Abstract
Abstract
Fingolimod (FTY-720) and its non-immunosuppressive analogue (OSU2S) possess anticancer activity against hepatocellular carcinoma attributed to interference with protein kinase Cδ (PKCδ) signaling. Avascular penetration represents a major limitation for the treatment of solid tumors nonetheless colorectal cancer. Herein, we are assessing the differential antiproliferative activity of OSU2S compared to FTY720 against multicellular spheroids of HCT-116 and HT-29 colorectal cancer cell lines. In addition, we are comparing the avascular penetration properties of OSU2S to FTY720 within the avascular multicellular layers model.
The IC50's of FTY720 and OSU2S were calculated in monolayer and spheroid culture models of HCT-116 and HT-29 cells using Emax model. Generally, OSU2S was found to be 1.5 to 3 folds more potent than FTY720 in both cell lines using monolayer and spheroid culture systems. The ratios between the IC50's of FTY720 in spheroid compared to monolayer cultures of HCT-116 and HT-29 cells were found to be to 5.7 and 3.4 folds, respectively. On the other hand, the ratios between the IC50's of OSU2S in spheroid compared to monolayer cultures of HCT-116 and HT-29 cells were found to be 4.5 and 3.4 folds, respectively. This might be attributed to avascular penetration problem for OSU2S and FTY720 in colorectal cancer. The pre-calculated IC50's of FTY720 and OSU2S induced significant increase in the cleaved fraction of PKCδ in both monolayer and spheroid model in HCT-116 and HT-29 cells. The influence of FTY720 and OSU2S on cell cycle analysis was studied using DNA flow cytometry analysis. Both FTY720 and OSU2S changed the cell cycle distribution of both HCT-116 and HT-29 cell lines in the monolayer culture and to a lesser extent in the spheroid culture model. The avascular penetration of OSU2S through multicellular layers of HCT-116 was 1.9 and 1.2 fold faster than FTY720 after 12 and 24 h of penetration, respectively. Also, OSU2S was faster than FTY720 in penetrating multicellular layers of HT-29 by 2.1 to 1.7 folds after 12 and 24 h of penetration, respectively. In conclusion, OSU2S possess better antiproliferative and avascular penetration profile within colorectal cancer cells compared to FTY720.
Citation Format: Samir A. Zaahkouk, Serag Eldin I. Elbehairi, Aly F. El-Sayed, Sayed Bakry, Alaa Khedr, Hany A. Omar, Ahmed M. Al-Abd. Activity and avascular penetration of FTY720 (fingolimod) and its non-immune suppressant analogue (OSU2S) within three dimensional tissue culture model of colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4505. doi:10.1158/1538-7445.AM2015-4505