Search: onr:"swepub:oai:research.chalmers.se:84670e35-4f87-4b11-a731-178fefb352ee" >
Identification of a...
Identification of anticancer drugs for hepatocellular carcinoma through personalized genome-scale metabolic modeling
-
- Ågren, Rasmus, 1982 (author)
- Chalmers tekniska högskola,Chalmers University of Technology
-
- Mardinoglu, Adil, 1982 (author)
- Chalmers tekniska högskola,Chalmers University of Technology
-
- Asplund, Anna (author)
- Uppsala universitet,Molekylär och morfologisk patologi
-
show more...
-
- Kampf, Caroline (author)
- Uppsala universitet,Molekylär och morfologisk patologi
-
- Uhlén, Mathias (author)
- KTH,Proteomik och nanobioteknologi,Science for Life Laboratory, SciLifeLab
-
- Nielsen, Jens B, 1962 (author)
- KTH,Science for Life Laboratory, SciLifeLab
-
show less...
-
(creator_code:org_t)
- 2014-03-28
- 2014
- English.
-
In: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 10:3
- Related links:
-
http://publications.... (primary) (free)
-
show more...
-
https://doi.org/10.1...
-
https://uu.diva-port... (primary) (Raw object)
-
https://research.cha...
-
https://doi.org/10.1...
-
https://urn.kb.se/re...
-
https://urn.kb.se/re...
-
show less...
Abstract
Subject headings
Close
- Synopsis Personalized GEMs for six hepatocellular carcinoma patients are reconstructed using proteomics data and a task-driven model reconstruction algorithm. These GEMs are used to predict antimetabolites preventing tumor growth in all patients or in individual patients. The presence of proteins encoded by 15,841 genes in tumors from 27 HCC patients is evaluated by immunohistochemistry. Personalized GEMs for six HCC patients and GEMs for 83 healthy cell types are reconstructed based on HMR 2.0 and the tINIT algorithm for task-driven model reconstruction. 101 antimetabolites are predicted to inhibit tumor growth in all patients. Antimetabolite toxicity is tested using the 83 cell type-specific GEMs. Genome-scale metabolic models (GEMs) have proven useful as scaffolds for the integration of omics data for understanding the genotype-phenotype relationship in a mechanistic manner. Here, we evaluated the presence/absence of proteins encoded by 15,841 genes in 27 hepatocellular carcinoma (HCC) patients using immunohistochemistry. We used this information to reconstruct personalized GEMs for six HCC patients based on the proteomics data, HMR 2.0, and a task-driven model reconstruction algorithm (tINIT). The personalized GEMs were employed to identify anticancer drugs using the concept of antimetabolites; i.e., drugs that are structural analogs to metabolites. The toxicity of each antimetabolite was predicted by assessing the in silico functionality of 83 healthy cell type-specific GEMs, which were also reconstructed with the tINIT algorithm. We predicted 101 antimetabolites that could be effective in preventing tumor growth in all HCC patients, and 46 antimetabolites which were specific to individual patients. Twenty-two of the 101 predicted antimetabolites have already been used in different cancer treatment strategies, while the remaining antimetabolites represent new potential drugs. Finally, one of the identified targets was validated experimentally, and it was confirmed to attenuate growth of the HepG2 cell line.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- FATTY-ACID OXIDATION
- hepatocellular carcinoma
- GLOBAL
- genome-scale metabolic models
- INHIBITION
- CARNITINE
- CANCER METABOLISM
- antimetabolites
- MEDICINE
- HUMAN PROTEIN ATLAS
- personalized medicine
- CELLS
- ADULTS
- RECONSTRUCTION
- proteome
Publication and Content Type
- art (subject category)
- ref (subject category)
Find in a library
To the university's database