Abstract 2843: Calcium blockers modulate the steroid resistance in acute lymphoblastic leukemia

Abstract

Abstract Background: Acute lymphoblastic leukemia (ALL) is one of common cancers in children and adults, and a fair number of ALL patients still die although the overall survival rate is approaching 90% with risk-directed therapy in many developed countries. Response to steroid is the most important prognostic factor of patients with ALL, and the development of steroid resistance is lethal to the ALL patients. To improve survival for steroid-resistant ALL patients, it is necessary to develop new concepts to overcome the steroid resistance of ALL. Methods: We generated the steroid-adapted subclones through prolonged cultures of ALL cell lines with gradually increased steroid concentration.Also, we used biochemical and molecular methodologies to demonstrate the signaling axis of tissue transglutaminase (TG2)-nuclear factor-kappa B (NF-kappa B) and cell cycle to evaluate the effect of calcium blockers on the steroid-resistant ALL cells. Results: Steroid-adapted ALL cells that were generated by culture with gradually increased steroid concentration were much more resistant to steroid than their parent ALL cells. We found that calcium blockers altered TG2 activity and nuclear factor-kappa B (NF-kappa B) expression in these steroid-resistant ALL cells. Also, calcium blockers induced the change of expression of NF-kappa B target genes in steroid-adapted ALL cells. In addition, calcium blockers induced the change of ABC transporter expression and the quiescence of steroid-resistant ALL cells. We also found that calcium blockers induced apoptosis of steroid-resistant ALL cells and reduced the steroid resistance of steroid-resistant ALL cells. Conclusion: This study shows that calcium blockers improved the cytotoxicity of steroid on steroid-resistant ALL cells via manipulation of TG2 and NF-kappa B activities and cell cycle. The combination of calcium blockers with chemotherapeutic agents may be a new alternative strategy to overcome the steroid resistance of ALL. Citation Format: Hyun Joo Jung. Calcium blockers modulate the steroid resistance in acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2843.