Investigation of the antitumor activity of lapatinib and NNC 55-0396 dihydrochloride combination in gastric adenocarcinoma.

Targeted drugs such as Lapatinib and Everolimus have limited efficacy in the treatment of gastric cancer due to heterogeneous tumor structure. Combination therapies may offer a promising alternative to overcome this limitation. In this study, the potential synergistic effects of the combination of T-type calcium channel blocker NNC 55-0396 dihydrochloride (NNC) with Lapatinib and Everolimus were investigated in gastric cancer cell lines. In the first stage of the experiment, all three drugs were applied to AGS and SNU-1 cell lines at different doses, and IC values were calculated. Since Lapatinib was found to be more effective than Everolimus at low doses in AGS cells, its combination with NNC was further analyzed. Apoptosis and related molecular markers were evaluated by flow cytometry and ELISA. The combination of Lapatinib and NNC drug application demonstrated a significant antiproliferative effect on AGS cells and significantly increasing the percentage of apoptotic cells. It was also observed that it increased the levels of Nitric Oxide, Bax, cleaved caspase-3, cleaved PARP, and 8-hydroxy-deoxyguanosine (8-oxo-dG) and decreased the expression of BCL-2. In light of all these findings, the combination of Lapatinib and NNC, which did not show the desired anticancer activity alone in AGS cells, increased apoptosis and showed a strong antiproliferative effect. Further clinical and preclinical studies will contribute to the creation of personalized treatment approaches by providing detailed evaluation of the molecular mechanisms and clinical benefits of this combination.