An exploratory study on the effect of kynurenine metabolites on sEnd-2 endothelioma cells.

Cancer is the second leading cause of mortality worldwide. The development of anticancer therapy plays a crucial role in mitigating tumour progression and metastasis. Epithelioid hemangioendothelioma is a very rare cancer, however, with a high systemic involvement. Kynurenine metabolites which include l-kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid have been shown to inhibit T-cell proliferation resulting in a decrease in cell growth of natural killer cells and T cells. Furthermore, metabolites such as  l-kynurenine have been shown to inhibit proliferation of melanoma cells in vitro. Considering these metabolite properties, the present study aimed to explore the in vitro effects of  l-kynurenine, quinolinic acid and kynurenic acid on endothelioma sEnd-2 cells and on endothelial (EA. hy926 cells) (control cell line). The in vitro effect at 24, 48, and 72 h exposure to a range of 1-4 mM of the respective kynurenine metabolites on the two cell lines in terms of cell morphology, cell cycle progression and induction of apoptosis was assessed. The half inhibitory concentration (IC50), as determined using nonlinear regression, for  l-kynurenine, quinolinic acid and kynurenic acid was 9.17, 15.56, and 535.40 mM, respectively. Optical transmitted light differential interference contrast and hematoxylin and eosin staining revealed cells blocked in metaphase, formation of apoptotic bodies and compromised cell density in  l-kynurenine-treated cells. A statistically significant increase in the number of cells present in the sub-G1 phase was observed in  l-kynurenine-treated sample. To our knowledge, this was the first in vitro study conducted to investigate the mechanism of action of kynurenine metabolites on endothelioma sEnd-2 cells. It can be concluded that  l-kynurenine exerts an antiproliferative effect on the endothelioma sEnd-2 cell line by decreasing cell growth and proliferation as well as a metaphase block. These hallmarks suggest cell death via apoptosis. Further research will be conducted on  l-kynurenine to assess the effect on cell adhesion in vitro and in vivo as cell-cell adhesion has been shown to increase metastasis to distant organs therefore, the inhibition of adhesion may lead to a decrease in metastasis.

The involvement of a chemokine receptor antagonist CTCE-9908 and kynurenine metabolites in cancer development.

Cancer is the second leading cause of mortality worldwide. Skin cancer is the most common cancer in South Africa with nearly 20,000 reported cases every year and 700 deaths. If diagnosed early, the 5-year survival rate is about 90%, however, when diagnosed late, the 5-year survival rate decreases to about 20%. Melanoma is a type of skin cancer with an estimated 5-year survival rate of approximately 90%. Neuroblastoma is a paediatric cancer with a low survival rate. Sixty percent of patients with metastatic disease do not survive 5 years after diagnosis. Despite recent advances in targeted therapies, there is a crucial need to identify reliable prognostic biomarkers which will be able to contribute to the development of more precision-based chemotherapeutic strategies to prevent tumour migration and metastasis. The compound, CTCE-9908 inhibits the binding of CXC chemokine ligand 12 (CXCL12) to the CXC chemokine receptor 4 (CXCR4) receptor leading to reduced metastasis. Kynurenine metabolites are derived tryptophan, which is an essential amino acid. Kynurenine metabolites inhibit T-cell proliferation resulting in cell growth arrest. For this reason, chemokines receptors represent potential targets for the treatment of cancer growth and metastasis. In this review paper, the role of the CXCL12/CXCR4 signalling pathway in the development of cancer is highlighted together with the current available treatments involving the CTCE-9908 compound in combination with microtubule inhibitors like paclitaxel and docetaxel.