Cell Line Anticancer Drug Screen Research Articles

Ferroptosis-related gene signature for predicting prognosis and identifying potential therapeutic drug in EGFR wild-type lung adenocarcinoma

Epidermal growth factor receptor wild type lung adenocarcinoma (EGFRWT LUAD) still has limited treatment options and unsatisfactory clinical outcomes. Ferroptosis, as a form of cell death, has been reported to play a dual role in regulating tumor cell survival. In this study, we constructed a 3-ferroptosis-gene signature, FeSig, and verified its accuracy and efficacy in predicting EGFRWT LUAD prognosis at both the RNA and protein levels. Patients with higher FeSig scores were found to have worse clinical outcomes. Additionally, we explored the relationship between FeSig and tumor microenvironment, revealing that enhanced interactions between fibroblasts and tumor cells in FeSighigh patients causing tumor resistance to ferroptosis. To address this challenge, we screened potential drugs from NCI-60 (The US National Cancer Institute 60 human tumour cell line anticancer drug screen) and Connectivity map database, ultimately identifying 6-mercatopurine (6-MP) as a promising candidate. Both in vitro and in vivo experiments demonstrated its efficacy in treating FeSighigh EGFRWT LUAD tumor models. In summary, we develop a novel FeSig for predicting prognosis and guiding drug application.

Identifying new topoisomerase II poison scaffolds by combining publicly available toxicity data and 2D/3D-based virtual screening

Molecular descriptor (2D) and three dimensional (3D) shape based similarity methods are widely used in ligand based virtual drug design. In the present study pairwise structure comparisons among a set of 4858 DTP compounds tested in the NCI60 tumor cell line anticancer drug screen were computed using chemical hashed fingerprints and 3D molecule shapes to calculate 2D and 3D similarities, respectively. Additionally, pairwise biological activity similarities were calculated by correlating the 60 element vectors of pGI50 values corresponding to the cytotoxicity of the compounds across the NCI60 panel. Subsequently, we compared the power of 2D and 3D structural similarity metrics to predict the toxicity pattern of compounds. We found that while the positive predictive value and sensitivity of 3D and molecular descriptor based approaches to predict biological activity are similar, a subset of molecule pairs yielded contradictory results. By simultaneously requiring similarity of biological activities and 3D shapes, and dissimilarity of molecular descriptor based comparisons, we identify pairs of scaffold hopping candidates displaying characteristic core structural changes such as heteroatom/heterocycle change and ring closure. Attempts to discover scaffold hopping candidates of mitoxantrone recovered known Topoisomerase II (Top2) inhibitors, and also predicted new, previously unknown chemotypes possessing in vitro Top2 inhibitory activity.

Predictive power of the Triticum root elongation test for the assessment of novel anti‑proliferative therapies.

The use of alternative techniques to reduce the number of animals used in anticancer research is an issue of current interest. The aim of this study was to validate the use of a simple and efficient alternative tool for the assessment of the potential of novel anti-proliferative agents. A set of 20 compounds with various mechanisms were tested in the Triticum aestivum root elongation assay, using aminophyl-line as negative control. Hierarchical cluster analyses were performed using the furthest neighbor method based on Euclidean distance measure, and the compounds were statistically analyzed in reference to their anti-proliferative pattern registered in the NCI60 human tumor cell line anticancer drug screen. A correlation between the Triticum test results and the NCI60 anti-proliferative profile was made for a number of human cells that we defined as the Triticum cell panel. Linear equations were computed that can be used to transform the inhibitory effect measured in any future Triticum assay in order to predict the effect on particular human cells. Of the tested anti-proliferative agents, methotrexate, colchicine, cantharidin, cisplatin and verapamil produced a growth inhibition over 50%. On the whole, the findings of this study suggest that the Triticum test can be used to detect several types of anti-proliferative mechanisms, particularly those targeting tubulin, rendering it a useful tool with which to identify novel mitotic spindle inhibitors.

