Abstract LBA050: Bioenergetic evaluation of Mito-compound Mito-Met as potent cytotoxic agents in gastric cancer (2021)

Abstract Gastric cancer (GC) kills around 800,000 people each year around the world, placing it among the deadliest types of cancer. The evolution of intestinal metaplasia is unknown, but there are different factors that are involved in its development, the diet rich in salt, the Epstein-Barr virus, Helicobacter pylori and a wide variety of genes that affect cell activity. Currently, surgical resection with chemotherapy is the main treatment with a 5-year survival of 30% that varies according to the metastatic extension. The mitochondria is now one of the therapeutic targets in the development of new compounds with anticancer capacity and it has been observed that metformin behaves as an insulin sensitizer at high concentrations, inhibiting the mitochondrial complex I. For this reason, Mito-metformin (Mito-Met) was designed, this is a mitochondrial analogue of metformin that is linked to the lipophilic alkyl triphenylphosphonium cation (TPP) with a mitochondrial effect 1000 times greater at low concentrations. In this study, the effects of Mito-Met were evaluated in two GC cell lines (AGS and KATO III) and in the healthy gastric epithelium cell line (HPSEC). Cell viability, cytotoxicity, colony formation and cell migration assays were performed. Also, it was evaluated whether Mito-Met had the potential to affect mitochondrial bioenergetics by evaluating the OCR oxygen consumption rate, ECAR extracellular acidity rate, glycolytic capacity and mitochondrial fuel oxidation in live cells in real time using the analyzer XFe24 extracellular flux from Seahorse Biosciences. A dose-time-dependent decrease in cell viability was observed with IC50 values of 2.9 µM, 19,3 µM and 22,1 µM in AGS, KATO and HPSEC cells, respectively. The results in clonogenic assay showed that Mito-Met strongly affected AGS with an IC50 of 11.7 uM and a greater impact was observed in HPSEC than in KATO III, with IC50 values of 31.8 uM and 3.6 x 103 uM, respectively. The results of the wound healing assay showed that Mito-Met has a significant time-dependent dose effect on metastasis. Mito-Met affects the mitocondrial bioenergetics, our results showed affectation of basal respiration, maximum respiration, ATP production and reserve capacity in both cell lines. Mito-Met decreased baseline OCR and stressed OCR in a dose-dependent manner in both GC cell lines. Mito-Met increased the metabolic potential in a dose-dependent manner of OCR in AGS, on the contrary, a dose-dependent decrease of ECAR was observed in KATO III. There was no change in HPSEC. These results show that Mito-Met is promising compound for treatment of GC. Citation Format: Giovanni A Lineros Franco, Yenny Bueno, Micael Hardy, Olivier Ouari, Julio C. Montoya-Villegas, Marcos López-Casilla, Sandra M. Sanabria-Barrera. Bioenergetic evaluation of Mito-compound Mito-Met as potent cytotoxic agents in gastric cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA050.