Latest Publications

@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}

}

@article{pernicova_role_2014,

title = {The role of high cell density in the promotion of neuroendocrine transdifferentiation of prostate cancer cells.},

author = {Zuzana Pernicová and Eva Slabáková and Radek Fedr and Šárka Šimečková and Josef Jaroš and Tereza Suchánková and Jan Bouchal and Gvantsa Kharaishvili and Milan Král and Alois Kozubík and Karel Souček},

doi = {10.1186/1476-4598-13-113},

issn = {1476-4598},

year  = {2014},

date = {2014-05-01},

journal = {Molecular cancer},

volume = {13},

pages = {113},

abstract = {BACKGROUND: Tumor heterogeneity and the plasticity of cancer cells present challenges for effective clinical diagnosis and therapy. Such challenges are epitomized by neuroendocrine transdifferentiation (NED) and the emergence of neuroendocrine-like cancer cells in prostate tumors. This phenomenon frequently arises from androgen-depleted prostate adenocarcinoma and is associated with the development of castration-resistant prostate cancer and poor prognosis. RESULTS: In this study, we showed that NED was evoked in both androgen receptor (AR)-positive and AR-negative prostate epithelial cell lines by growing the cells to a high density. Androgen depletion and high-density cultivation were both associated with cell cycle arrest and deregulated expression of several cell cycle regulators, such as p27Kip1, members of the cyclin D protein family, and Cdk2. Dual inhibition of Cdk1 and Cdk2 using pharmacological inhibitor or RNAi led to modulation of the cell cycle and promotion of NED. We further demonstrated that the cyclic adenosine 3', 5'-monophosphate (cAMP)-mediated pathway is activated in the high-density conditions. Importantly, inhibition of cAMP signaling using a specific inhibitor of adenylate cyclase, MDL-12330A, abolished the promotion of NED by high cell density. CONCLUSIONS: Taken together, our results imply a new relationship between cell cycle attenuation and promotion of NED and suggest high cell density as a trigger for cAMP signaling that can mediate reversible NED in prostate cancer cells.},

note = {Place: England},

keywords = {*Cell Transdifferentiation/drug effects, Androgen/metabolism, Androgens/pharmacology, CDC2 Protein Kinase, Cell Count, Cell Cycle Checkpoints/drug effects, Cell Line, Cyclic AMP/metabolism, Cyclin-Dependent Kinase 2/metabolism, Cyclin-Dependent Kinases/metabolism, Epithelial Cells/drug effects/enzymology/pathology, Humans, Immunohistochemistry, Male, Neuroendocrine Cells/drug effects/*pathology, Prostatic Neoplasms/*pathology, Protein Kinase Inhibitors/pharmacology, Receptors, Signal Transduction/drug effects, Tumor},

pubstate = {published},

tppubtype = {article}

}

@article{lincova_multiple_2009,

title = {Multiple defects in negative regulation of the PKB/Akt pathway sensitise human cancer cells to the antiproliferative effect of non-steroidal anti-inflammatory drugs.},

author = {Eva Lincová and Ales Hampl and Zuzana Pernicová and Andrea Starsíchová and Pavel Krcmár and Miroslav Machala and Alois Kozubík and Karel Soucek},

doi = {10.1016/j.bcp.2009.05.001},

issn = {1873-2968 0006-2952},

year  = {2009},

date = {2009-09-01},

journal = {Biochemical pharmacology},

volume = {78},

number = {6},

pages = {561–572},

abstract = {Antitumorigenic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are well established in several types of cancer disease. However, the mechanisms driving these processes are not understood in all details. In our study, we observed significant differences in sensitivity of cancer epithelial cell lines to COX-independent antiproliferative effects of NSAIDs. The prostate cancer cell line LNCaP, lacking both critical enzymes in the negative control of PKB/Akt activation, PTEN and SHIP2, was the most sensitive to these effects, as assessed by analysing the cell cycle profile and expression of cell cycle regulating proteins. We found that p53 protein and its signalling pathway is not involved in early antiproliferative action of the selected NSAID-indomethacin. RNAi provided evidence for the involvement of p21(Cip1/Waf1), but not GDF-15, in antiproliferative effects of indomethacin in LNCaP cells. Interestingly, we also found that indomethacin activated PKB/Akt and induced nuclear localisation of p21(Cip1/Waf1) and Akt2 isoform. Our results are in agreement with other studies and suggest that maintaining of the p21(Cip1/Waf1) level and its intracellular localisation might be influenced by Akt2. Knock-down of SHIP2 by RNAi in PTEN negative prostate and colon cancer cell lines resulted in higher sensitivity to antiproliferative effects of indomethacin. Our data suggest novel mechanisms of NSAIDs antiproliferative action in cancer epithelial cells, which depends on the status of negative regulation of the PKB/Akt pathway and the isoform-specific action of Akt2. Thus, unexpectedly, multiple defects in negative regulation of the PKB/Akt pathway may contribute to increased sensitivity to chemopreventive effects of these widely used drugs.},

note = {Place: England},

keywords = {Anti-Inflammatory Agents, Antineoplastic Agents/pharmacology, Cell Cycle Proteins/metabolism, Cell Cycle/*drug effects/physiology, Cell Line, Cyclin-Dependent Kinase Inhibitor p21/*biosynthesis, Enzyme Induction, Epithelial Cells/*drug effects/pathology, Extracellular Signal-Regulated MAP Kinases/metabolism, Gene Expression/drug effects, Growth Differentiation Factor 15/biosynthesis, Humans, Indomethacin/pharmacology, Male, Non-Steroidal/*pharmacology, Phosphatidylinositol 3-Kinases, Prostatic Neoplasms/*pathology, Proto-Oncogene Proteins c-akt/*metabolism, RNA Interference, Signal Transduction/drug effects/physiology, Tumor, Tumor Suppressor Protein p53/genetics/*metabolism},

pubstate = {published},

tppubtype = {article}

}