EFFECT OF THE INHIBITION OF LEUKOTRIENE A4 HYDROLASE (LTA4H) WITH SC-57461A IN LIVER CANCER PROLIFERATION

OVIEDO BUSTOS, L; QUIROGA, AD; ALVAREZ, ML

Congreso; Sociedad Argentina de Fisiología; 2023

Instituto de Fisiología Experimental–CONICET. Facultad de Ciencias Bioquímicas y Farmacéuticas, UNR. 2 Área Morfología-Facultad de Ciencias Bioquímicas y Farmacéuticas, UNR. 3 CAECIHS. Universidad Abierta Interamericana (UAI).Introduction: Leukotriene B4 (LTB4) is a lipid mediator generated from arachidonic acid through the sequential action of severalenzymes, including LTA4H. LTB4 is overexpressed in different types of cancer and plays an important role in cancer cellproliferation. The use of SC-57461A (a specific inhibitor of LTA4H) has been demonstrated to modulate the immune system indifferent studies; but its effect on liver cancer has not been reported. Objectives: to evaluate the effect of LTA4H inhibition inliver cancer cells proliferation, both in vivo and in vitro. Methods: In vitro studies: Human cell lines: hepatocellular carcinomaHuh7, endothelial EA.hy926 and hepatic stellate LX2 cells. For dose-response studies cells were treated with different doses ofSC-57461A for 72 h or left untreated. Cell viability was determined (MTT assay) and the IC50 was calculated. In vivo studies: Axenograft model for liver cancer was generated in athymic mice by injecting 5x106 Huh7 cells into the flank (n=10). Half ofanimals were treated with SC-57461A 10 mg/kg, by gavage 2 days/week for 2 weeks and the remaining were left untreated(control group). Tumor dimensions were measured with a calliper and volumes were calculated. Tumors were excised andprocessed for immunohistochemical studies to detect the marker of proliferation PCNA. Results: In vitro studies: Treatment withSC-57461A showed a dose-dependent decrease in cell viability and the following IC50s were established for each cell line: Huh7259.45 μM, LX2 316.38 μM and EA.hy926 288.38 μM. In vivo studies: Tumor size was significantly reduced in the group treatedwith SC-57461A (-68%, p<0.01) compared with control group. Also, immunohistochemical analyses revealed a decreasedstaining for PCNA in the SC-57461A group compared to the control group. Conclusions: SC-57461A reduced proliferation both inhepatocellular carcinoma cells and in critical environmental tumor cells. In addition, in vivo administration of the inhibitorreduced tumor size and proliferation in tumor-bearing mice. These results, despite being preliminary, show that the inhibition ofLTA4H has potential as a pharmacological tool to inhibit liver tumor growth.