scholarly journals De novo Prediction of Cell-Drug Sensitivities Using Deep Learning-based Graph Regularized Matrix Factorization

2021 ◽  
Author(s):  
Shuangxia Ren ◽  
Yifeng Tao ◽  
Ke Yu ◽  
Yifan Xue ◽  
Russell Schwartz ◽  
...  
Keyword(s):  
Deep Learning ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Cancer Cell ◽  
Matrix Factorization ◽  
De Novo ◽  
Cancer Cell Line ◽  
The Cancer Genome Atlas ◽  
Precision Oncology ◽  
Chemical Structures

Application of artificial intelligence (AI) in precision oncology typically involves predicting whether the cancer cells of a patient (previously unseen by AI models) will respond to any of a set of existing anticancer drugs, based on responses of previous training cell samples to those drugs. To expand the repertoire of anticancer drugs, AI has also been used to repurpose drugs that have not been tested in an anticancer setting, i.e., predicting the anticancer effects of a new drug on previously unseen cancer cells de novo. Here, we report a computational model that addresses both of the above tasks in a unified AI framework. Our model, referred to as deep learning-based graph regularized matrix factorization (DeepGRMF), integrates neural networks, graph models, and matrix-factorization techniques to utilize diverse information from drug chemical structures, their impact on cellular signaling systems, and cancer cell cellular states to predict cell response to drugs. DeepGRMF learns embeddings of drugs so that drugs sharing similar structures and mechanisms of action (MOAs) are closely related in the embedding space. Similarly, DeepGRMF also learns representation embeddings of cells such that cells sharing similar cellular states and drug responses are closely related. Evaluation of DeepGRMF and competing models on Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE) datasets show its superiority in prediction performance. Finally, we show that the model is capable of predicting effectiveness of a chemotherapy regimen on patient outcomes for the lung cancer patients in The Cancer Genome Atlas (TCGA) dataset.

scholarly journals Rapid advancement in cancer genomic big data in the pursuit of precision oncology

2021 ◽  
Author(s):  
Tiara Bunga Mayang Permata ◽  
Sri Mutya Sekarutami ◽  
Endang Nuryadi ◽  
Angela Giselvania ◽  
Soehartati Gondhowiardjo
Keyword(s):  
Big Data ◽  
Open Access ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Genomic Data ◽  
The Cancer Genome Atlas ◽  
Clinical Samples ◽  
Precision Oncology ◽  
Cancer Data ◽  
User Friendly

In the current big data era, massive genomic cancer data are available for open access from anywhere in the world. They are obtained from popular platforms, such as The Cancer Genome Atlas, which provides genetic information from clinical samples, and Cancer Cell Line Encyclopedia, which offers genomic data of cancer cell lines. For convenient analysis, user-friendly tools, such as the Tumor Immune Estimation Resource (TIMER), which can be used to analyze tumor-infiltrating immune cells comprehensively, are also emerging. In clinical practice, clinical sequencing has been recommended for patients with cancer in many countries. Despite its many challenges, it enables the application of precision medicine, especially in medical oncology. In this review, several efforts devoted to accomplishing precision oncology and applying big data for use in Indonesia are discussed. Utilizing open access genomic data in writing research articles is also described.

Link synthetic lethality to drug sensitivity of cancer cells

2017 ◽  
Vol 20 (4) ◽  
pp. 1295-1307 ◽  
Author(s):  
Ruiping Wang ◽  
Yue Han ◽  
Zhangxiang Zhao ◽  
Fan Yang ◽  
Tingting Chen ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Drug Sensitivity ◽  
Target Genes ◽  
Synthetic Lethality ◽  
Cancer Cell Line ◽  
The Cancer Genome Atlas ◽  
Breast Cancer Cell Lines

