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.
Highlights
Colorectal carcinoma is among the most common cancers in both men and women
Kinase inhibitors are regularly used in the therapy of various cancers
The most intoxicating substances were identified after three selection steps, and substance codes were used to analyze in a blinded fashion (Figure 1a)
Summary
Colorectal carcinoma is among the most common cancers in both men and women. Risk factors are smoking and obesity, besides a lack of exercise and a diet low in carbohydrates but rich in alcohol and red meat diet is to be named as a risk factor. Cancers 2020, 12, 122 patients at risk [1,2]. The relative 5-year survival rates are 63% in men and 63% in women. The prognosis is highly dependent on the stage at diagnosis. Diffuse metastasis in the abdomen is often present before diagnosis [3,4]. This complication of peritoneal carcinomatosis (PC), in particular, is associated with inferior survival and is still challenging in its treatment [5,6]
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