Tetrandrine inhibits Wnt/β-catenin signaling and suppresses tumor growth of human colorectal cancer.
As one of the most common malignancies, colon cancer is initiated by abnormal activation of the Wnt/β-catenin pathway. Although the treatment options have increased for some patients, overall progress has been modest. Thus, there is a great need to develop new treatments. We have found that bisbenzylisoquinoline alkaloid tetrandrine (TET) exhibits anticancer activity. TET is used as a calcium channel blocker to treat hypertensive and arrhythmic conditions in Chinese medicine. Here, we investigate the molecular basis underlying TET's anticancer activity. We compare TET with six chemotherapy drugs in eight cancer lines and find that TET exhibits comparable anticancer activities with camptothecin, vincristine, paclitaxel, and doxorubicin, and better than that of 5-fluorouracil (5-FU) and carboplatin. TET IC₅₀ is ≤5 μM in most of the tested cancer lines. TET exhibits synergistic anticancer activity with 5-FU and reduces migration and invasion capabilities of HCT116 cells. Furthermore, TET induces apoptosis and inhibits xenograft tumor growth of colon cancer. TET treatment leads to a decrease in β-catenin protein level in xenograft tumors, which is confirmed by T-cell factor/lymphocyte enhancer factor and c-Myc reporter assays. It is noteworthy that HCT116 cells with allelic oncogenic β-catenin deleted are less sensitive to TET-mediated inhibition of proliferation, viability, and xenograft tumor growth. Thus, our findings strongly suggest that the anticancer effect of TET in colon cancer may be at least in part mediated by targeting β-catenin activity. Therefore, TET may be used alone or in combination as an effective anticancer agent.
Department of Pharmacology and the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
Bai-Cheng
BC
He
Jian-Li
JL
Gao
Bing-Qiang
BQ
Zhang
Qing
Q
Luo
Qiong
Q
Shi
Stephanie H
SH
Kim
Enyi
E
Huang
Yanhong
Y
Gao
Ke
K
Yang
Eric R
ER
Wagner
Linyuan
L
Wang
Ni
N
Tang
Jinyong
J
Luo
Xing
X
Liu
Mi
M
Li
Yang
Y
Bi
Jikun
J
Shen
Gaurav
G
Luther
Ning
N
Hu
Qixin
Q
Zhou
Hue H
HH
Luu
Rex C
RC
Haydon
Yingming
Y
Zhao
Tong-Chuan
TC
He
D000818:Animals; D044182:Benzylisoquinolines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects*; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
D044182:Benzylisoquinolines; D051153:Wnt Proteins; D051176:beta Catenin; C009438:tetrandrine