Pharmacological profiling of a berbamine derivative for lymphoma treatment
Senlin Xu, Shun‐Quan Wu, Mingfeng Zhang, Jun Xie, Min Lin, Lihua Jin, Jiawei Zhang, Yangmeng Wang, Mingjie Fan, Zhipeng Fang, Weini Li, Ching Ouyang, Choon Hyuck David Kwon, Natalie Que, Zhirou Li, Jinge Mao, Haonan Chen, Josephine P. Harris, Xiwei Wu, Jun Wu, Hongwei Yin, Wing C. Chan, David Horne, Wendong Huang
Abstract
ABSTRACT: Ca2+/calmodulin-dependent protein kinase II γ (CAMKIIγ) has been identified as a potential target for treating cancer. Based on our previous study of berbamine (BBM) as a CAMKIIγ inhibitor, we have synthesized a new BBM derivative termed PA4. Compared with BBM, PA4 showed improved potency and specificity and was more cytotoxic against lymphoma and leukemia than against other types of cancer. In addition to indirectly targeting c-Myc protein stability, we demonstrated that its cytotoxic effects were also mediated via increased reactive oxygen species production in lymphoma cells. PA4 significantly impeded tumor growth in vivo in a xenograft T-cell lymphoma mouse model. Pharmacokinetics studies demonstrated quick absorption into plasma after oral administration, with a maximum concentration of 1680 ± 479 ng/mL at 5.33 ± 2.31 hours. The calculated oral absolute bioavailability was 34.1%. Toxicity assessment of PA4 showed that the therapeutic window used in our experiments was safe for future development. Given its efficacy, safety, and favorable pharmacokinetic profile, PA4 is a potential lead candidate for treating lymphoma.