Abstract 1098: Structure-activity relationship of pentacyclic triterpenes against chemoresistance and metastasis on non-small lung adenocarcinoma cells

Abstract

Abstract Lung cancer is the second most common and leading cause of cancer-related death worldwide, 85% of these cases being non-small cell lung carcinoma (NSCLC). Although chemotherapy is the first-line treatment for lung cancer, its effectiveness is hampered by the dose-limiting toxic effects, chemoresistance, and metastatic process. Recently, plant-derived cyclic triterpenoids (eg, cholesterol-structure like compounds) have shown a wide spectrum of pharmacological activities, especially their potential against different cancer cells. Herein, we investigated the structure-activity relationship of several pentacyclic triterpenes: oleanolic acid (OleA), ursolic acid (UrA), betulinic acid (BeA), Asiatic acid (AsA), betulin (BeN), lupeol (Lupe), diosgenin (Dio), stigmasterol (Stg) and β-sitosterol (β-Sito) on NSCLC A549 cells. From our studies, the IC50 for OleA, UrA, BeA, AsA, BeN, Lupe, Dio were in the low µM range (from 10-75 µM) after 24h of incubation. β-Sito and Stg did not show any significant cytotoxic pattern in this µM range. In addition, BeA showed the highest cytotoxic pattern in these cells. We performed metabolic activity assays to determine the mechanism of action of these triterpenes. Mitochondrial membrane and caspases activity assays showed that all the cytotoxic triterpenes induced activation of caspase-3 and decline in the mitochondrial potential, except BeA and AsA. Our results also show that all the cytotoxic triterpenes disrupt cell membrane, except for OleA. However, there is no reactive oxygen species production for all of them. Gene expression assays of chemoresistance- and metastasis-related genes (EGFR, VEGF, MMP9, Pgp, TP53, NDRG1, CHD4) using qPCR demonstrated the downregulation of all of these genes after the incubation with the cytotoxic triterpenes. These results demonstrated that even slight structural changes in these triterpenes could influence the cytotoxic and metabolic pathways responses. This study opens promising perspectives for further research on the role of phytochemical triterpenes, which ultimately will contribute to a more rational application in lung cancer therapy. Citation Format: Yamixa Delgado, Daraishka Perez, Grace Torres. Structure-activity relationship of pentacyclic triterpenes against chemoresistance and metastasis on non-small lung adenocarcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1098.