A Synergistic activity of Hsp90 inhibitors and anticancer drugs in pancreatic cancer cell lines
| Author | Affiliation | |
|---|---|---|
Matulis, Daumantas | Vilniaus universitetas | |
Vilniaus universitetas. Biotechnologijos institutas |
| Date |
|---|
2018-01-03 |
The abstract texts have not been edited.
Bibliogr.: p. 54
no. 45.
Heat shock protein 90 (Hsp90) is a molecular chaperone with over 200 identified client proteins. This chaperone protein is crucial for protein folding and stabillization and interfere in many pathways of cancer cells, therefore it is a potential target for anticancer therapy. Hsp90 inhibitors bind to the N-terminal ATP domain of Hsp90, and several of them have entered clinical trials. Recent studies show that Hsp90 inhibitors in combination with clinically used chemotherapeutic agents may act synergistically, therefore such effect can reduce the dose and toxicity of used drugs, and minimize or delay the induction of drug resistance [1]. The aim of our study was to evaluate activity of different combinations of two Hsp90 inhibitors (ICPD47 and ICPD62) and three anticancer agents (gemcitabine, 5fluorouracil and doxorubicin) against pancreatic cancer cells. The effect of Hsp90 inhibitors, other agents and different combinations on cell viability was evaluated by MTT assay in two pancreatic cancer cell lines: MIA PaCa-2 and Panc-1. The type of combination effect was determined by calculating combination index (CI), using CompuSyn software based on Chou-Talalay method [2]. Synergism was considered when CI < 1, antagonism when CI > 1, and CI value of 1 defined an additive effect of the drug combination. Results. Among tested Hsp90 inhibitors ICPD62 had the greatest effect on cell viability (EC50 values after 72 h on MIA PaCa-2 and Panc-1 were 0.446 ± 0.06 µM and 0.41 ± 0.08 µM, respectively) and among other anticancer agents doxorubicin showed the greatest effect on cell viability (EC50 values after 72 h on MIA PaCa-2 and Panc-1 were 0.076 ± 0.03 µM and 0.074 ± 0.02 µM, respectively). The combination of ICPD47 and gemcitabine with concentration ratio 5:1, showed the greatest synergistic activity in MIA PaCa-2 cell line (CI = 0.192, when fa = 0.5), and the combination of ICPD62 and gemcitabine with concentration rat[...].