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Synergistic activity of Hsp90 inhibitors and anticancer agents in pancreatic cancer cell cultures.

ABSTRACT: Heat shock protein 90 (Hsp90) is a widely investigated target for anticancer therapy. The experimental Hsp90 inhibitors ICPD47 and ICPD62 demonstrated anticancer activity against colorectal, osteosarcoma and cervical cancer cell lines. However, their anticancer activity has not been investigated against pancreatic cancer cell lines yet, and there are no data about synergistic activity of these compounds in combination with clinically used anticancer agents. Pancreatic cancer cell lines, MIA PaCa-2 and PANC-1 were exposed to ICPD47 and ICPD62 alone and in combinations with antimetabolites gemcitabine (GEM), 5-fluorouracil (5-FU) and topoisomerase inhibitor doxorubicin (DOX). Effects on cell viability were determined by MTT assay. The synergistic activity was evaluated using Chou-Talalay method. Also, 3D cell cultures were formed using 3D Bioprinting method and the activity of each compound and their combinations was examined by measuring the size change of spheroids. The strongest synergistic activities were determined in combinations using all ratios of ICPD47 with GEM and ICPD62 with GEM in MIA PaCa-2 cell line (combination index <0.5). The combinations of ICPD47 with 5-FU and ICPD47 with GEM in a ratio of 1:5 showed the greatest effect on tumour spheroid growth in both cell lines. The ICPD47 in combination with mild hyperthermia showed significant results, where the EC50 value in PANC-1 cell line dropped from 4.04?±?0.046 to 1.68?±?0.004?µM. The ICPD47 and ICPD62 under the same conditions could act synergistically with GEM, 5-FU and DOX and is worth of further investigations, and studies of synergistic effect is a promising path for more efficient anticancer therapies.

SUBMITTER: Daunys S

PROVIDER: S-EPMC6838130 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Synergistic activity of Hsp90 inhibitors and anticancer agents in pancreatic cancer cell cultures.

Daunys Simonas S Matulis Daumantas D Petrikaitė Vilma V

Scientific reports 20191107 1

Heat shock protein 90 (Hsp90) is a widely investigated target for anticancer therapy. The experimental Hsp90 inhibitors ICPD47 and ICPD62 demonstrated anticancer activity against colorectal, osteosarcoma and cervical cancer cell lines. However, their anticancer activity has not been investigated against pancreatic cancer cell lines yet, and there are no data about synergistic activity of these compounds in combination with clinically used anticancer agents. Pancreatic cancer cell lines, MIA PaCa ...[more]

PMID: 31700053

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Project description:Pancreatic cancer is one of the most aggressive, heterogeneous and fatal type of human cancers for which more effective therapeutic agents are urgently needed. Here, we investigated the sensitivity of a panel of seven human pancreatic cancer cell lines (HPCCLs) to treatment with various tyrosine kinase inhibitors (TKIs), cyclin‑dependent kinase (CDK) inhibitors, an inhibitor of STAT3 stattic, and a cytotoxic agent gemcitabine both as single agents and in combination. The membranous expression of various receptors and the effect of selected agents on cell cycle distribution, cell signaling pathways and migration was determined using flow cytometry, western blot analysis and scratch wound healing assays, respectively. While the expression of both HER‑3 and HER‑4 was low or negative, the expression of EGFR and HER2 was high or intermediate in all HPCCLs. Of all the agents examined, the CDK1/2/5/9 inhibitor, dinacicilib, was the most potent agent which inhibited the proliferation of all seven HPCCLs with IC50 values of ≤10 nM, followed by SRC targeting TKI dasatinib (IC50 of ≤258 nM), gemcitabine (IC50 of ≤330 nM), stattic (IC50 of ≤2 µM) and the irreversible pan‑HER TKI afatinib (IC50 of ≤2.95 µM). Treatment with afatinib and dasatinib inhibited the ligand‑induced phosphorylation of EGFR and SRC respectively. Statistically significant associations were found between HER2 expression and response to treatment with the ALK/IGF‑IR/InsR inhibitor ceritinib and fibroblast growth factor receptor (FGFR)1/2/3 inhibitor AZD4547, HER3 and IGF‑IR expression and their response to treatment with TKIs targeting HER family members (erlotinib and afatinib), and c‑MET and ALK7 expression and their response to treatment with stattic. Interestingly, treatment with a combination of afatinib with dasatinib and gemcitabine with dasatinib resulted in synergistic tumor growth inhibition in all HPCCLs examined. In contrast, the combination of afatinib with dinaciclib was found to be antagonistic. Finally, the treatment with afatinib, dasatinib and dinaciclib strongly inhibited the migration of all HPCCLs examined. In conclusion, the CDK1/2/5/9 inhibitor dinaciclib, irreversible pan‑HER TKI afatinib and SRC targeting TKI dasatinib were most effective at inhibiting the proliferation and migration of HPCCLs and the combination of afatinib with dasatinib and gemcitabine with dasatinib led to synergistic tumor growth inhibition in all HPCCLs examined. Our results support further investigation on the therapeutic potential of these combinations in future clinical trials in pancreatic cancer.

Dataset Information

Synergistic activity of Hsp90 inhibitors and anticancer agents in pancreatic cancer cell cultures.

Publications

Synergistic activity of Hsp90 inhibitors and anticancer agents in pancreatic cancer cell cultures.

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