Integrative cancer pharmacogenomics to establish drug mechanism of action: drug repurposing.

Integrative cancer pharmacogenomics to establish drug mechanism of action: drug repurposing.

Transcriptome profile of OVCAR3 cisplatin-resistant ovarian cancer cell line

BackgroundThe NIH:OVCAR-3 is a cisplatin refractory cell lineestablished from malignant ascites of a patient with pro-gressive adenocarcinoma of the ovary after combinationchemotherapy with cyclophosphamide, Adriamycin, andcisplatin [1]. Thus, OVCAR3 serves as a model cell linefor drug resistance in ovarian cancer. Here, we perform acomparative transcriptome analysis from the US NationalCancer Institute human tumor cell line anticancer drugscreen (NCI60) dataset [2]. Our results indicate a specificgene transcription profile of OVCAR3 genes relative tonon-cancerous Human Ovarian Surface Epithelial cells(HOSE) and drug sensitive Serous Ovarian CancerEpithelial Samples (CEPI) and SKOV3 cell lines. Pathwayenrichment analysis from OVCAR3 unique transcriptswas conducted using KEGG; Disease and Drug termenrichment used the PharmGKB [3] databases.Materials and methodsDatasets from the NCI60 were obtained from the GeneExpression Omnibus (GEO) of NCBI [4] (OVCAR3 andSKOV3 from series GSE2003, OSE and CEPI from series

New 5-Aryl-1H-imidazoles Display in Vitro Antitumor Activity against Apoptosis-Resistant Cancer Models, Including Melanomas, through Mitochondrial Targeting

We designed and synthesized 48 aryl-1H-imidazole derivatives and investigated their in vitro growth inhibitory activity in cancer cell lines known to present various levels of resistance to proapoptotic stimuli. The IC50 in vitro growth inhibitory concentration of these compounds ranged from >100 μM to single digit μM. Among the most active compounds, 2i displayed similar in vitro growth inhibition in cancer cells independent of the cells' levels of resistance to proapoptotic stimuli and was found to be cytostatic in melanoma cell lines. Compound 2i was then tested by the National Cancer Institute Human Tumor Cell Line Anti-Cancer Drug Screen, and the NCI COMPARE algorithm did not reveal any correlation between its growth inhibition profiles with the NCI database compound profiles. The use of transcriptomically characterized melanoma models then enabled us to highlight mitochondrial targeting by 2i. This hypothesis was further confirmed by reactive oxygen production measurement and oxygen consumption analysis.

Polyalkoxy Substituted 4H-Chromenes: Synthesis by Domino Reaction and Anticancer Activity

A series of 4H-chromenes containing various modifications in the ring B and polyalkoxy substituents in the ring E has been synthesized by Knoevenagel-Michael-hetero-Thorpe-Ziegler three-component domino reaction with the overall yield of 45-82%. The targeted molecules were evaluated in a phenotypic sea urchin embryo assay for antimitotic and microtubule destabilizing activity. The most active compounds 5{1,5} and 5{5,5} featured sesamol-derived ring B and m-methoxyphenyl or m-methoxymethylenedioxyphenyl ring E. Compounds 5{3,1}, 5{1,2}, 5{5,4}, 5{1,5}, and 5{5,5} exhibited strong cytotoxicity in the NCI60 human tumor cell line anticancer drug screen. Surprisingly, cell growth inhibition caused by these agents was more pronounced in the multidrug resistant NCI/ADR-RES cells than the parent OVCAR-8 cell line. The results suggest that polyalkoxy substited 4H-chromenes may prove to be advantageous for further design as anticancer agents.

