Anticancer and Antiangiogenic Activities of Novel α-Mangostin Glycosides in Human Hepatocellular Carcinoma Cells via Downregulation of c-Met and HIF-1α
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 im...
Main Authors: | , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2020-06-01
|
Series: | International Journal of Molecular Sciences |
Subjects: | |
Online Access: | https://www.mdpi.com/1422-0067/21/11/4043 |
id |
doaj-2f5a85b640f34240b7d030e2f78da76a |
---|---|
record_format |
Article |
spelling |
doaj-2f5a85b640f34240b7d030e2f78da76a2020-11-25T02:26:46ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-06-01214043404310.3390/ijms21114043Anticancer and Antiangiogenic Activities of Novel α-Mangostin Glycosides in Human Hepatocellular Carcinoma Cells via Downregulation of c-Met and HIF-1αSung Min Kim0Jang Mi Han1Tuoi Thi Le2Jae Kyung Sohng3Hye Jin Jung4Department of Pharmaceutical Engineering and Biotechnology, Sun Moon University, Asan 31460, KoreaDepartment of Life Science and Biochemical Engineering, Sun Moon University, Asan 31460, KoreaDepartment of Life Science and Biochemical Engineering, Sun Moon University, Asan 31460, KoreaDepartment of Pharmaceutical Engineering and Biotechnology, Sun Moon University, Asan 31460, KoreaDepartment of Pharmaceutical Engineering and Biotechnology, Sun Moon University, Asan 31460, KoreaHepatocellular 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-<i>O</i>-<i>β</i>-D-2-deoxyglucopyranoside (Man-3DG) and α-mangostin 6-<i>O</i>-<i>β</i>-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.https://www.mdpi.com/1422-0067/21/11/4043hepatocellular carcinomaα-mangostin glycosidesapoptosisautophagytumor angiogenesisc-Met |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sung Min Kim Jang Mi Han Tuoi Thi Le Jae Kyung Sohng Hye Jin Jung |
spellingShingle |
Sung Min Kim Jang Mi Han Tuoi Thi Le Jae Kyung Sohng Hye Jin Jung Anticancer and Antiangiogenic Activities of Novel α-Mangostin Glycosides in Human Hepatocellular Carcinoma Cells via Downregulation of c-Met and HIF-1α International Journal of Molecular Sciences hepatocellular carcinoma α-mangostin glycosides apoptosis autophagy tumor angiogenesis c-Met |
author_facet |
Sung Min Kim Jang Mi Han Tuoi Thi Le Jae Kyung Sohng Hye Jin Jung |
author_sort |
Sung Min Kim |
title |
Anticancer and Antiangiogenic Activities of Novel α-Mangostin Glycosides in Human Hepatocellular Carcinoma Cells via Downregulation of c-Met and HIF-1α |
title_short |
Anticancer and Antiangiogenic Activities of Novel α-Mangostin Glycosides in Human Hepatocellular Carcinoma Cells via Downregulation of c-Met and HIF-1α |
title_full |
Anticancer and Antiangiogenic Activities of Novel α-Mangostin Glycosides in Human Hepatocellular Carcinoma Cells via Downregulation of c-Met and HIF-1α |
title_fullStr |
Anticancer and Antiangiogenic Activities of Novel α-Mangostin Glycosides in Human Hepatocellular Carcinoma Cells via Downregulation of c-Met and HIF-1α |
title_full_unstemmed |
Anticancer and Antiangiogenic Activities of Novel α-Mangostin Glycosides in Human Hepatocellular Carcinoma Cells via Downregulation of c-Met and HIF-1α |
title_sort |
anticancer and antiangiogenic activities of novel α-mangostin glycosides in human hepatocellular carcinoma cells via downregulation of c-met and hif-1α |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-06-01 |
description |
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-<i>O</i>-<i>β</i>-D-2-deoxyglucopyranoside (Man-3DG) and α-mangostin 6-<i>O</i>-<i>β</i>-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. |
topic |
hepatocellular carcinoma α-mangostin glycosides apoptosis autophagy tumor angiogenesis c-Met |
url |
https://www.mdpi.com/1422-0067/21/11/4043 |
work_keys_str_mv |
AT sungminkim anticancerandantiangiogenicactivitiesofnovelamangostinglycosidesinhumanhepatocellularcarcinomacellsviadownregulationofcmetandhif1a AT jangmihan anticancerandantiangiogenicactivitiesofnovelamangostinglycosidesinhumanhepatocellularcarcinomacellsviadownregulationofcmetandhif1a AT tuoithile anticancerandantiangiogenicactivitiesofnovelamangostinglycosidesinhumanhepatocellularcarcinomacellsviadownregulationofcmetandhif1a AT jaekyungsohng anticancerandantiangiogenicactivitiesofnovelamangostinglycosidesinhumanhepatocellularcarcinomacellsviadownregulationofcmetandhif1a AT hyejinjung anticancerandantiangiogenicactivitiesofnovelamangostinglycosidesinhumanhepatocellularcarcinomacellsviadownregulationofcmetandhif1a |
_version_ |
1724845759312953344 |