Abstract 4066: The dihydroartemisinin oxime dimer (NSC735847) displays a selective toxicity in colon cancer cells which is potentially mediated by endoplasmic reticulum stress

Abstract

Abstract Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States. Common chemotherapeutic regimens for CRC include a combination of chemotherapeutic agents to produce synergistic drug activity and reduce adverse effects. However, adverse effects due to lack of selective toxicity is still a major problem with many chemotherapeutic agents. Novel drugs that display tumor selective toxicity are desperately needed. Several studies have shown that artemisinin monomers (Clinically used anti-malarial agent) possess antineoplastic activity with minimal toxicity. Interestingly, artemisinin dimers showed more potent antineoplastic activity compared to the monomers. However, few studies have fully characterized the activity of these molecules. In this study, we tested the antitumor activity of five chemically-synthesized dihydroartemisinin (DHA) dimers using the human colon cancer cell lines, HT29 and HCT116 and the non-tumorigenic colon cell line, FHC. Compared to other tested dimers, the DHA oxime dimer, NSC735847 showed pronounced selective toxicity in HT29 and HCT116 cells. Using MTS cell viability assays, NSC735847caused a preferential reduction in the viability of HT29 and HCT116 colon cancer cells compared to the non-tumorigenic FHC cells. In addition, NSC735847 significantly increased caspase 3/7 activity in HT29 and HCT116 cells but not in FHC cells which suggests that this compound causes selective apoptosis in these colon cancer cell lines. The combination of NSC735847 and the topoisomerase I inhibitor, irinotecan (commonly used chemotherapeutic agent for colorectal cancer) showed synergistic antitumor activity in HT29 cells. The combination of the two drugs caused a significant increase in cell death and caspase 3/7 activity which were greater than those caused by the individual drugs. Previous studies using other tumorigenic cell lines, suggested that NSC735847 induces oxidative and endoplasmic reticulum (ER) stress. To gain insight into the potential mechanisms of anti-colorectal cancer activity of NSC735847, we tested if this compound causes ER stress and/ or oxidative stress in HT29 cells and whether ER stress was required for NSC735847-induced apoptotic cell death. NSC735847 increased the expression of ER stress marker C/EBP homologous protein 10 (CHOP10) in HT29 cells and the use of ER stress inhibitor, salubrinal, significantly decreased NSC735847-induced cell death and apoptosis. Additionally, NSC735847 caused oxidative stress in HT29 cells which was inhibited by pretreatment of the cells with the antioxidant, trolox. The crosstalk between oxidative stress and ER stress in NSC735847-induced apoptosis in colon cancer cells is still under investigation. Our results suggest that NSC735847 causes ER stress in HT29 cells which plays a major role in drug-induced cell death and apoptosis in these cells. Citation Format: Ahmed E. Elhassanny, Eman Soliman, Paul McGuire, Mahmoud ElSohly, Waseem Gul, Rukiyah Van Dross. The dihydroartemisinin oxime dimer (NSC735847) displays a selective toxicity in colon cancer cells which is potentially mediated by endoplasmic reticulum stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4066. doi:10.1158/1538-7445.AM2017-4066