2020
Drápela, Stanislav; Khirsariya, Prashant; Weerden, Wytske M.; Fedr, Radek; Suchánková, Tereza; Búzová, Diana; Červený, Jan; Hampl, Aleš; Puhr, Martin; Watson, William R.; Culig, Zoran; Krejčí, Lumír; Paruch, Kamil; Souček, Karel
In: Molecular oncology, vol. 14, no. 10, pp. 2487–2503, 2020, ISSN: 1878-0261 1574-7891, (Place: United States).
Abstract | Links | BibTeX | Tags: *Mitosis/drug effects, Animals, castration-resistant prostate cancer, Cell Death/drug effects, Cell Line, Cell Proliferation/drug effects, Checkpoint Kinase 1, Checkpoint Kinase 1/*antagonists & inhibitors/metabolism, Deoxycytidine/*analogs & derivatives/pharmacology, Docetaxel resistance, Docetaxel/*pharmacology, Drug resistance, gemcitabine, Humans, Male, Mice, mitotic catastrophe, MU380, Neoplasm/*drug effects, Piperidines/chemistry/*pharmacology, Prostatic Neoplasms/*pathology, Pyrazoles/chemistry/*pharmacology, Pyrimidines/chemistry/*pharmacology, S Phase/drug effects, SCID, Tumor, Xenograft Model Antitumor Assays
@article{drapela_chk1_2020,
title = {The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe.},
author = {Stanislav Drápela and Prashant Khirsariya and Wytske M. Weerden and Radek Fedr and Tereza Suchánková and Diana Búzová and Jan Červený and Aleš Hampl and Martin Puhr and William R. Watson and Zoran Culig and Lumír Krejčí and Kamil Paruch and Karel Souček},
doi = {10.1002/1878-0261.12756},
issn = {1878-0261 1574-7891},
year = {2020},
date = {2020-10-01},
journal = {Molecular oncology},
volume = {14},
number = {10},
pages = {2487–2503},
abstract = {As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo-naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC.},
note = {Place: United States},
keywords = {*Mitosis/drug effects, Animals, castration-resistant prostate cancer, Cell Death/drug effects, Cell Line, Cell Proliferation/drug effects, Checkpoint Kinase 1, Checkpoint Kinase 1/*antagonists & inhibitors/metabolism, Deoxycytidine/*analogs & derivatives/pharmacology, Docetaxel resistance, Docetaxel/*pharmacology, Drug resistance, gemcitabine, Humans, Male, Mice, mitotic catastrophe, MU380, Neoplasm/*drug effects, Piperidines/chemistry/*pharmacology, Prostatic Neoplasms/*pathology, Pyrazoles/chemistry/*pharmacology, Pyrimidines/chemistry/*pharmacology, S Phase/drug effects, SCID, Tumor, Xenograft Model Antitumor Assays},
pubstate = {published},
tppubtype = {article}
}
As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo-naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC.
2019
Boudny, Miroslav; Zemanova, Jana; Khirsariya, Prashant; Borsky, Marek; Verner, Jan; Cerna, Jana; Oltova, Alexandra; Seda, Vaclav; Mraz, Marek; Jaros, Josef; Jaskova, Zuzana; Spunarova, Michaela; Brychtova, Yvona; Soucek, Karel; Drapela, Stanislav; Kasparkova, Marie; Mayer, Jiri; Paruch, Kamil; Trbusek, Martin
Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells. Journal Article
In: Haematologica, vol. 104, no. 12, pp. 2443–2455, 2019, ISSN: 1592-8721 0390-6078, (Place: Italy).
