6′-Hydroxy Justicidin B Triggers a Critical Imbalance in Ca2+ Homeostasis and Mitochondrion-Dependent Cell Death in Human Leukemia K562 Cells

Abstract

Justicia procumbens (J. procumbens) is a traditional Chinese herbal medicine which was used for the treatment of fever, pain, and cancer. A compound 6′-hydroxy justicidin B (HJB) isolated from J. procumbens exhibits promising biological properties. However, the mechanism of action and the in vivo behavior of HJB remain to be elucidated. In this study, we investigated the mechanism of action of HJB on human leukemia K562 cells and its pharmacokinetic properties in rats. The results demonstrated that HJB significantly inhibited the proliferation of K562 cells and promoted apoptosis. Besides, HJB resulted in decreased mitochondrial membrane potential deltaPSIm, increased the level of the calcium homeostasis regulator protein TRPC6 and cytosolic calcium. The activity of caspase-8, caspase-9 and the expression of p53 were significantly increased after treatment with HJB. Additionally, HJB has rapid absorption rate and relative long elimination t1/2, indicating a longer residence time in vivo. The results indicate that HJB inhibited the proliferation of K562 cells and induced apoptosis by affecting the function of mitochondria and calcium homeostasis to activate the p53 signaling pathway. The pharmacokinetic study of HJB suggested it is absorbed well and has moderate metabolism in vivo. These results present HJB as a potential novel alternative to standard human leukemia therapies.

Ginsenoside Rb1 Attenuates Triptolide-Induced Cytotoxicity in HL-7702 Cells via the Activation of Keap1/Nrf2/ARE Pathway

“…In normal cells with high mitochondrial membrane potential, a large amount JC-1 in the mitochondrial matrix produces red fluorescence. In contrast, in apoptotic cells, the reduced MMP promotes the transfer of JC-1 to the cytoplasm, where it appears green fluorescence ( Luo et al, 2018 ). Therefore, changes in MMP can be judged by changes in fluorescence of JC-1.…”

Arylnaphthalene lactones: structures and pharmacological potentials

“…The IC 50 of justicidin H (3) was 15.07 lM for K562 cells and reduced mitochondria membrane potential (deltapsi(m)). It also increased the expression of TRPC6 related to regulating calcium homeostasis in cell signaling and induced apoptosis through the caspase pathway (Luo et al 2018).…”

“…Their minimum inhibitory concentration (MIC) values were less than 0.25 lg/mL whereas 6 0 -glucosides justicidinoside A-C (106, 35, 9) and Type II justicidin C and D (103, 105) exhibited lower antiviral activity (the MICs ranged from 16 to 125 lg/mL). It is tempting to suggest that the weak activity of justicidinoside A-C (106, 35, 9) is because of the steric bulk of their sugar moiety and that Type I arylnaphthalene lactones were more effective than Type II (Luo et al 2018). Using the standard plaque reduction assay against human cytomegalovirus, only taiwanin C (2) and retrojusticidin B (91) showed clear antiviral activity with half maximal effective concentration (EC 50 ) values at 1.2 and 7.2 lM, respectively (Chen et al 1996).…”