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Cancers
Volume 12
Issue 1
10.3390/cancers12010122
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Article

Identification of Two Kinase Inhibitors with Synergistic Toxicity with Low-Dose Hydrogen Peroxide in Colorectal Cancer Cells In vitro

by
Eric Freund
1,2,
Kim-Rouven Liedtke
1,
Lea Miebach
1,2,
Kristian Wende
2,
Amanda Heidecke
2,
Nagendra Kumar Kaushik
3,
Eun Ha Choi
3,
Lars-Ivo Partecke
1,4 and
Sander Bekeschus
2,*
1
Department of General, Visceral, Thoracic and Vascular Surgery, Greifswald University Medical Centre, 17475 Greifswald, Germany
2
Centre for Innovation Competence (ZIK) Plasmatis, Leibniz Institute for Plasma Science and Technology (INP Greifswald), 17489 Greifswald, Germany
3
Plasma Bioscience Research Center (PBRC), Kwangwoon University, Seoul 139-710, Korea
4
General-, Visceral-, and Thoracic Surgery, Helios Clinic Schleswig, 24837 Schleswig, Germany
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(1), 122; https://doi.org/10.3390/cancers12010122
Submission received: 4 December 2019 / Accepted: 20 December 2019 / Published: 2 January 2020
(This article belongs to the Special Issue Plasma in Cancer Treatment)
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Abstract

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.
Keywords: anticancer drugs; pancreatic cancer; screening; tumor spheroids anticancer drugs; pancreatic cancer; screening; tumor spheroids

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MDPI and ACS Style

Freund, E.; Liedtke, K.-R.; Miebach, L.; Wende, K.; Heidecke, A.; Kaushik, N.K.; Choi, E.H.; Partecke, L.-I.; Bekeschus, S. Identification of Two Kinase Inhibitors with Synergistic Toxicity with Low-Dose Hydrogen Peroxide in Colorectal Cancer Cells In vitro. Cancers 2020, 12, 122. https://doi.org/10.3390/cancers12010122

AMA Style

Freund E, Liedtke K-R, Miebach L, Wende K, Heidecke A, Kaushik NK, Choi EH, Partecke L-I, Bekeschus S. Identification of Two Kinase Inhibitors with Synergistic Toxicity with Low-Dose Hydrogen Peroxide in Colorectal Cancer Cells In vitro. Cancers. 2020; 12(1):122. https://doi.org/10.3390/cancers12010122

Chicago/Turabian Style

Freund, Eric, Kim-Rouven Liedtke, Lea Miebach, Kristian Wende, Amanda Heidecke, Nagendra Kumar Kaushik, Eun Ha Choi, Lars-Ivo Partecke, and Sander Bekeschus. 2020. "Identification of Two Kinase Inhibitors with Synergistic Toxicity with Low-Dose Hydrogen Peroxide in Colorectal Cancer Cells In vitro" Cancers 12, no. 1: 122. https://doi.org/10.3390/cancers12010122

APA Style

Freund, E., Liedtke, K.-R., Miebach, L., Wende, K., Heidecke, A., Kaushik, N. K., Choi, E. H., Partecke, L.-I., & Bekeschus, S. (2020). Identification of Two Kinase Inhibitors with Synergistic Toxicity with Low-Dose Hydrogen Peroxide in Colorectal Cancer Cells In vitro. Cancers, 12(1), 122. https://doi.org/10.3390/cancers12010122

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