC protein and this process was blocked by pretreatment with the proteasome inhibitor MG-132 or GSK 3β inhibitor LiCl in HCT116 cells. Taken together, ARTs might be useful in the treatment of c-MYC-overexpressing tumors. We also suggest that c-MYC may potentially be a biomarker candidate for prediction of the antitumor efficacies of ARTs. [Copyright &y& Elsevier]

Abstract: Various agents have been synthesized and proved useful for the National Cancer Institute’s anticancer testing as potential new drugs, but most agents suffer side effects from their limited selectivity against cancer cells over healthy ones. Therefore, this paper attempts to describe drugs in terms of the level of tumor cell selectivity which they possess to define the features of molecules that are essential for useful cytotoxicity. Selected cyclic amidinothymine analogues (NSC 697864, NSC 697865, and NSC 697869) have nanomolar inhibitory activities against leukemia cell lines: CCRF-CEM, HL-60(TB), while bisfunctional cancer fighters NSC 702408 and NSC 702409, showing larger numbers of cytostatic and cytotoxic effects, in an extended conformation would probably adopt a similar to NSC 715653 conformation leaving both opposite H-bond donor groups at the same distance to interact with DNA in a similar way. Such specific interactions (cell line selectivity to unique mutated patterns) lower considerably the observed dose-response concentrations. This in vitro selectivity is shown to translate into in vivo efficacy indicated by the inflection in the cumulative testing curve. [Copyright &y& Elsevier]

The primary functions of cancer chemotherapeutic agents are not only to inhibit the growth or kill the cancer cells, but to do so without eliciting unreasonable cytotoxic effects on the healthy cells and to withstand the ability of the cancer cells to develop resistance against it. This has unfortunately been proven so far to be a very difficult objective. In this perspective, the ability of small molecules (anti- tumor agents) to ‘see’ different cell types differently can be a key attribute. Thus the term ‘differential cytotoxicity’ is normally used to describe the drug’s specificity. In the present paper, we have quantified differential cytotoxicity from a study of the chemicals tested in the National Cancer Institute’s Developmental Therapeutics Program. The MULTICASE (Multiple Computer Automated Structure Evaluation) methodology was used to discover statistically significant structural fragments (biophores) related to the differential cytotoxicity of the compounds. We found that even small structural features often become important in this regard which is evident from the biophores that were found in structurally diverse chemicals. By utilizing the difference between the raw and normalized differential cytotoxicity indices, we found that the α,β-unsaturated carbonyl group (O＝C—C＝CH2) is the major biophore associated with compounds with essentially parallel concentration profiles in the cell lines in question. These compounds have high non-normalized differential cytotoxicity but considerably low normalized differential cytotoxocity. The models developed were cross validated for their predictive ability. [Copyright &y& Elsevier]

Modifications at C 6 and C 7 positions of 3-cyanoquinolines 6 and 7 led to potent inhibitors of the ErbB family of kinases particularly against EGFRWT and Her4 enzymes in the radioisotope filter binding assay. The lead (4 , SAB402) displayed potent dual biochemical activities with EGFRWT/Her4 IC 50 ratio of 80 due to its potent inhibition of Her4 activity (IC 50 0.03 nM), however, the selectivity towards activating mutations (EGFRL858R, EGFRex19del) was decreased. Inhibitor 4 also exhibited excellent growth inhibition in seven different cancer types and reduced cell viability in female NMRI nude mice in the intraperitoneally implanted hollow fibers which have been loaded with MOLT-4 (leukemia) and NCI-H460 (NSCLC) cells in a statistically significant manner. [ABSTRACT FROM AUTHOR]

A new series of 1,2,3-triazole-chalcone hybrids has been synthesized and screened in vitro against a panel of 60 human cancer cell lines according to NCI (USA) protocol. Compound 4d having 3, 4-dimethoxyphenyl chalcone moiety, the most potent derivative, inhibited the growth of RPMI-8226 and SR leukemia cell lines by 99.73% and 94.95% at 10 μM, respectively. Also, it inhibited the growth of M14 melanoma, K-562 leukemia, and MCF7 breast cancer cell lines by more than 80% at the same test concentration. 4d showed IC 50 values less than 1 μM on six types of tumor cells and high selectivity index reached to 104 fold on MCF7. Compound 4d showed superior activity than methotrexate and gefitinib against the most sensitive leukemia cell lines in addition to higher or comparable activity against the rest sensitive cell lines. Flow cytometry analysis in RPMI-8226 cells revealed that compound 4d caused cell cycle arrest at G2/M phase and induced apoptosis in a dose dependant manner. Mechanistic evaluation referred this apoptosis induction to triggering mitochondrial apoptotic pathway through inducing ROS accumulation, increasing Bax/Bcl-2 ratio and activation of caspases 3, 7 and 9. Image 1 • New 1,2,3-triazole-chalcone hybrids were synthesized and screened against NCI-60 human cancer cell lines. • Compound 4d (with 3, 4-dimethoxyphenyl) was the most potent anticancer agent. • Compound 4d showed IC 50 values less than 1 μM on 6 cancer cell lines with high SI. • Compound 4d induce cell cycle arrest in RPMI-8226 cell line at G2/M phase. • Compound 4d triggered mitochondrial apoptotic pathway. • The action of compound 4d is through accumulation of ROS, up regulation of BAX, down regulation of Bcl-2 and activation of caspases 3, 7, 9. [ABSTRACT FROM AUTHOR]

Botanical-based natural products are an important resource for medicinal drug discovery and continue to provide diverse pharmacophores with therapeutic potential against cancer and other human diseases. A prototype Traditional Chinese Medicine (TCM) plant extract library has been established at the US National Cancer Institute, which contains both the organic and aqueous extracts of 132 authenticated medicinal plant species that collectively represent the potential therapeutic contents of most commonly used TCM herbal prescriptions. This library is publicly available in 96- and 384- well plates for high throughput screening across a broad array of biological targets, as well as in larger quantities for isolation of active chemical ingredients. Herein, we present the methodology used to generate the library and the preliminary assessment of the anti-proliferative activity of this crude extract library in NCI-60 human cancer cell lines screen. Particularly, we report the chemical profiling and metabolome comparison analysis of four commonly used TCM plants, namely Brucea javanica , Dioscorea nipponica , Cynanchum atratum , and Salvia miltiorrhiza. Bioassay-guided isolation resulted in the identification of the active compounds, and different extraction methods were compared for their abilities to extract cytotoxic compounds and to concentrate biologically active natural products. Unlabelled Image [ABSTRACT FROM AUTHOR]