Abstract Synthetic lethal (SL) interactions occur when alterations in two genes lead to cell death but alteration in only one of them is not lethal. SL interactions provide a new strategy for molecular-targeted cancer therapy. Currently, there are few drugs targeting SL interactions that entered into clinical trials. Therefore, it is necessary to investigate the link between SL interactions and drug sensitivity of cancer cells systematically for drug development purpose. We identified SL interactions by integrating the high-throughput data from The Cancer Genome Atlas, small hairpin RNA data and genetic interactions of yeast. By integrating SL interactions from other studies, we tested whether the SL pairs that consist of drug target genes and the genes with genomic alterations are related with drug sensitivity of cancer cells. We found that only 6.26%∼34.61% of SL interactions showed the expected significant drug sensitivity using the pooled cancer cell line data from different tissues, but the proportion increased significantly to approximately 90% using the cancer cell line data for each specific tissue. From an independent pharmacogenomics data of 41 breast cancer cell lines, we found three SL interactions (ABL1–IFI16, ABL1–SLC50A1 and ABL1–SYT11) showed significantly better prognosis for the patients with both genes being altered than the patients with only one gene being altered, which partially supports the SL effect between the gene pairs. Our study not only provides a new way for unraveling the complex mechanisms of drug sensitivity but also suggests numerous potentially important drug targets for cancer therapy.

A Novel Triazole Derivative Drug Presenting In Vitro and In Vivo Anticancer Properties

2018 ◽  
Vol 18 (17) ◽  
pp. 1483-1493
Author(s):  
Ricardo Imbroisi Filho ◽  
Daniel T.G. Gonzaga ◽  
Thainá M. Demaria ◽  
João G.B. Leandro ◽  
Dora C.S. Costa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Hepatic Function ◽  
Anticancer Properties ◽  
Mcf 7

Background: Cancer is a major cause of death worldwide, despite many different drugs available to treat the disease. This high mortality rate is largely due to the complexity of the disease, which results from several genetic and epigenetic changes. Therefore, researchers are constantly searching for novel drugs that can target different and multiple aspects of cancer. Experimental: After a screening, we selected one novel molecule, out of ninety-four triazole derivatives, that strongly affects the viability and proliferation of the human breast cancer cell line MCF-7, with minimal effects on non-cancer cells. The drug, named DAN94, induced a dose-dependent decrease in MCF-7 cells viability, with an IC50 of 3.2 ± 0.2 µM. Additionally, DAN94 interfered with mitochondria metabolism promoting reactive oxygen species production, triggering apoptosis and arresting the cancer cells on G1/G0 phase of cell cycle, inhibiting cell proliferation. These effects are not observed when the drug was tested in the non-cancer cell line MCF10A. Using a mouse model with xenograft tumor implants, the drug preventing tumor growth presented no toxicity for the animal and without altering biochemical markers of hepatic function. Results and Conclusion: The novel drug DAN94 is selective for cancer cells, targeting the mitochondrial metabolism, which culminates in the cancer cell death. In the end, DAN94 has been shown to be a promising drug for controlling breast cancer with minimal undesirable effects.

scholarly journals Enhanced Vasculogenic Capacity Induced by 5-Fluorouracil Chemoresistance in a Gastric Cancer Cell Line

2021 ◽  
Vol 22 (14) ◽  
pp. 7698
Author(s):  
Sara Peri ◽  
Alessio Biagioni ◽  
Giampaolo Versienti ◽  
Elena Andreucci ◽  
Fabio Staderini ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Intracellular Signaling ◽  
Gastric Cancer Cell ◽  
Gastric Cancer Cell Line ◽  
Cancer Cell Line ◽  
Tumor Evolution ◽  
Selective Growth Advantage

Chemotherapy is still widely used as a coadjutant in gastric cancer when surgery is not possible or in presence of metastasis. During tumor evolution, gatekeeper mutations provide a selective growth advantage to a subpopulation of cancer cells that become resistant to chemotherapy. When this phenomenon happens, patients experience tumor recurrence and treatment failure. Even if many chemoresistance mechanisms are known, such as expression of ATP-binding cassette (ABC) transporters, aldehyde dehydrogenase (ALDH1) activity and activation of peculiar intracellular signaling pathways, a common and universal marker for chemoresistant cancer cells has not been identified yet. In this study we subjected the gastric cancer cell line AGS to chronic exposure of 5-fluorouracil, cisplatin or paclitaxel, thus selecting cell subpopulations showing resistance to the different drugs. Such cells showed biological changes; among them, we observed that the acquired chemoresistance to 5-fluorouracil induced an endothelial-like phenotype and increased the capacity to form vessel-like structures. We identified the upregulation of thymidine phosphorylase (TYMP), which is one of the most commonly reported mutated genes leading to 5-fluorouracil resistance, as the cause of such enhanced vasculogenic ability.

