Synergistic Cytotoxicity and Molecular Interaction on Drug Targets of Sorafenib and Gemcitabine in Human Pancreas Cancer Cells

Chemotherapy ◽  
2010 ◽  
Vol 56 (4) ◽  
pp. 303-312 ◽  
Author(s):  
Simona Ricciardi ◽  
Valentina Mey ◽  
Sara Nannizzi ◽  
Giuseppe Pasqualetti ◽  
Francesco Crea ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Molecular Interaction ◽  
Drug Targets ◽  
Pancreas Cancer ◽  
Human Pancreas ◽  
Synergistic Cytotoxicity

scholarly journals Landscape of Chimeric RNAs in Non-Cancerous Cells

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 466
Author(s):  
Chen Chen ◽  
Samuel Haddox ◽  
Yue Tang ◽  
Fujun Qin ◽  
Hui Li
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Drug Targets ◽  
Neoplastic Cell ◽  
Multiple Cancer ◽  
Chimeric Rnas ◽  
Healthy Donors ◽  
Cancer Types ◽  
Chimeric Rna ◽  
Cancerous Cells

Gene fusions and their products (RNA and protein) have been traditionally recognized as unique features of cancer cells and are used as ideal biomarkers and drug targets for multiple cancer types. However, recent studies have demonstrated that chimeric RNAs generated by intergenic alternative splicing can also be found in normal cells and tissues. In this study, we aim to identify chimeric RNAs in different non-neoplastic cell lines and investigate the landscape and expression of these novel candidate chimeric RNAs. To do so, we used HEK-293T, HUVEC, and LO2 cell lines as models, performed paired-end RNA sequencing, and conducted analyses for chimeric RNA profiles. Several filtering criteria were applied, and the landscape of chimeric RNAs was characterized at multiple levels and from various angles. Further, we experimentally validated 17 chimeric RNAs from different classifications. Finally, we examined a number of validated chimeric RNAs in different cancer and non-cancer cells, including blood from healthy donors, and demonstrated their ubiquitous expression pattern.

SWATH-MS proteomics of PANC-1 and MIA PaCa-2 pancreatic cancer cells allows identification of drug targets alternative to MEK and PI3K inhibition

2021 ◽  
Vol 552 ◽  
pp. 23-29
Author(s):  
Alain Aguilar-Valdés ◽  
Lilia G. Noriega ◽  
Armando R. Tovar ◽  
María de J. Ibarra-Sánchez ◽  
Víctor A. Sosa-Hernández ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Drug Targets ◽  
Pancreatic Cancer Cells ◽  
Pi3k Inhibition

scholarly journals Pathway-guided deep neural network toward interpretable and predictive modeling of drug sensitivity

2020 ◽  
Author(s):  
Lei Deng ◽  
Yideng Cai ◽  
Wenhao Zhang ◽  
Wenyi Yang ◽  
Bo Gao ◽  
...  
Keyword(s):  
Neural Network ◽  
Cancer Cells ◽  
Drug Targets ◽  
Deep Neural Network ◽  
Drug Sensitivity ◽  
Predictive Ability ◽  
Biological Knowledge ◽  
Data Sets ◽  
Source Codes ◽  
Sensitivity Data

AbstractMotivationTo efficiently save cost and reduce risk in drug research and development, there is a pressing demand to develop in-silico methods to predict drug sensitivity to cancer cells. With the exponentially increasing number of multi-omics data derived from high-throughput techniques, machine learning-based methods have been applied to the prediction of drug sensitivities. However, these methods have drawbacks either in the interpretability of mechanism of drug action or limited performance in modeling drug sensitivity.ResultsIn this paper, we presented a pathway-guided deep neural network model, referred to as pathDNN, to predict the drug sensitivity to cancer cells. Biological pathways describe a group of molecules in a cell that collaborates to control various biological functions like cell proliferation and death, thereby abnormal function of pathways can result in disease. To make advantage of both the excellent predictive ability of deep neural network and the biological knowledge of pathways, we reshape the canonical DNN structure by incorporating a layer of pathway nodes and their connections to input gene nodes, which makes the DNN model more interpretable and predictive compared to canonical DNN. We have conducted extensive performance evaluations on multiple independent drug sensitivity data sets, and demonstrate that pathDNN significantly outperformed canonical DNN model and seven other classical regression models. Most importantly, we observed remarkable activity decreases of disease-related pathway nodes during forward propagation upon inputs of drug targets, which implicitly corresponds to the inhibition effect of disease-related pathways induced by drug treatment on cancer cells. Our empirical experiments show that pathDNN achieves pharmacological interpretability and predictive ability in modeling drug sensitivity to cancer cells.AvailabilityThe web server, as well as the processed data sets and source codes for reproducing our work, is available at http://pathdnn.denglab.org

scholarly journals DGAT1 is a lipid metabolism oncoprotein that enables cancer cells to accumulate fatty acid while avoiding lipotoxicity

2020 ◽  
Author(s):  
Daniel J. Wilcock ◽  
Andrew P. Badrock ◽  
Rhys Owen ◽  
Melissa Guerin ◽  
Andrew D. Southam ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Cell Growth ◽  
Cancer Cells ◽  
Melanoma Cell ◽  
Drug Targets ◽  
Lipid Peroxides ◽  
Acid Oxidation ◽  
Growth Factor Signaling ◽  
Bona Fide

