Taxodione induces apoptosis in BCR-ABL-positive cells through ROS generation.

Taxodione induces apoptosis in BCR-ABL-positive cells through ROS generation.
Biochem Pharmacol. 2018 May 31;:
Authors: Uchihara Y, Tago K, Taguchi H, Narukawa Y, Kiuchi F, Tamura H, Funakoshi-Tago M
Abstract
Chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) are hematopoietic malignancies caused by the constitutive activation of BCR-ABL tyrosine kinase. Although direct BCR-ABL inhibitors, such as imatinib, were initially successful in the treatment of leukemia, many patients developed drug resistance over time due to the gatekeeper mutation of BCR-ABL T315I. In the present study, we found that taxodione, a quinone methide diterpene isolated from Taxodium distichum, significantly induced apoptosis in human myelogenous leukemia-derived K562 cells, which were transformed by BCR-ABL. Taxodione reduced the activities of mitochondrial respiratory chain (MRC) complexes III and V, which appeared to induce the production of reactive oxygen species (ROS). N-acetylcysteine (NAC), an antioxidant agent, canceled taxodione-induced ROS production, reductions in MRC activities, particularly complex V, and apoptotic cell death. Furthermore, in K562 cells treated with taxodione, BCR-ABL and its major signaling molecules, such as STAT5 and Akt were sequestered in mitochondrial fraction, and their localization changes decrease their abilities to stimulate cell proliferation, suggesting that these actions seem to be a mechanism how ta...

Source: Biochemical Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Uchihara Y, Tago K, Taguchi H, Narukawa Y, Kiuchi F, Tamura H, Funakoshi-Tago M Tags: Biochem Pharmacol Source Type: research