scholarly journals Seeding of breast cancer cell line (MDA-MB-231LUC+) to the mandible induces overexpression of substance P and CGRP throughout the trigeminal ganglion and widespread peripheral sensory neuropathy throughout all three of its divisions

2021 ◽  
Vol 17 ◽  
pp. 174480692110240
Author(s):  
Silvia Gutierrez ◽  
James C Eisenach ◽  
M Danilo Boada
Keyword(s):  
Breast Cancer ◽  
Substance P ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Trigeminal Ganglion ◽  
Breast Cancer Cell Line ◽  
Cancer Cell Line ◽  
The Impact

Some types of cancer are commonly associated with intense pain even at the early stages of the disease. The mandible is particularly vulnerable to metastasis from breast cancer, and this process has been studied using a bioluminescent human breast cancer cell line (MDA-MB-231LUC+). Using this cell line and anatomic and neurophysiologic methods in the trigeminal ganglion (TG), we examined the impact of cancer seeding in the mandible on behavioral evidence of hypersensitivity and on trigeminal sensory neurons. Growth of cancer cells seeded to the mandible after arterial injection of the breast cancer cell line in Foxn1 animals (allogeneic model) induced behavioral hypersensitivity to mechanical stimulation of the whisker pad and desensitization of tactile and sensitization of nociceptive mechanically sensitive afferents. These changes were not restricted to the site of metastasis but extended to sensory afferents in all three divisions of the TG, accompanied by widespread overexpression of substance P and CGRP in neurons through the ganglion. Subcutaneous injection of supernatant from the MDA-MB-231LUC+ cell culture in normal animals mimicked some of the changes in mechanically responsive afferents observed with mandibular metastasis. We conclude that released products from these cancer cells in the mandible are critical for the development of cancer-induced pain and that the overall response of the system greatly surpasses these local effects, consistent with the widespread distribution of pain in patients. The mechanisms of neuronal plasticity likely occur in the TG itself and are not restricted to afferents exposed to the metastatic cancer microenvironment.

Potential Mechanisms of miR-143/Krupple Like Factor 5 Axis in Impeding the Proliferation of Michigan Cancer Foundation-7 Breast Cancer Cell Line

2021 ◽  
Vol 11 (2) ◽  
pp. 326-332
Author(s):  
Le Ma ◽  
Zhenyu Liu ◽  
Zhimin Fan
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cell Model ◽  
Cancer Cell Line ◽  
Breast Cancer Cell Model ◽  
Underlying Mechanisms ◽  
Mcf 7

Breast cancer is one of the most prevailing cancers in females, while the cancerous heterogeneity hinders its early diagnosis and subsequent therapy. miR-143-3p is a critical mediator in malignancy development and tumorigenesis as a tumor suppressor. Its role in various tumor entities has been investigated, such as colon cancer and breast cancer. Using MCF-7 breast cancer cell model, we planned to explore the underlying mechanisms of miR-143/KLF-5 axis in retarding breast cancer cells growth. Bioinformatics analysis searched the target KLF5 of miR-143, and the miR-143-targeted mimic and inhibitor were employed to detect the changes of KLF5. After transfection of mimic miR-143, the CCK-8 reagent assessed cell proliferation. Based on optimal stimulation time, miR-143 stimulation model was established, followed by determining expression of KLF5, EGFR and PCNA via western blot and qPCR. Eventually, siRNA-KLF5 was applied to silencing KLF5 level to evaluate its role in MCF-7 cells. The transcription and translation levels of KLF5 were diminished in miR-143-mimic transfected MCF-7 cells, while enhanced in miR-143-inhibitor transfected MCF-7 cells. When MCF-7 cells were transfected with miR-143-mimic at different time points, 48 hours was found to be the optimal transfection time, with reduced transcription and translation levels of KLF5, EGFR and PCNA. The transcription and translation levels of PNCA and EGFR were declined after silencing KLF5 by siRNA. miR-143/KLF5 axis could retard the proliferation of MCF-7 breast cancer cells.

