Identification of Two Kinase Inhibitors with Synergistic Toxicity with Low-Dose Hydrogen Peroxide in Colorectal Cancer Cells In vitro
| Autor: | Lea Miebach, Kristian Wende, Kim-Rouven Liedtke, Eun Ha Choi, Amanda Heidecke, Eric Freund, Lars-Ivo Partecke, Nagendra Kumar Kaushik, Sander Bekeschus |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Colorectal cancer medicine.medical_treatment pancreatic cancer tumor spheroids lcsh:RC254-282 Article 03 medical and health sciences 0302 clinical medicine Pancreatic cancer medicine Cytotoxic T cell Cytotoxicity Protein kinase A Chemotherapy Kinase business.industry screening lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease anticancer drugs 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer cell Cancer research business |
| Zdroj: | Cancers Volume 12 Issue 1 Cancers, Vol 12, Iss 1, p 122 (2020) |
| ISSN: | 2072-6694 |
| Popis: | Colorectal carcinoma is among the most common types of cancers. With this disease, diffuse scattering in the abdominal area (peritoneal carcinosis) often occurs before diagnosis, making surgical removal of the entire malignant tissue impossible due to a large number of tumor nodules. Previous treatment options include radiation and its combination with intraperitoneal heat-induced chemotherapy (HIPEC). Both options have strong side effects and are often poor in therapeutic efficacy. Tumor cells often grow and proliferate dysregulated, with enzymes of the protein kinase family often playing a crucial role. The present study investigated whether a combination of protein kinase inhibitors and low-dose induction of oxidative stress (using hydrogen peroxide, H2O2) has an additive cytotoxic effect on murine, colorectal tumor cells (CT26). Protein kinase inhibitors from a library of 80 substances were used to investigate colorectal cancer cells for their activity, morphology, and immunogenicity (immunogenic cancer cell death, ICD) upon mono or combination. Toxic compounds identified in 2D cultures were confirmed in 3D cultures, and additive cytotoxicity was identified for the substances lavendustin A, GF109203X, and rapamycin. Toxicity was concomitant with cell cycle arrest, but except HMGB1, no increased expression of immunogenic markers was identified with the combination treatment. The results were validated for GF109203X and rapamycin but not lavendustin A in the 3D model of different colorectal (HT29, SW480) and pancreatic cancer cell lines (MiaPaca, Panc01). In conclusion, our in vitro data suggest that combining oxidative stress with chemotherapy would be conceivable to enhance antitumor efficacy in HIPEC. |
| Databáze: | OpenAIRE |
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