Systems pharmacodynamic model of combined gemcitabine and trabectedin in pancreatic cancer cells. Part I.Çô Effects on signal transduction pathways related to tumor growth.
J Pharm Sci
; 113(1): 214-227, 2024 01.
Article
in En
| MEDLINE
| ID: mdl-38498417
ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is often chemotherapy-resistant, and novel drug combinations would fill an unmet clinical need. Previously we reported synergistic cytotoxic effects of gemcitabine and trabectedin on pancreatic cancer cells, but underlying protein-level interaction mechanisms remained unclear. We employed a reliable, sensitive, comprehensive, quantitative, high-throughput IonStar proteomic workflow to investigate the time course of gemcitabine and trabectedin effects, alone and combined, upon pancreatic cancer cells. MiaPaCa-2 cells were incubated with vehicle (controls), gemcitabine, trabectedin, and their combinations over 72 hours. Samples were collected at intervals and analyzed using the label-free IonStar liquid chromatography-mass spectrometry (LC-MS/MS) workflow to provide temporal quantification of protein expression for 4,829 proteins in four experimental groups. To characterize diverse signal transduction pathways, a comprehensive systems pharmacodynamic (SPD) model was developed. The analysis is presented in two parts. Here, Part I describes drug responses in cancer cell growth and migration pathways included in the full model receptor tyrosine kinase- (RTK), integrin-, G-protein coupled receptor- (GPCR), and calcium-signaling pathways. The developed model revealed multiple underlying mechanisms of drug actions, provides insight into the basis of drug interaction synergism, and offers a scientific rationale for potential drug combination strategies.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pancreatic Neoplasms
/
Gemcitabine
Limits:
Humans
Language:
En
Journal:
J Pharm Sci
Year:
2024
Document type:
Article