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Article

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

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Department of Internal Medicine, Medical Clinic III—Hematology, Oncology, Palliative Medicine, University Medical Center Rostock, 18057 Rostock, Germany
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Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University Medical Center Rostock, 18057 Rostock, Germany
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Institute of Pathology, University Medical Center Rostock, Strempelstr.14, 18057 Rostock, Germany
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Core Facility for Cell Sorting & Cell Analysis, Laboratory for Clinical Immunology, University Medical Center Rostock, 18057 Rostock, Germany
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University Children’s Hospital, Rostock University Medical Centre, 18057 Rostock, Germany
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Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy (RTC), University Medical Center Rostock, 18057 Rostock, Germany
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Department of Cardiology, University Medical Center Rostock, 18059 Rostock, Germany
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Department Life, Light & Matter, Faculty of Interdisciplinary Research, University Rostock, 18059 Rostock, Germany
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Author to whom correspondence should be addressed.
Academic Editor: Samuel C. Mok
Cancers 2021, 13(10), 2396; https://doi.org/10.3390/cancers13102396
Received: 1 March 2021 / Revised: 7 April 2021 / Accepted: 11 May 2021 / Published: 15 May 2021
(This article belongs to the Special Issue Targeting Cyclin-Dependent Kinases in Human Cancers)
This study examined the therapeutic potential of a combined therapy approach, based on clinical approved drugs (5-FU, Cisplatin, cetuximab) and cyclin-dependent kinase inhibitors (CDKi, dinaciclib, palbociclib, THZ1). We identified individual effects on head and neck squamous cell carcinoma cells, including induction of apoptosis/necrosis, and senescence as well as reduced invasiveness. Besides, we describe the relevance of the sequential timing of each combination partner to achieve synergistic effects. Another interesting finding of our study is the upregulation of immunologically relevant molecules on the tumor cell surface under certain CDKi-drug combinations. Here, dinaciclib and palboclicb had highest impact on immunogenicity, which even exceeded effects of the standard drugs. Finally, a therapeutic in vivo approach partially confirmed cell line-based results. Here, effective tumor growth control was seen when cisplatin was combined with dinaciclib. However, antitumoral effects were highly individual and nicely confirm the heterogeneity of this tumor entity.
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. View Full-Text
Keywords: targeted therapy; combination strategies; immunogenic cell death; xenograft model targeted therapy; combination strategies; immunogenic cell death; xenograft model
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MDPI and ACS Style

Schoenwaelder, N.; Salewski, I.; Engel, N.; Krause, M.; Schneider, B.; Müller, M.; Riess, C.; Lemcke, H.; Skorska, A.; Grosse-Thie, C.; Junghanss, C.; Maletzki, C. The Individual Effects of Cyclin-Dependent Kinase Inhibitors on Head and Neck Cancer Cells—A Systematic Analysis. Cancers 2021, 13, 2396. https://doi.org/10.3390/cancers13102396

AMA Style

Schoenwaelder N, Salewski I, Engel N, Krause M, Schneider B, Müller M, Riess C, Lemcke H, Skorska A, Grosse-Thie C, Junghanss C, Maletzki C. The Individual Effects of Cyclin-Dependent Kinase Inhibitors on Head and Neck Cancer Cells—A Systematic Analysis. Cancers. 2021; 13(10):2396. https://doi.org/10.3390/cancers13102396

Chicago/Turabian Style

Schoenwaelder, Nina, Inken Salewski, Nadja Engel, Mareike Krause, Björn Schneider, Michael Müller, Christin Riess, Heiko Lemcke, Anna Skorska, Christina Grosse-Thie, Christian Junghanss, and Claudia Maletzki. 2021. "The Individual Effects of Cyclin-Dependent Kinase Inhibitors on Head and Neck Cancer Cells—A Systematic Analysis" Cancers 13, no. 10: 2396. https://doi.org/10.3390/cancers13102396

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