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.