Ginsenoside 20(s)-Rh2 as potent natural histone deacetylase inhibitors suppressing the growth of human leukemia cells.
OBJECTIVE
Activation and abnormal expression of histone deacetylase (HDAC) which is important target for cancer therapeutics are related to the occurrence of human leukemia. 20(s)-Ginsenoside Rh2 (20(s)-Rh2) may be a potential HDAC inhibitor (HDACi) of leukemia, but the mechanism has not been reported.


METHODS
The cell proliferation and apoptosis was assessed in cultured K562 and KG-1α cells. The protein expression was measured with immunoblotting. The activities of HDAC and histone acetyltransferase (HAT) were measured with BCA. In vivo experiments were performed on naked mice carrying K562 cells for assessment of tumor growth, apoptosis, protein expression, and HDAC/HAT activities.


RESULTS
20(s)-Rh2 effectively induced cell cycle arrest at G0/G1 phase and apoptosis in K562 and KG1-α cells, decreased the levels of proteins associated with cell proliferation (Cyclin D1, Bcl-2, ERK, p-ERK) and activated pro-apoptotic proteins (Bax, cleaved Caspase-3, p38, p-p38, JNK, p-JNK). 20(s)-Rh2 down-regulated HDAC1, HDAC2, HDAC6, increased histone H3 acetylation and HAT activity. Moreover, 20(s)-Rh2 inhibited the growth of human leukemia xenograft tumors in vivo.


CONCLUSIONS
20(s)-Rh2 inhibited the proliferation of K562 and KG1-α cell by reducing the expression and activity of HDACs, increasing histone acetylation, and regulating key proteins in the downstream signaling pathways. Therefore, 20(s)-Rh2 could become a potential natural HDACi for chemotherapy of leukemia.
Laboratory of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University, Chongqing 400016, China.
Ze-Hong
ZH
Liu
Laboratory of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University, Chongqing 400016, China.
Jing
J
Li
Department of Human Anatomy, Chongqing Medical and Health School, Chongqing 400016, China.
Jing
J
Xia
Laboratory of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University, Chongqing 400016, China.
Rong
R
Jiang
Key Laboratories of Clinical Diagnostics, Province and Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
Guo-Wei
GW
Zuo
Laboratory of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University, Chongqing 400016, China.
Xiao-Peng
XP
Li
Laboratory of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University, Chongqing 400016, China.
Yi
Y
Chen
Laboratory of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University, Chongqing 400016, China.
Wei
W
Xiong
Laboratory of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University, Chongqing 400016, China. Electronic address: xinmengyuandlc@163.com.
Di-Long
DL
Chen
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D036145:Ginsenosides / Q000494:pharmacology*; D051548:Histone Acetyltransferases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects; D051379:Mice
D000970:Antineoplastic Agents; D036145:Ginsenosides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; C055305:ginsenoside Rh2; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases
Apoptotic; Ginsenoside; HDAC; Leukemia