Inhibition of protein kinase C by isojacareubin suppresses hepatocellular carcinoma metastasis and induces apoptosis in vitro and in vivo.

Xing Yuan,Hao Chen,Weidong Zhang,Huawu Zeng,Lei Shan,Xia Li,Qingyan Sun,Ming Dai

doi:10.1038/srep12889

Xing Yuan, Hao Chen + Show 6 more

Open Access

https://doi.org/10.1038/srep12889

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Abstract

Targeted inhibition of protein kinase C (PKC) inhibits hepatocellular carcinoma (HCC) proliferation and metastasis. We previously reported the cytotoxicity of a series of synthetic phenyl-substituted polyoxygenated xanthone derivatives against human HCC. In the current study, the most potent natural product, isojacareubin (ISJ), was synthesized, and its cellular-level antihepatoma activities were evaluated. ISJ significantly inhibited cell proliferation and was highly selective for HCC cells in comparison to nonmalignant QSG-7701 hepatocytes. Moreover, ISJ exhibited pro-apoptotic effects on HepG2 hepatoma cells, as well as impaired HepG2 cell migration and invasion. Furthermore, ISJ was a potent inhibitor of PKC, with differential actions against various PKC isotypes. ISJ selectively inhibited the expression of aPKC (PKCζ) in the cytosol and the translocation of cytosolic PKCζ to membrane site. ISJ also directly interacted with cPKC (PKCα) and nPKC (PKCδ, PKCε and PKCμ) and thereby inhibited the early response of major MAPK phosphorylation and the late response of HCC cell invasion and proliferation. In a hepatoma xenograft model, ISJ pretreatment resulted in significant antihepatoma activity in vivo. These findings identify ISJ as a promising lead compound for the development of new antihepatoma agents and may guide the search for additional selective PKC inhibitors.

Highlights

Human hepatocellular carcinoma (HCC) is one of the most common solid epithelial malignant neoplasms worldwide[1]
The protein kinase C (PKC) family of serine/threonine kinases can be divided into three groups: conventional PKCs, novel PKCs, and atypical PKCs4
The PKC modulatory activities of twenty xanthone derivatives were evaluated using an in vivo yeast phenotypic assay, and the tested xanthones differed in efficacy and potency towards individual PKC isoforms[25]

Summary

Introduction

Human hepatocellular carcinoma (HCC) is one of the most common solid epithelial malignant neoplasms worldwide[1]. Xanthones interact with several biological targets and exhibit many pharmacological activities, including antioxidant[14], antidiabetic[15], and anti-inflammatory effects[16]. These compounds inhibit proliferation in multiple human tumor types[17,18,19], including HCC20–22. Xanthone derivatives may represent an important family of potent and selective PKC inhibitors for HCC therapy. ISJ directly interacted with cPKC (PKCα ) and nPKC (PKCδ , PKCε and PKCμ ), leading to inhibition of the early response of major MAPK phosphorylation and the late response of HCC cell invasion and proliferation. Polyoxygenated xanthone-based small molecule inhibitors represent promising candidates for antihepatoma drug development and may guide the search for additional selective PKC inhibitors

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Conclusion