Pharmacological profiling of a berbamine derivative for lymphoma treatment
Ca2+/calmodulin-dependent protein kinase II gamma (CAMKII?) has been identified as a potential target for treating cancer. Based on our previous study of Berbamine (BBM) as a CAMKII? inhibitor, we have synthesized a new BBM derivative termed PA4. Compared to BBM, PA4 showed improved potency and specificity, and was more cytotoxic against lymphoma and leukemia compared to other types of cancer. In addition to indirectly targeting c-Myc protein stability, we demonstrated that its cytotoxic effects were also mediated via increased ROS production in lymphoma cells. PA4 significantly impeded tumor growth in vivo in a xenograft T-cell lymphoma (TCL) mouse model. Pharmacokinetics studies depicted quick absorption into plasma after oral administration with a max concentration of 1680 ± 479 ng/mL at 5.33 ± 2.31 hr. 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. Overall design: To determine the underlying mechanisms of PA4-induced cell death, we compared the global gene profiles between vehicle control (DMSO) and 1 µM PA4 treatment in H9 cells