Schoenwaelder Nina, Salewski Inken, Engel Nadja, Krause Mareike, Schneider Björn, Müller Michael, Riess Christin, Lemcke Heiko, Skorska Anna, Grosse-Thie Christina, Junghanss Christian, Maletzki Claudia
Department of Internal Medicine, Medical Clinic III-Hematology, Oncology, Palliative Medicine, University Medical Center Rostock, 18057 Rostock, Germany.
Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University Medical Center Rostock, 18057 Rostock, Germany.
Cancers (Basel). 2021 May 15;13(10):2396. doi: 10.3390/cancers13102396.
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.
细胞周期蛋白依赖性激酶抑制剂（CDKi）对包括头颈部鳞状细胞癌（HNSCC）在内的不同恶性肿瘤具有细胞毒性活性。通过协调DNA损伤反应，这些物质可与细胞抑制剂联合使用以增强细胞毒性。在此，我们研究了不同的CDKi（帕博西尼、地西他滨、THZ1）在单药治疗以及与临床批准药物（5-氟尿嘧啶、顺铂、西妥昔单抗）联合治疗时对两种HNSCC细胞系的影响。研究了细胞凋亡/坏死、细胞周期、侵袭性、衰老、辐射诱导的γ-H2AX DNA双链断裂以及对肌动蛋白丝的影响。此外，通过分析钙网蛋白易位和免疫相关表面标志物评估了增加肿瘤免疫原性的潜力。最后，使用体内小鼠模型分析地西他滨和顺铂联合治疗的效果。低剂量治疗后，地西他滨、帕博西尼和THZ1显示出抗肿瘤活性，而后两种物质略微增强了放射敏感性。地西他滨减缓伤口愈合、降低侵袭性并诱导MHC-I，同时伴有大量表面结合的钙网蛋白。早期和晚期凋亡细胞数量最初增加（24小时），随后坏死占主导。选择性CDKi帕博西尼的抗肿瘤作用较弱，但与5-氟尿嘧啶联合可增强单药治疗的效果。此外，CDKi以及CDKi/化疗联合诱导MHC I，表明免疫原性增强。体内研究揭示了联合治疗方法中细胞系特异性反应以及最佳的肿瘤生长控制。应进一步研究全身性作用的CDKi作为HNSCC的靶向药物，单独使用或与选定药物联合使用。地西他滨增加肿瘤细胞免疫原性的能力使其成为基于免疫的肿瘤治疗方案中特别有吸引力的候选药物。