Novel Trisubstituted Harmine Derivatives with Original in Vitro Anticancer Activity

To overcome the intrinsic resistance of cancer cells to apoptotic stimuli, we designed and synthesized approximately 50 novel β-carbolines structurally related to harmine. Harmine is known for its anticancer properties and is a DYRK1A inhibitor. Of the synthesized compounds, the most active in terms of growth inhibition of five cancer cell lines are cytostatic and approximately 100 times more potent than harmine but demonstrated no DYRK1A inhibitory activity. These novel β-carbolines display similar growth inhibitory activity in cancer cells that are sensitive and resistant to apoptotic stimuli. Using ChemGPS-NP, we found that the more active β-carbolines are all more lipophilic and larger than the less active compounds. Lastly, on the basis of the NCI human tumor cell line anticancer drug screen and the NCI COMPARE algorithm, it appears that some of these compounds, including 5a and 5k, seem to act as protein synthesis inhibitors.

Abstract 3838: NKP-2235 exhibits a novel pattern of cytotoxicity with synergism across a broad range of antitumor agents demonstrated in multiple tumor types

Abstract Background: NKP-2235 is a first-in-class, orally bioavailable gallium based anti-cancer compound. The intracellular targets for NKP-2235 include the endoplasmic reticulum (ER). NKP-2235 treatment of tumor cells causes ER stress, intracellular Ca2+ release and induction of pro-apoptotic factors. In single agent in vitro cytotoxicity assays, NKP-2235 has shown activity against tumor lines resistant to many standard anti-cancer agents. The aims of this study were to evaluate the anti-tumor effects of NKP-2235 in combination with standard cytotoxics or targeted agents and assess its single agent cytotoxicity pattern in the NCI 60 tumor cell line anti-cancer drug screen and COMPARE analysis. Methods: NKP-2235 testing in the NCI 60 tumor cell line anticancer drug screen was performed by the NCI. COMPARE analysis was conducted using cytotoxicity data from 170 compounds in the NCI compound library. In vitro combination studies were performed in breast, colon, glioma, lung and prostate tumor cell lines. NKP-2235 was tested in combination with 5-FU, temozolomide, gemcitabine, paclitaxel, erlotinib, temsirolimus, or docetaxel either simultaneously or sequentially. For simultaneous combinations, cells were exposed to NKP-2235 and a combination agent, at their respective ED50, for 72hrs. For sequential NKP-2235 combinations cells were exposed to different dosing sequences, all agents at their respective ED50, for a total of 96 hrs. Cytotoxicity was determined using the MTT assay and combination index (CI) values were calculated using the Chou-Talalay method. Results: Screening against the NCI 60 tumor cell line panel and COMPARE analysis show that single agent NKP-2235 has a markedly different pattern of cytotoxicity from the 170 anti-cancer agents previously tested by the NCI. In addition, the screening confirmed that the NKP-2235 cytotoxicity is distinct from that of gallium salts such as gallium nitrate. The combination studies demonstrated that NKP-2235 has synergistic activity when combined simultaneously with: 5-FU (CI 0.6), temozolomide (CI 0.8), gemcitabine (CI 0.7), temsirolimus (CI 0.7), and docetaxel (CI 0.7) in the cell lines tested. Interestingly, while simultaneous combination is synergistic with docetaxel in prostate cancer cells, the NKP-2235-paclitaxel combinations required sequential dosing for synergistic activity (CI 0.09) in lung cancer cells. Similarly, the NKP-2235-temsirolimus combination is synergistic in simultaneous setting, while NKP-2235-erlotinib combination required sequential dosing for synergistic activity (CI 0.3) in lung cancer cells. Conclusions: This study demonstrates that NKP-2235 has a novel pattern of cytotoxicity and marked synergism in combination with a broad range of anti-tumor agents in many tumor types. These data support the study of this novel agent in single agent and combination clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3838. doi:1538-7445.AM2012-3838

Identifying Compound-Target Associations by Combining Bioactivity Profile Similarity Search and Public Databases Mining

