scholarly journals Cellular Fitness Phenotypes of Cancer Target Genes from Oncobiology to Cancer Therapeutics

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 433
Author(s):  
Bijesh George ◽  
P. Mukundan Pillai ◽  
Aswathy Mary Paul ◽  
Revikumar Amjesh ◽  
Kim Leitzel ◽  
...  
Keyword(s):  
Drug Targets ◽  
Target Genes ◽  
Human Cancer ◽  
Cancer Therapeutics ◽  
Survival Duration ◽  
Cancer Drug ◽  
Targeted Therapeutics ◽  
Cellular Targets ◽  
Human Cancer Cells ◽  
Cancer Types

To define the growing significance of cellular targets and/or effectors of cancer drugs, we examined the fitness dependency of cellular targets and effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out of 47 cellular effectors and/or targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting or utilizing these molecules for their actions were approved. Additionally, our analysis recognized 43 cellular molecules as fitness genes in several cancer types in which these drugs were not approved, and thus, providing clues for repurposing certain approved oncology drugs in such cancer types. For example, we found a widespread upregulation and fitness dependency of several components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these molecules and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which such drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended cellular effectors of drug might not be good fitness genes and that this study offers a potential rationale for repurposing certain approved oncology drugs for targeted therapeutics in additional cancer types.

scholarly journals Cellular Fitness Phenotypes of Cancer Target Genes in Cancer Therapeutics

2019 ◽  
Author(s):  
Bijesh George ◽  
P. Mukundan Pillai ◽  
Aswathy Mary Paul ◽  
Kim Leitzel ◽  
Suhail M. Ali ◽  
...  
Keyword(s):  
Drug Targets ◽  
Target Genes ◽  
Human Cancer ◽  
Cancer Therapeutics ◽  
Survival Duration ◽  
Cancer Drug ◽  
Cellular Targets ◽  
Human Cancer Cells ◽  
Cancer Types ◽  
Approved Drugs

AbstractTo define the growing significance of cellular targets of targeted cancer drugs, we examined the fitness dependency of cancer drug targets across human cancer cells in a CRISPR-Cas9 fitness screening dataset wherein cellular genes were selectively knocked out before assaying for their fitness dependency in cancer cell lines representing 19 cancer types. We observed that the deletion of 35 out of 47 fitness targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting these molecules were approved. This raised the possibility of undesirable off-target effects of these drugs in such cancers. Additionally, our analysis recognized 43 drug targets which were fitness genes observed in several cancer types as candidate targets for repurposing approved oncology drugs in cancer types in which these drugs were not approved. For example, we found the widespread upregulation and fitness dependency of the components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these targets and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which these drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended drug targets are not fitness genes. The study also offers a rationale for repurposing approved oncology drugs for cancer types that have significant fitness dependency on cellular targets of such approved drugs.

scholarly journals Cardiac Glycoside Ouabain Exerts Anticancer Activity via Downregulation of STAT3

2021 ◽  
Vol 11 ◽  
Author(s):  
Jie Du ◽  
Lijun Jiang ◽  
Fuqiang Chen ◽  
Huantao Hu ◽  
Meijuan Zhou
Keyword(s):  
Cardiac Glycosides ◽  
Human Cancer ◽  
Cancer Therapeutics ◽  
Initiation Factor ◽  
Ros Generation ◽  
Dna Double Strand Breaks ◽  
Atpase Inhibitor ◽  
Anticancer Activities ◽  
Downstream Target ◽  
Human Cancer Cells

Cardiac glycosides are plant-derived steroid-like compounds which have been used for the treatment of cardiovascular diseases. Ouabain, a cardiotonic steroid and specific Na+/K+-ATPase inhibitor, has been rediscovered for its potential use in the treatment of cancer. However, the cellular targets and anticancer mechanism of ouabain in various cancers remain largely unexplored. In this study, we confirmed the cytotoxic effects of ouabain on several cancer cell lines. Further examination revealed the increase of apoptosis, intracellular ROS generation and DNA double-strand breaks induced by ouabain treatment. Besides, ouabain effectively suppressed STAT3 expression as well as phosphorylation in addition to block STAT3-mediated transcription and downstream target proteins. Interestingly, these inhibitory activities seemed to be independent of the Na+/K+-ATPase. Furthermore, we found that ouabain inhibited protein synthesis through regulation of the eukaryotic initiation factor 4E (eIF4E) and eIF4E binding protein 1 (4EBP1). Taken together, our study provided a novel molecular insight of anticancer activities of ouabain in human cancer cells, which could raise the hope of using cardiac glycosides for cancer therapeutics more rational.

scholarly journals Biochemical Basis of Anti-Cancer-Effects of Phloretin—A Natural Dihydrochalcone

Molecules ◽  
2019 ◽  
Vol 24 (2) ◽  
pp. 278 ◽  
Author(s):  
Bu Choi
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Human Cancer ◽  
Cancer Drug ◽  
Biochemical Basis ◽  
Human Cancer Cells ◽  
Anti Cancer ◽  
Anti Inflammatory ◽  
Natural Agent ◽  
Growth Of Tumor