scholarly journals Establishment and Characterization of a Novel Multidrug Resistant Human Ovarian Cancer Cell Line With Heterogenous MRP7 Overexpression

2021 ◽  
Vol 11 ◽  
Author(s):  
Jing-Quan Wang ◽  
Zhuo-Xun Wu ◽  
Yuqi Yang ◽  
Jin-Sui Li ◽  
Dong-Hua Yang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Multidrug Resistance ◽  
Cell Line ◽  
Anticancer Drugs ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Ovarian Cancer Cell Line ◽  
Cancer Cell Line ◽  
Chemotherapeutic Drugs ◽  
Mesenchymal Transition

Ovarian cancer is one of the leading female malignancies which accounts for the highest mortality rate among gynecologic cancers. Surgical cytoreduction followed by chemotherapy is the mainstay of treatment. However, patients with recurrent ovarian cancer are likely to exhibit resistance to chemotherapy due to reduced sensitivity to chemotherapeutic drugs. Adenosine triphosphate (ATP)-binding cassette (ABC) transporters have been extensively studied as multidrug resistance (MDR) mediators since they are responsible for the efflux of various anticancer drugs. Multidrug resistance protein 7 (MRP7, or ABCC10) was discovered in 2001 and revealed to transport chemotherapeutic drugs. Till now, only limited knowledge was obtained regarding its roles in ovarian cancer. In this study, we established an MRP7-overexpressing ovarian cancer cell line SKOV3/MRP7 via transfecting recombinant MRP7 plasmids. The SKOV3/MRP7 cell line was resistant to multiple anticancer drugs including paclitaxel, docetaxel, vincristine and vinorelbine with a maximum of 8-fold resistance. Biological function of MRP7 protein was further determined by efflux-accumulation assays. Additionally, MTT results showed that the drug resistance of the SKOV3/MRP7 cells was reversed by cepharanthine, a known inhibitor of MRP7. Moreover, we also found that the overexpression of MRP7 enhanced the migration and epithelial-mesenchymal transition (EMT) induction. In conclusion, we established an in vitro model of MDR in ovarian cancer and suggested MRP7 overexpression as the leading mechanism of chemoresistance in this cell line. Our results demonstrated the potential relationship between MRP7 and ovarian cancer MDR.

scholarly journals Synthesis, Antibacterial and Anticancer Activities Evaluation of New 4-Thiazolidinone-Indolin-2-One Analogs

2021 ◽  
Vol 12 (6) ◽  
pp. 8094-8104
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
A549 Cells ◽  
Cancer Cell Line ◽  
Mitochondrial Pathway ◽  
Knoevenagel Reaction ◽  
Anticancer Activities ◽  
Dapi Staining ◽  
Mcf 7

A series of novel thiazolidinone-isatin hybrids have been synthesized through the Knoevenagel reaction of isatin derivatives with synthesized thiazolidinone scaffolds and then evaluated for their in vitro antibacterial effects on Escherichia coli (E.coli) and Staphylococcus aureus (S.aureus). Cytotoxic effects of the compounds on non-small-cell lung cancer cells (A549 cells), breast epithelial cancer cell line (MCF-7), and prostate cancer cells (PC3 cells) were investigated. Among compounds tested for antibacterial activity, S. aureus was susceptible to compound 7d. The most potent compounds against A549, MCF-7, and PC3 tumor cells were found to be 7g. DAPI staining of all cancer cell lines treated with compound 7g, associated with cell death. We finally confirmed that apoptosis occurred in A549 cells by up-regulated Bax expression and down-regulated Bcl-2 expression from the mitochondrial pathway of apoptosis by using the quantitative reverse transcription-polymerase chain reaction (qRT-PCR) method. Our findings suggested that compound 7g may be a good target in designing cancer therapy strategies.

