Evaluation and SAR analysis of the cytotoxicity of tanshinones in colon cancer cells.
OBJECTIVE
This study was designed to evaluate the anti-cancer actions of tanshinone I and tanshinone IIA, and six derivatives of tanshinone IIA on normal and cancerous colon cells. Structure activity relationship (SAR) analysis was conducted to delineate the significance of the structural modifications of tanshinones for improved anti-cancer action.


METHODS
Tanshinone derivatives were designed and synthesized according to the literature. The cytotoxicity of different compounds on colon cancer cells was determined by the MTT assay. Apoptotic activity of the tanshinones was measured by flow cytometry (FCM).


RESULTS
Tanshinone I and tanshinone IIA both exhibited significant cytotoxicity on colon cancer cells. They are more effective in p53(+/+) colon cancer cell line. It was also noted that the anti-cancer activity of tanshinone I was more potent and selective. Two of the derivatives of tanshinone IIA (N1 and N2) also exhibited cytotoxicity on colon cancer cells.


CONCLUSIONS
The anti-colon cancer activity of tanshinone I was more potent and selective than tanshinone IIA, and is p53 dependent. The derivatives obtained by structural modifications of tanshinone IIA exhibited lower cytotoxicity on both normal and colon cancer cells. From steric and electronic characteristics point of view, it was concluded that structural modifications of ring A and furan or dihydrofuran ring D on the basic structure of tanshinones influences the activity. An increase of the delocalization of the A and B rings could enhance the cytotoxicity of such compounds, while a non-planar and small sized D ring region would provide improved anti-cancer activity.
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
Lin
L
Wang
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100070, China.
An
A
Liu
Department of Chemistry, University of Science and Technology Beijing, Beijing 100083, China.
Fei-Long
FL
Zhang
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
John H K
JH
Yeung
Department of Chemistry, University of Science and Technology Beijing, Beijing 100083, China. Electronic address: lixuqin@ustb.edu.cn.
Xu-Qin
XQ
Li
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: chcho@cuhk.edu.hk.
Chi-Hin
CH
Cho
D045784:Abietanes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D003106:Colon / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008517:Phytotherapy; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D013329:Structure-Activity Relationship
D045784:Abietanes; D000972:Antineoplastic Agents, Phytogenic; D004365:Drugs, Chinese Herbal; C021751:tanshinone; C028972:dan-shen root extract
Colon cancer; Cytotoxicity; SAR analysis; Synthetic derivatives; Tanshinones