Abstract | Links | BibTeX | Tags: *Drug Synergism, *Mutation, Animals, Antimetabolites, Antineoplastic/pharmacology, Apoptosis, B-Cell/*drug therapy/genetics/pathology, Biomarkers, Cell Cycle, Cell Proliferation, Checkpoint Kinase 1/*antagonists & inhibitors, Chronic, Cultured, Deoxycytidine/analogs & derivatives/pharmacology, Drug resistance, Female, gemcitabine, Gene Expression Regulation, Humans, Inbred NOD, Leukemia, Lymphocytic, Mice, Neoplasm/drug effects, Neoplastic/*drug effects, Piperidines/*pharmacology, Protein Kinase Inhibitors/pharmacology, Pyrazoles/*pharmacology, Pyrimidines/*pharmacology, SCID, Tumor Cells, Tumor Suppressor Protein p53/*genetics, Tumor/genetics, Xenograft Model Antitumor Assays
@article{boudny_novel_2019,
title = {Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells.},
author = {Miroslav Boudny and Jana Zemanova and Prashant Khirsariya and Marek Borsky and Jan Verner and Jana Cerna and Alexandra Oltova and Vaclav Seda and Marek Mraz and Josef Jaros and Zuzana Jaskova and Michaela Spunarova and Yvona Brychtova and Karel Soucek and Stanislav Drapela and Marie Kasparkova and Jiri Mayer and Kamil Paruch and Martin Trbusek},
doi = {10.3324/haematol.2018.203430},
issn = {1592-8721 0390-6078},
year = {2019},
date = {2019-12-01},
journal = {Haematologica},
volume = {104},
number = {12},
pages = {2443–2455},
abstract = {Introduction of small-molecule inhibitors of B-cell receptor signaling and BCL2 protein significantly improves therapeutic options in chronic lymphocytic leukemia. However, some patients suffer from adverse effects mandating treatment discontinuation, and cases with TP53 defects more frequently experience early progression of the disease. Development of alternative therapeutic approaches is, therefore, of critical importance. Here we report details of the anti-chronic lymphocytic leukemia single-agent activity of MU380, our recently identified potent, selective, and metabolically robust inhibitor of checkpoint kinase 1. We also describe a newly developed enantioselective synthesis of MU380, which allows preparation of gram quantities of the substance. Checkpoint kinase 1 is a master regulator of replication operating primarily in intra-S and G(2)/M cell cycle checkpoints. Initially tested in leukemia and lymphoma cell lines, MU380 significantly potentiated efficacy of gemcitabine, a clinically used inducer of replication stress. Moreover, MU380 manifested substantial single-agent activity in both TP53-wild type and TP53-mutated leukemia and lymphoma cell lines. In chronic lymphocytic leukemia-derived cell lines MEC-1, MEC-2 (both TP53-mut), and OSU-CLL (TP53-wt) the inhibitor impaired cell cycle progression and induced apoptosis. In primary clinical samples, MU380 used as a single-agent noticeably reduced the viability of unstimulated chronic lymphocytic leukemia cells as well as those induced to proliferate by anti-CD40/IL-4 stimuli. In both cases, effects were comparable in samples harboring p53 pathway dysfunction (TP53 mutations or ATM mutations) and TP53-wt/ATM-wt cells. Lastly, MU380 also exhibited significant in vivo activity in a xenotransplant mouse model (immunodeficient strain NOD-scid IL2Rγ(null) ) where it efficiently suppressed growth of subcutaneous tumors generated from MEC-1 cells.},
note = {Place: Italy},
keywords = {*Drug Synergism, *Mutation, Animals, Antimetabolites, Antineoplastic/pharmacology, Apoptosis, B-Cell/*drug therapy/genetics/pathology, Biomarkers, Cell Cycle, Cell Proliferation, Checkpoint Kinase 1/*antagonists & inhibitors, Chronic, Cultured, Deoxycytidine/analogs & derivatives/pharmacology, Drug resistance, Female, gemcitabine, Gene Expression Regulation, Humans, Inbred NOD, Leukemia, Lymphocytic, Mice, Neoplasm/drug effects, Neoplastic/*drug effects, Piperidines/*pharmacology, Protein Kinase Inhibitors/pharmacology, Pyrazoles/*pharmacology, Pyrimidines/*pharmacology, SCID, Tumor Cells, Tumor Suppressor Protein p53/*genetics, Tumor/genetics, Xenograft Model Antitumor Assays},
pubstate = {published},
tppubtype = {article}
}
Introduction of small-molecule inhibitors of B-cell receptor signaling and BCL2 protein significantly improves therapeutic options in chronic lymphocytic leukemia. However, some patients suffer from adverse effects mandating treatment discontinuation, and cases with TP53 defects more frequently experience early progression of the disease. Development of alternative therapeutic approaches is, therefore, of critical importance. Here we report details of the anti-chronic lymphocytic leukemia single-agent activity of MU380, our recently identified potent, selective, and metabolically robust inhibitor of checkpoint kinase 1. We also describe a newly developed enantioselective synthesis of MU380, which allows preparation of gram quantities of the substance. Checkpoint kinase 1 is a master regulator of replication operating primarily in intra-S and G(2)/M cell cycle checkpoints. Initially tested in leukemia and lymphoma cell lines, MU380 significantly potentiated efficacy of gemcitabine, a clinically used inducer of replication stress. Moreover, MU380 manifested substantial single-agent activity in both TP53-wild type and TP53-mutated leukemia and lymphoma cell lines. In chronic lymphocytic leukemia-derived cell lines MEC-1, MEC-2 (both TP53-mut), and OSU-CLL (TP53-wt) the inhibitor impaired cell cycle progression and induced apoptosis. In primary clinical samples, MU380 used as a single-agent noticeably reduced the viability of unstimulated chronic lymphocytic leukemia cells as well as those induced to proliferate by anti-CD40/IL-4 stimuli. In both cases, effects were comparable in samples harboring p53 pathway dysfunction (TP53 mutations or ATM mutations) and TP53-wt/ATM-wt cells. Lastly, MU380 also exhibited significant in vivo activity in a xenotransplant mouse model (immunodeficient strain NOD-scid IL2Rγ(null) ) where it efficiently suppressed growth of subcutaneous tumors generated from MEC-1 cells.