Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Therefore, exploring effective anticancer agents and their modes of action is essential for the prevention and treatment of HCC. Glycosylation can significantly improve the physicochemical and biological properties of small molecules, such as high solubility, stability increase, and lower toxicity. In the present study, for the first time, we evaluated the anticancer and antiangiogenic activities of α-mangostin-3-O-β-D-2-deoxyglucopyranoside (Man-3DG) and α-mangostin 6-O-β-D-2-deoxyglucopyranoside (Man-6DG), glycosides of α-mangostin, against human HCC cells. Our results demonstrated that Man-3DG and Man-6DG significantly suppressed the growth of three different HCC cells (Hep3B, Huh7, and HepG2) as well as the migration of Hep3B cells. Furthermore, they induced cell cycle arrest in the G0/G1 phases and apoptotic cell death by regulating apoptosis-related proteins of mitochondria in Hep3B cells. Noticeably, Man-3DG and Man-6DG also caused autophagy, while co-treatment of the α-mangostin glycosides with an autophagy inhibitor 3-MA enhanced the inhibitory effect on Hep3B cell growth in comparison to single agent treatment. Moreover, Man-3DG and Man-6DG inhibited the c-Met signaling pathway that plays a critical role in the pathogenesis of HCC. Furthermore, the α-mangostin glycosides decreased Hep3B cell-induced angiogenesis in vitro through the downregulation of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). Notably, Man-6DG more effectively inhibited the growth, tumorsphere formation, and expression of cancer stemness regulators compared to α-mangostin and Man-3DG in 3D spheroid-cultured Hep3B cells. These findings suggest that the α-mangostin glycosides might be promising anticancer agents for HCC treatment with superior pharmacological properties than the parent molecule α-mangostin.
Highlights
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world and it accounts for 85%–90% of all cases of liver cancer
We first examined the effects of α-mangostin glycosides, mangostin 3-O-β-D-2-deoxyglucopyranoside (Man-3DG), and mangostin 6-O-β-D-2-deoxyglucopyranoside (Man-6DG), on the growth of three different HCC cell lines (HepG2, Huh7, and Hep3B)
Effects of α-Mangostin Glycosides on the Hypoxia-Induced Accumulation of hypoxia-inducible factor-1α (HIF-1α) Protein We further investigated the effects of α-mangostin, Man-3DG, and Man-6DG on the invasion of HUVoEfCpsrHoinaIdnFg-u1icαoegidesnkbinycofHwacentpoar3ssB,thsceuecmlhlsoasustspvinoatgsecnautlcainord-ecunucdletorutohrfeetlaiuasmlsgaoryro.awAngtshioafgarecentsoeursil(stV,tthEhaGetFrH)eg[U1u2Vl–aE1te4Cs].sthTceooe-axcsupsrletesusssriteohdne with Hep3cBoncterlilbsustihoonwoefdHsIiFg-n1iαficiannmt iendviaatsiniogntchoemtupmaroerdatnogHiogUeVneEsCissi(nFhiigbuitroery8Be)f.feHctowofeαv-emr,aHngeops3tiBn cells treategdlywcoistihdeαs,mthaenegffoescttsino,fMα-amna-n3gDoGst,ina,nMdaMn-a3Dn-G6,DaGndeMffeacnt-i6vDeGlyopnrtehveeHntIeFd-1αtheexpinrecsrseiaosneodf iHnevpa3sBion of human umbilical vein endothelial cells (HUVECs), implying that the α-mangostin glycosides can inhibit HCC cell-induced angiogenesis
Summary
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world and it accounts for 85%–90% of all cases of liver cancer. It has been reported as the second most prevalent cause of global cancer mortality [1,2]. HCC is a multifactorial disease that is caused by smoking, alcohol, mycotoxins, human hepatitis virus, fatigue, and obesity [3]. The current therapy for HCC includes surgical operation, radiofrequency ablation, and chemotherapy. The therapeutic outcomes are unsatisfactory due to metastasis and a high recurrence rate [4]. It is still necessary to develop new anticancer drugs for the prevention and treatment of HCC
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