scholarly journals The Individual Effects of Cyclin-Dependent Kinase Inhibitors on Head and Neck Cancer Cells—A Systematic Analysis

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2396
Author(s):  
Nina Schoenwaelder ◽  
Inken Salewski ◽  
Nadja Engel ◽  
Mareike Krause ◽  
Björn Schneider ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Head And Neck ◽  
Kinase Inhibitors ◽  
In Vivo Studies ◽  
Specific Response ◽  
Cyclin Dependent Kinase ◽  
Systematic Analysis ◽  
Mhc I ◽  
Oncological Treatment

Cyclin-dependent kinase inhibitors (CDKi´s) display cytotoxic activity against different malignancies, including head and neck squamous cell carcinomas (HNSCC). By coordinating the DNA damage response, these substances may be combined with cytostatics to enhance cytotoxicity. Here, we investigated the influence of different CDKi´s (palbociclib, dinaciclib, THZ1) on two HNSCC cell lines in monotherapy and combination therapy with clinically-approved drugs (5-FU, Cisplatin, cetuximab). Apoptosis/necrosis, cell cycle, invasiveness, senescence, radiation-induced γ-H2AX DNA double-strand breaks, and effects on the actin filament were studied. Furthermore, the potential to increase tumor immunogenicity was assessed by analyzing Calreticulin translocation and immune relevant surface markers. Finally, an in vivo mouse model was used to analyze the effect of dinaciclib and Cisplatin combination therapy. Dinaciclib, palbociclib, and THZ1 displayed anti-neoplastic activity after low-dose treatment, while the two latter substances slightly enhanced radiosensitivity. Dinaciclib decelerated wound healing, decreased invasiveness, and induced MHC-I, accompanied by high amounts of surface-bound Calreticulin. Numbers of early and late apoptotic cells increased initially (24 h), while necrosis dominated afterward. Antitumoral effects of the selective CDKi palbociclib were weaker, but combinations with 5-FU potentiated effects of the monotherapy. Additionally, CDKi and CDKi/chemotherapy combinations induced MHC I, indicative of enhanced immunogenicity. The in vivo studies revealed a cell line-specific response with best tumor growth control in the combination approach. Global acting CDKi’s should be further investigated as targeting agents for HNSCC, either individually or in combination with selected drugs. The ability of dinaciclib to increase the immunogenicity of tumor cells renders this substance a particularly interesting candidate for immune-based oncological treatment regimens.

scholarly journals Overriding of cyclin-dependent kinase inhibitors by high and low risk human papillomavirus types: evidence for an in vivo role in cervical lesions

Oncogene ◽  
1999 ◽  
Vol 18 (13) ◽  
pp. 2201-2211 ◽  
Author(s):  
Ingeborg Zehbe ◽  
Andreas Rätsch ◽  
Marianna Alunni-Fabbroni ◽  
Annett Burzlaff ◽  
Evi Bakos ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Kinase Inhibitors ◽  
Low Risk ◽  
Cyclin Dependent Kinase ◽  
Cervical Lesions

scholarly journals Identification of a cyclin-cdk2 recognition motif present in substrates and p21-like cyclin-dependent kinase inhibitors.

1996 ◽  
Vol 16 (12) ◽  
pp. 6623-6633 ◽  
Author(s):  
P D Adams ◽  
W R Sellers ◽  
S K Sharma ◽  
A D Wu ◽  
C M Nalin ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Cyclin A ◽  
Cdk Inhibitors ◽  
Cyclin Dependent Kinase ◽  
Binding Motifs ◽  
Recognition Motif ◽  
Binding Inhibition ◽  
In Vivo Growth

Understanding how cyclin-cdk complexes recognize their substrates is a central problem in cell cycle biology. We identified an E2F1-derived eight-residue peptide which blocked the binding of cyclin A and E-cdk2 complexes to E2F1 and p21. Short peptides spanning similar sequences in p107, p130, and p21-like cdk inhibitors likewise bound to cyclin A-cdk2 and cyclin E-cdk2. In addition, these peptides promoted formation of stable cyclin A-cdk2 complexes in vitro but inhibited the phosphorylation of the retinoblastoma protein by cyclin A- but not cyclin B-associated kinases. Mutation of the cyclin-cdk2 binding motifs in p107 and E2F1 likewise prevented their phosphorylation by cyclin A-associated kinases in vitro. The cdk inhibitor p21 was found to contain two functional copies of this recognition motif, as determined by in vitro kinase binding/inhibition assays and in vivo growth suppression assays. Thus, these studies have identified a cyclin A- and E-cdk2 substrate recognition motif. Furthermore, these data suggest that p21-like cdk inhibitors function, at least in part, by blocking the interaction of substrates with cyclin-cdk2 complexes.

scholarly journals Cyclin-dependent Kinases Participate in Death of Neurons Evoked by DNA-damaging Agents