scholarly journals Intrinsic growth heterogeneity of mouse leukemia cells underlies differential susceptibility to a growth-inhibiting anticancer drug

2020 ◽  
Author(s):  
Akihisa Seita ◽  
Hidenori Nakaoka ◽  
Reiko Okura ◽  
Yuichi Wakamoto
Keyword(s):  
Cancer Cells ◽  
Anticancer Drugs ◽  
Cancer Cell ◽  
Anticancer Drug ◽  
Differential Susceptibility ◽  
Leukemia Cells ◽  
Continuous Exposure ◽  
Phenotypic Differences ◽  
Cell Lineages ◽  
Slow Cycling

AbstractCancer cell populations consist of phenotypically heterogeneous cells. Growing evidence suggests that pre-existing phenotypic differences among cancer cells correlate with differential susceptibility to anticancer drugs and eventually lead to a relapse. Such phenotypic differences can arise not only externally driven by the environmental heterogeneity around individual cells but also internally by the intrinsic fluctuation of cells. However, the quantitative characteristics of intrinsic phenotypic heterogeneity emerging even under constant environments and their relevance to drug susceptibility remain elusive. Here we employed a microfluidic device, mammalian mother machine, for studying the intrinsic heterogeneity of growth dynamics of mouse lymphocytic leukemia cells (L1210) across tens of generations. The generation time of this cancer cell line had a distribution with a long tail and a heritability across generations. We determined that a minority of cell lineages exist in a slow-cycling state for multiple generations. These slow-cycling cell lineages had a higher chance of survival than the fast-cycling lineages under continuous exposure to the anticancer drug Mitomycin C. This result suggests that heritable heterogeneity in cancer cells’ growth in a population influences their susceptibility to anticancer drugs.

scholarly journals A human cancer cell line initiates DNA replication normally in the absence of ORC5 and ORC2 proteins

2020 ◽  
Vol 295 (50) ◽  
pp. 16949-16959
Author(s):  
Etsuko Shibata ◽  
Anindya Dutta
Keyword(s):  
Dna Replication ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Origin Recognition Complex ◽  
Human Cancer ◽  
Cancer Cell Line ◽  
Aaa Atpase ◽  
Normal Number ◽  
Mutant Cells

The origin recognition complex (ORC), composed of six subunits, ORC1–6, binds to origins of replication as a ring-shaped heterohexameric ATPase that is believed to be essential to recruit and load MCM2–7, the minichromosome maintenance protein complex, around DNA and initiate DNA replication. We previously reported the creation of viable cancer cell lines that lacked detectable ORC1 or ORC2 protein without a reduction in the number of origins firing. Here, using CRISPR-Cas9–mediated mutations, we report that human HCT116 colon cancer cells also survive when ORC5 protein expression is abolished via a mutation in the initiator ATG of the ORC5 gene. Even if an internal methionine is used to produce an undetectable, N terminally deleted ORC5, the protein would lack 80% of the AAA+ ATPase domain, including the Walker A motif. The ORC5-depleted cells show normal chromatin binding of MCM2–7 and initiate replication from a similar number of origins as WT cells. In addition, we introduced a second mutation in ORC2 in the ORC5 mutant cells, rendering both ORC5 and ORC2 proteins undetectable in the same cells and destabilizing the ORC1, ORC3, and ORC4 proteins. Yet the double mutant cells grow, recruit MCM2–7 normally to chromatin, and initiate DNA replication with normal number of origins. Thus, in these selected cancer cells, either a crippled ORC lacking ORC2 and ORC5 and present at minimal levels on the chromatin can recruit and load enough MCM2–7 to initiate DNA replication, or human cell lines can sometimes recruit MCM2–7 to origins independent of ORC.

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