Apple is a rich source of bioactive phytochemicals that help improve health by preventing and/or curing many disease processes, including cancer. One of the apple polyphenols is phloretin [2′,4′,6′-Trihydroxy-3-(4-hydroxyphenyl)-propiophenone], which has been widely investigated for its antioxidant, anti-inflammatory and anti-cancer activities in a wide array of preclinical studies. The efficacy of phloretin in suppressing xenograft tumor growth in athymic nude mice implanted with a variety of human cancer cells, and the ability of the compound to interfere with cancer cells signaling, have made it a promising candidate for anti-cancer drug development. Mechanistically, phloretin has been reported to arrest the growth of tumor cells by blocking cyclins and cyclin-dependent kinases and induce apoptosis by activating mitochondria-mediated cell death. The blockade of the glycolytic pathway via downregulation of GLUT2 mRNA and proteins, and the inhibition of tumor cells migration, also corroborates the anti-cancer effects of phloretin. This review sheds light on the molecular targets of phloretin as a potential anti-cancer and anti-inflammatory natural agent.

scholarly journals NRF2-dependent bioactivation of mitomycin C as a novel strategy to target KEAP1-NRF2 pathway activation in human cancer

2020 ◽  
Author(s):  
Liam Baird ◽  
Masayuki Yamamoto
Keyword(s):  
Mitomycin C ◽  
Target Genes ◽  
Drug Repositioning ◽  
Human Cancer ◽  
Pentose Phosphate ◽  
Nrf2 Pathway ◽  
Human Cancer Cells ◽  
Human Tumours ◽  
Nrf2 Activation ◽  
Approved Drugs

Activating mutations in the KEAP1-NRF2 pathway are found in approximately 25% of lung tumours, where the hijacking of NRF2's cytoprotective functions results in aggressive tumour growth, chemoresistance, and a poor prognosis for patients. There are currently no approved drugs which target aberrant NRF2 activation, which means that there is an urgent clinical need to target this orphan oncogenic pathway in human tumours. In this study, we used an isogenic pair of wild-type and Keap1 knockout cells to screen a range of chemotherapeutic and pathway targeted anti-cancer drugs in order to identify compounds which display enhanced toxicity towards cells with high levels of Nrf2 activity. Through this approach, complemented by validation across a panel of eight human cancer cells lines from a range of different tissues, we identified the DNA damaging agent mitomycin C to be significantly more toxic in cells with aberrant Nrf2 activation. Mechanistically, we found that the NRF2 target genes cytochrome P450 reductase, NQO1, and enzymes in the pentose phosphate pathway, are all responsible for the NRF2-dependent enhanced bioactivation of mitomycin C. As mitomycin C is already approved for clinical use, it represents as excellent drug repositioning candidate to target the currently untreatable NRF2 activation in human tumours.

A simple yeast-based system for analyzing inhibitor resistance in the human cancer drug targets Hsp90α/β

2010 ◽  
Vol 79 (11) ◽  
pp. 1581-1588 ◽  
Author(s):  
Stefan H. Millson ◽  
Chrisostomos Prodromou ◽  
Peter W. Piper
Keyword(s):  
Drug Targets ◽  
Human Cancer ◽  
Cancer Drug ◽  
Inhibitor Resistance

scholarly journals Network Pharmacology Analysis of the active components and anticancer targets of Rhubarb

2021 ◽  
Author(s):  
Hu Junrui ◽  
Duan Yongqiang ◽  
Cui Gongning ◽  
Luo Qiang ◽  
Xi Shanshan ◽  
...  
Keyword(s):  
Pathway Analysis ◽  
Drug Targets ◽  
Target Genes ◽  
Kegg Pathway ◽  
Enrichment Analysis ◽  
Network Pharmacology ◽  
Active Components ◽  
Active Compounds ◽  
Cellular Targets ◽  
Kegg Pathway Analysis

AbstractTo investigate the mechanisms and active components governing the anticancer activity of rhubarb.The TCMSP database was screened to identify the active components of rhubarb and Swiss target predictions were generated to predict their cellular targets. TTD and OMIM databases were used to predict tumor-related target genes. "Cytoscape" was used to construct drug targets. PPI network analysis, GO enrichment analysis and KEGG pathway analysis of the key targets were investigated using String and David databases. A total of 33 components and 116 corresponding targets were screened. Amongst them, the key active compounds in rhubarb included emodin, aloe emodin, β-sitosterol, emodin methyl ether and rhein, which were predicted to target TP53, AKT1, STAT3, PIK3CA, HRAS, and VEGFA. GO analysis revealed that the cellular targets clustered into 159 biological processes, including those involved in cellular composition (n=24) and molecular functions (n=42, P<0.01). KEGG pathway analysis revealed 85 (P < 0.01) pathways related to cancer. The active compounds in rhubarb target TP53, AKT1 and PIK3CA. Rhubarb therefore regulates cancer development through an array of biological pathways.

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