1998 ◽  
Vol 143 (2) ◽  
pp. 457-467 ◽  
Author(s):  
David S. Park ◽  
Erick J. Morris ◽  
Jaya Padmanabhan ◽  
Michael L. Shelanski ◽  
Herbert M. Geller ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Sindbis Virus ◽  
Kinase Inhibitors ◽  
Sympathetic Neurons ◽  
Dominant Negative ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinases ◽  
Dna Damaging Agents

Previous reports have indicated that DNA-damaging treatments including certain anticancer therapeutics cause death of postmitotic nerve cells both in vitro and in vivo. Accordingly, it has become important to understand the signaling events that control this process. We recently hypothesized that certain cell cycle molecules may play an important role in neuronal death signaling evoked by DNA damage. Consequently, we examined whether cyclin-dependent kinase inhibitors (CKIs) and dominant-negative (DN) cyclin-dependent kinases (CDK) protect sympathetic and cortical neurons against DNA-damaging conditions. We show that Sindbis virus–induced expression of CKIs p16ink4, p21waf/cip1, and p27kip1, as well as DN-Cdk4 and 6, but not DN-Cdk2 or 3, protect sympathetic neurons against UV irradiation– and AraC-induced death. We also demonstrate that the CKIs p16 and p27 as well as DN-Cdk4 and 6 but not DN-Cdk2 or 3 protect cortical neurons from the DNA damaging agent camptothecin. Finally, in consonance with our hypothesis and these results, cyclin D1–associated kinase activity is rapidly and highly elevated in cortical neurons upon camptothecin treatment. These results suggest that postmitotic neurons may utilize Cdk4 and 6, signals that normally control proliferation, to mediate death signaling resulting from DNA-damaging conditions.

scholarly journals Current understanding of nonsurgical interventions for refractory differentiated thyroid cancer: a systematic review

2021 ◽  
pp. FSO738
Author(s):  
Heidi Jones ◽  
Victoria Green ◽  
James England ◽  
John Greenman
Keyword(s):  
Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Oncolytic Viruses ◽  
In Vivo Studies ◽  
T Cell Therapy ◽  
Treatment Regimens ◽  
Number Of Patients ◽  
Related Mortality

Thyroid cancer incidence and related mortality is increasing year-on-year, and although treatment for early disease with surgery and radioiodine results in a 98% 5-year survival rate, recurrence and treatment refractory disease is evident in an unacceptable number of patients. Alternative treatment regimens have therefore been sought in the form of tyrosine kinase inhibitors, immunotherapy, vaccines, chimeric antigen receptor T-cell therapy and oncolytic viruses. The current review aims to consolidate knowledge and highlight the latest clinical trials using secondary therapies in thyroid cancer treatment, focusing on both in vitro and in vivo studies, which have investigated therapies other than radioiodine.

scholarly journals CD8 Tregs Promote Gvhd Prevention and Restore Impaired GVL Effect Mediated By CD4 Tregs in Mice

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1873-1873
Author(s):  
Jessica Lauren Heinrichs ◽  
Hung Nguyen ◽  
David Bastian ◽  
Yongxia Wu ◽  
Anusara Daenthanasanmak ◽  
...  
Keyword(s):  
T Cells ◽  
Combination Therapy ◽  
Immune Suppression ◽  
Conflicts Of Interest ◽  
Granzyme B ◽  
Leukemia Cell ◽  
In Vivo Studies ◽  
Leukemia Cell Line ◽  
Hematopoietic Stem

Abstract Adoptive regulatory T-cell (Treg) therapy has enhanced the outcome of patients suffering from graft-versus-host (GVH) disease following allogeneic hematopoietic stem cell transplantation (allo-HCT); however, fear of broad immune suppression and subsequent dampening of the beneficial graft-versus-leukemic (GVL) responses remains a challenge. In order to subvert broad immune suppression, we generated alloantigen-specific induced Tregs (iTregs) from resting CD4 or CD8 T cells and tested the ability of iTregs to suppress GVH and maintain GVL responses. We utilized a clinically relevant murine model of haploidentical-HCT with the addition of host-original leukemia cell line to evaluate the effects of CD4 and CD8 iTregs in GVH and GVL responses. While alloantigen-specific CD4 iTregs were effective in preventing GVHD (Fig. 1 A and C), they completely abrogated the GVL effect against aggressive leukemia resulting in 100% tumor mortality (Fig. 1 B and D). Mechanistically, these CD4 iTregs were found to potently suppress the expansion of effector T cells (Teffs) and their ability to secrete IFNγ and granzyme B in the recipient spleen and liver, which may contribute to the impaired GVL activity. Using similar approach, we generated alloantigen-specific CD8 iTregs and found they express higher levels of granzyme B and CTLA-4 compared to nTreg and CD4 iTregs. In vivo studies showed these CD8 iTregs moderately attenuated GVHD (Fig. 1 A and C)while completely sparing the GVL effect (Fig. 1 B and D). We thus further reasoned that the combination of CD4 and CD8 iTregs could achieve the optimal goal of allo-HCT: GVHD suppression with GVL preservation. Indeed, the combination therapy potently suppressed GVHD resulting in increased survival and decreased pathological injury to target organs than either CD4 or CD8 iTreg singular therapy (Fig. 1 A and C). More importantly, the combination therapy maintained potent GVL responses reflected by significantly decreased tumor mortality and load (Fig. 1 B and D).Mechanistically, we observed addition of CD8 iTregs maintained the suppression of Teff expansion but restored the ability of Teffs in producing inflammatory cytokines (e.g. IFNγ and TFNα) and cytolytic effector molecules (e.g. granzyme B and TRAIL). To our knowledge the current findings are the first to support the use of combinational iTreg therapy to achieve optimal suppression of GVHD while maintaining GVL responses. This work was supported by NIH grants: R01 CA118116 and R01 CA169116 Disclosures No relevant conflicts of interest to declare.

