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.
Highlights
Heat shock protein 90 (Hsp90) is a widely investigated target for anticancer therapy
ICPD47 inhibited the viability of PANC-1 cells almost 2 times stronger than MIA PaCa-2 cells (p < 0.05)
In the anticancer agents group, DOX had the greatest activity on cell viability (EC50 after 72 h on MIA PaCa-2 and PANC-1 cells were 0.08 ± 0.03 μM and 0.07 ± 0.03 μM, respectively)
Summary
Heat shock protein 90 (Hsp90) is a widely investigated target for anticancer therapy. The experimental Hsp[90] inhibitors ICPD47 and ICPD62 demonstrated anticancer activity against colorectal, osteosarcoma and cervical cancer cell lines. 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. Hsp[90] is required for the folding and stability of proteins, which are critical for cell growth, differentiation and survival[4,5] Since this molecule regulates multiple signalling cascades, the inhibition of Hsp[90] has a suppressive effect on many client proteins and biochemical pathways[5]. Recent scientific and clinical data show that Hsp[90] inhibitors strongly affect cancer cell survival and using them in combinations with anticancer agents, it is possible to postpone cell resistance to chemotherapy[6,7]. This method is the most accurate to evaluate the type of combinatorial effect of different compounds
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