Molecular target identification is of central importance to drug discovery. Here, we developed a computational approach, named bioactivity profile similarity search (BASS), for associating targets to small molecules by using the known target annotations of related compounds from public databases. To evaluate BASS, a bioactivity profile database was constructed using 4296 compounds that were commonly tested in the US National Cancer Institute 60 human tumor cell line anticancer drug screen (NCI-60). Each compound was used as a query to search against the entire bioactivity profile database, and reference compounds with similar bioactivity profiles above a threshold of 0.75 were considered as neighbor compounds of the query. Potential targets were subsequently linked to the identified neighbor compounds by using the known targets of the query compound. About 45% of the predicted compound-target associations were successfully verified retrospectively, suggesting the possible application of BASS in identifying the targets of uncharacterized compounds and thus providing insight into the study of promiscuity and polypharmacology. Furthermore, BASS identified a significant fraction of structurally diverse compounds with similar bioactivities, indicating its feasibility of “scaffold hopping” in searching novel molecules against the target of interest.

Chemosensitivity Profiles Identify Polymorphisms in the p53 Network Genes 14-3-3τ and CD44 That Affect Sarcoma Incidence and Survival

The p53 regulatory network responds to cellular stresses by initiating processes such as cell cycle arrest and apoptosis. These responses inhibit cellular transformation and mediate the response to many forms of cancer therapies. Functional variants in the genes comprising this network could help identify individuals at greater risk for cancer and patients with poorer responses to therapies, but few such variants have been identified as yet. We use the NCI60 human tumor cell line anticancer drug screen in a scan of single nucleotide polymorphisms (SNP) in 142 p53 stress response genes and identify 7 SNPs that exhibit allelic differences in cellular responses to a large panel of cytotoxic chemotherapeutic agents. The greatest differences are observed for SNPs in 14-3-3tau (YWHAQ; rs6734469, P=5.6x10(-47)) and CD44 (rs187115, P=8.1x10(-24)). In soft-tissue sarcoma patients, we find that the alleles of these SNPs that associate with weaker growth responses to chemotherapeutics associate with poorer overall survival (up to 2.89 relative risk, P=0.011) and an earlier age of diagnosis (up to 10.7 years earlier, P=0.002). Our findings define genetic markers in 14-3-3tau and CD44 that might improve the treatment and prognosis of soft-tissue sarcomas.

The NCI60 human tumour cell line anticancer drug screen

The US National Cancer Institute (NCI) 60 human tumour cell line anticancer drug screen (NCI60) was developed in the late 1980s as an in vitro drug-discovery tool intended to supplant the use of transplantable animal tumours in anticancer drug screening. This screening model was rapidly recognized as a rich source of information about the mechanisms of growth inhibition and tumour-cell kill. Recently, its role has changed to that of a service screen supporting the cancer research community. Here I review the development, use and productivity of the screen, highlighting several outcomes that have contributed to advances in cancer chemotherapy.

Eukaryotic protein synthesis inhibitors identified by comparison of cytotoxicity profiles.

The National Cancer Institute (NCI) Human Tumor Cell Line Anti-Cancer Drug Screen has evaluated the cytotoxicity profiles of a large number of synthetic compounds, natural products, and plant extracts on 60 different cell lines. The data for each compound/extract can be assessed for similarity of cytotoxicity pattern, relative to a given test compound, using an algorithm called COMPARE. In applying a chemical biology approach to better understand the mechanism of eukaryotic protein synthesis, we used these resources to search for novel inhibitors of translation. The cytotoxicity profiles of 31 known protein synthesis inhibitors were used to identify compounds from the NCI database with similar activity profiles. Using this approach, two natural products, phyllanthoside and nagilactone C, were identified and characterized as novel protein synthesis inhibitors. Both compounds are specific for the eukaryotic translation apparatus, function in vivo and in vitro, and interfere with translation elongation. Our results demonstrate the feasibility of utilizing cytotoxicity profiles to identify new inhibitors of translation.