Abstract 1049: Combinatorial effects of thymoquinone on the anticancer activity of doxorubicin in adult T-cell leukemia

Abstract

Abstract Doxorubicin (Dox) is a clinically approved drug which suffers from drug resistance and cardiotoxicity. Recent studies have shown that thymoquinone (TQ) in combination with Dox can reduce Dox toxic side effects in vitro as well as in vivo. Both TQ and Dox have shown promising anticancer effects against aggressive adult T-cell leukemia (ATL), however, the anticancer potential of TQ and Dox combination treatment has never been tested against ATL. We hypothesized that co-treatment with TQ could enable the use of lower doses of Dox to achieve similar or enhanced anticancer activity. The effects of TQ and Dox combination on cell death and cell cycle were evaluated by trypan blue and propidium iodide. TUNEL assay was used to investigate the mode of cell death. The levels of reactive species (ROS) were determined using DCFH assay, and mitochondrial membrane potential was measured by rhodamine assay. The regulation of key proteins involved in cell cycle regulation and cell death was determined by Western blot. The results reveal that the human T-lymphotropic virus (HTLV-1) positive HuT-102 cells are more resistant to treatment with Dox alone, than the HTLV-1 negative Jurkat cells. However, treatment with high doses of TQ and low doses of Dox simultaneously, enhances cell death in both cancer cell lines as compared to treatment with Dox alone. TUNEL assay on Jurkat and HuT-102 cells further indicated that the combination of TQ and Dox caused cell death by apoptosis. An increase in ROS production was noted in response to treatment with TQ alone and with TQ and Dox combination in both Jurkat and HuT-102 cells. The oxidative stress; however, was only shown to play a role in the disruption of the mitochondria of Jurkat cells. Similarly, caspase activation was involved in the disruption of the mitochondria of Jurkat cells. The expression levels of key regulatory proteins were modulated in response to treatment with the combination. In conclusion, the combination of TQ and Dox effectively inhibits ATL leukemic cancer cell growth at lower doses of Dox which can potentially lower the side effects of the drug. In vivo studies are still warranted to assess the adjuvant chemotherapeutic potential of TQ in combination with Dox. Citation Format: Hala Gali-Muhtasib, Isabelle Fakhoury, Maamoun Fatfat, Rasha Mismar, Regine Schneider-Stock. Combinatorial effects of thymoquinone on the anticancer activity of doxorubicin in adult T-cell leukemia [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 1049. doi:10.1158/1538-7445.AM2017-1049