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.
Highlights
With chemotherapy remaining the popular cancer treatment, research and development of antitumor drugs has been a hotspot in recent years (Kerru et al, 2017)
The relative fluorescence intensity measured by the image analyzer significantly decreased (p < 0.01), indicating that the ψm decreased. These results show that hydroxy justicidin B (HJB) and IMA have a significant influence on the ψm of K562 cells, and that the apoptosis induced by HJB is possibly related to this change in ψm
Using Anti-p53 pS37-PE to label the p53 protein we found that p53 levels were significantly increased after HJB treatment, indicating that HJB-induced apoptosis of K562 cells might utilize the p53 pathway
Summary
With chemotherapy remaining the popular cancer treatment, research and development of antitumor drugs has been a hotspot in recent years (Kerru et al, 2017). Development of efficient anti-tumor drugs with low toxicity is still urgently needed. Studies have shown that justicidins have a variety of biological activities, such as neuroprotection (Gu et al, 2016), cytotoxicity (Hemmati and Seradj, 2016), antiviral activity (Asano et al, 1996), and a wide range of anti-tumor effects. As a potential bioactive substance, its cytotoxicity to numerous cells lines has been systematically studied (He et al, 2012; Ilieva et al, 2014; Jin et al, 2014; Momekov et al, 2014; Won et al, 2015). The associated mechanism of 6 -hydroxy justicidin B (HJB) as a potential antitumor compound remains unknown
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