ABSTRACTDysregulated cellular metabolism is a hallmark of cancer. As yet, few druggable oncoproteins directly responsible for this hallmark have been identified. Increased fatty acid acquisition allows cancer cells to meet their membrane biogenesis, ATP, and signaling needs. Excess fatty acids suppress growth factor signaling and cause oxidative stress in non-transformed cells, but surprisingly not in cancer cells. Molecules underlying this cancer adaptation may provide new drug targets. Here, we identify Diacylglycerol O-acyltransferase 1 (DGAT1), an enzyme integral to triacylglyceride synthesis and lipid droplet formation, as a frequently up-regulated oncoprotein allowing cancer cells to tolerate excess fatty acids. DGAT1 over-expression alone induced melanoma in zebrafish melanocytes, and co-operated with oncogenic BRAF or NRAS for more rapid melanoma formation. Mechanistically, DGAT1 stimulated melanoma cell growth through sustaining mTOR kinase–S6 kinase signaling and suppressed cell death by tempering fatty acid oxidation, thereby preventing accumulation of reactive oxygen species including lipid peroxides.SIGNIFICANCEWe show that DGAT1 is a bona fide oncoprotein capable of inducing melanoma formation and co-operating with other known drivers of melanoma. DGAT1 facilitates enhanced fatty acid acquisition by melanoma cells through suppressing lipototoxicity. DGAT1 is also critical for maintaining S6K activity required for melanoma cell growth.

Synergistic Cytotoxicity Effect of 5-fluorouracil and SHP2 Inhibitor Demethylincisterol A3 on Cervical Cancer Cell

2021 ◽  
Vol 21 ◽  
Author(s):  
Yang Liu ◽  
Hua Fu ◽  
Li Zuo
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Cytotoxic Effect ◽  
Signalling Pathways ◽  
Combined Effects ◽  
Cytotoxic Effects ◽  
Promising Strategy ◽  
Synergistic Cytotoxicity ◽  
Cervical Cancer Cells ◽  
Synergistic Cytotoxic Effect

Background: Demethylincisterol A3 (DTA3) has been identified as an SHP2 inhibitor and suppresses the growth of many cancer cells. 5-Fluorouracil (5-FU) is widely used for the clinical treatment of various cancers. However, the combined effects of 5-FU and DTA3 on cervical cancer cells remain unknown. Objective: his study evaluates the mechanism of the combined effects of 5-FU and DTA3 in cervical cancer cells. Methods: The synergistic cytotoxic effects of 5-FU and DTA3 in cervical cancer cells were calculated. Apoptosis was analysed by flow cytometry. Western blot analyses were used to examine the related signalling pathways. Results: DTA3 and 5-FU synergized to induce apoptosis and repress proliferation of cervical cancer cells by downregulating the activation of PI3K/AKT and NF-κB signalling pathway. We provided evidence that the upregulation of SHP2 expression by transfection significantly inhibited the cytotoxicity of 5-FU and DTA3. SHP2 knockdown enhanced the antiproliferation activity of 5-FU, indicating targeting SHP2 sensitized cervical cancer cells to 5-FU. Conclusion: Our study demonstrates that SHP2 inhibitor DTA3 and 5-FU have a synergistic cytotoxic effect on cervical cancer cells. The synergistic combination of SHP2 inhibitor and 5-FU may present a promising strategy for the treatment of cervical cancer.

scholarly journals An Anti-PSMA Immunotoxin Reduces Mcl-1 and Bcl2A1 and Specifically Induces in Combination with the BAD-Like BH3 Mimetic ABT-737 Apoptosis in Prostate Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1648
Author(s):  
Anie P. Masilamani ◽  
Viviane Dettmer-Monaco ◽  
Gianni Monaco ◽  
Toni Cathomen ◽  
Irina Kuckuck ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Xenograft Model ◽  
Target Cells ◽  
Prostate Cancer Cells ◽  
Mouse Xenograft Model ◽  
Synergistic Cytotoxicity ◽  
3D Spheroids

Background: Upregulation of anti-apoptotic Bcl-2 proteins in advanced prostate cancer leads to therapeutic resistance by prevention of cell death. New therapeutic approaches aim to target the Bcl-2 proteins for the restoration of apoptosis. Methods: The immunotoxin hD7-1(VL-VH)-PE40 specifically binds to the prostate specific membrane antigen (PSMA) on prostate cancer cells and inhibits protein biosynthesis. It was tested with respect to its effects on the expression of anti-apoptotic Bcl-2 proteins. Combination with the BAD-like mimetic ABT-737 was examined on prostate cancer cells and 3D spheroids and in view of tumor growth and survival in the prostate cancer SCID mouse xenograft model. Results: The immunotoxin led to a specific inhibition of Mcl-1 and Bcl2A1 expression in PSMA expressing target cells. Its combination with ABT-737, which inhibits Bcl-2, Bcl-xl, and Bcl-w, led to an induction of the intrinsic apoptotic pathway and to a synergistic cytotoxicity in prostate cancer cells and 3D spheroids. Furthermore, combination therapy led to a significantly prolonged survival of mice bearing prostate cancer xenografts based on an inhibition of tumor growth. Conclusion: The combination therapy of anti-PSMA immunotoxin plus ABT-737 represents the first tumor-specific therapeutic approach on the level of Bcl-2 proteins for the induction of apoptosis in prostate cancer.

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