Artemether and imatinib combination therapy against malaria infection

2021 ◽  
Vol 19 (1) ◽  
pp. 139-143
Author(s):  
A.V. Kondrashin ◽  
◽  
E.V. Stepanova ◽  
L.F. Morozova ◽  
V.P. Sergiev ◽  
...  
Keyword(s):  
Combination Therapy ◽  
World Health ◽  
In Vivo Studies ◽  
Telomerase Inhibitors ◽  
Combined Use ◽  
The World ◽  
Oncological Diseases ◽  
Health Organization ◽  
Key Words Malaria

Artemisinin-based combination therapy (ACT) is recommended by the World Health Organization (WHO) as the first and second line of treatment for uncomplicated malaria caused by P. falciparum, as well as for chloroquine-resistant P. vivax malaria. Despite the large number of antimalarial drugs, there is no any ideal drug, since each individual combination of drugs or monotherapy have their own limitations, ranging from their triple (activity) in relation to certain forms of the development of Plasmodium in the human body, side effects, toxicity and resistance. During the course of the study carried out, the most promising compound-candidate was selected – imatinib, which is currently used as targeted therapy for a number of oncological diseases. The objective of this work is to evaluate the efficacy of the combined use of imatinib and artemether in vivo studies on the human malarial model – the rodent malaria parasites Plasmodium berghei. Dut to the optimally selected treatment scheme, it was possible to reduce the dosage of imatinib twice – to 0,25 mg/kg, and that of artemether three times – to 33 mg/kg. The use of this scheme made it possible to considerably reduce the toxic effect of these drugs due to the potentiation of antimalarial effect. Key words: malaria, drug resistance, telomerase inhibitors, imatinib, chemotherapy of malaria

scholarly journals Neospora caninum: Structure and Fate of Multinucleated Complexes Induced by the Bumped Kinase Inhibitor BKI-1294

Pathogens ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 382 ◽  
Author(s):  
Pablo Winzer ◽  
Nicoleta Anghel ◽  
Dennis Imhof ◽  
Vreni Balmer ◽  
Luis-Miguel Ortega-Mora ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Neospora Caninum ◽  
Farm Animals ◽  
In Vivo Studies ◽  
Drug Pressure ◽  
Drug Removal

Background: Bumped kinase inhibitors (BKIs) are potential drugs for neosporosis treatment in farm animals. BKI-1294 exposure results in the formation of multinucleated complexes (MNCs), which remain viable in vitro under constant drug pressure. We investigated the formation of BKI-1294 induced MNCs, the re-emergence of viable tachyzoites following drug removal, and the localization of CDPK1, the molecular target of BKIs. Methods: N. caninum tachyzoites and MNCs were studied by TEM and immunofluorescence using antibodies directed against CDPK1, and against NcSAG1 and IMC1 as markers for tachyzoites and newly formed zoites, respectively. Results: After six days of drug exposure, MNCs lacked SAG1 surface expression but remained intracellular, and formed numerous zoites incapable of disjoining from each other. Following drug removal, proliferation continued, and zoites lacking NcSAG1 emerged from the periphery of these complexes, forming infective tachyzoites after 10 days. In intracellular tachyzoites, CDPK1 was evenly distributed but shifted towards the apical part once parasites were extracellular. This shift was not affected by BKI-1294. Conclusions: CDPK1 has a dynamic distribution depending on whether parasites are located within a host cell or outside. During MNC-to-tachyzoite reconversion newly formed tachyzoites are generated directly from MNCs through zoites of unknown surface antigen composition. Further in vivo studies are needed to determine if MNCs could lead to a persistent reservoir of infection after BKI treatment.

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