Isoangustone A induces apoptosis in SW480 human colorectal adenocarcinoma cells by disrupting mitochondrial functions.
Licorice and its components have been reported to posses various anti-tumor activities, but its active ingredients and underlying mechanisms are not well understood yet. In the present study, a group of representative licorice-derived compounds that could be detected in rat plasma or urine were screened for anti-tumor activity. Among these compounds, isoangustone A (IAA) was found to promptly inhibit the viability of SW480 human colorectal adenocarcinoma cells in a time- and concentration-dependent manner. Further analyses indicate that IAA activated caspase-dependent pro-apoptotic signaling and induced significant apoptosis, while had little effect on cell cycle. IAA strongly inhibited Akt phosphorylation within 5 min; however, overexpression of constitutively activated Akt could not rescue IAA-mediated inhibition, indicating that inhibition of Akt was not involved in IAA-induced apoptosis. Further examinations show that IAA induced dissipation of mitochondria membrane potential and release of cytochrome C within 1h, accompanied by swelling of mitochondrial matrix and disrupting of mitochondrial outer membrane, and followed by decreasing of cellular ATP. The above results suggest that IAA induced apoptosis in colorectal cancer cells principally by inducing mitochondrial outer membrane permeabilization, and deserves further investigations as a novel anti-colorectal cancer agent.
State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China; Department of Chemical Biology, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China.
Wei
W
Huang
Department of Chemical Biology, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China.
Shunan
S
Tang
State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China.
Xue
X
Qiao
Department of Chemical Biology, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China.
Wanwan
W
Ma
State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China.
Shuai
S
Ji
State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China; Department of Chemical Biology, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China.
Kui
K
Wang
State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China. Electronic address: yemin@bjmu.edu.cn.
Min
M
Ye
Department of Chemical Biology, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China. Electronic address: swang_yu@bjmu.edu.cn.
Siwang
S
Yu
D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000187:drug effects / Q000378:metabolism; D029882:Glycyrrhiza uralensis / Q000737:chemistry*; D006801:Humans; D007529:Isoflavones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D061945:Caspase Inhibitors; D007529:Isoflavones; D010936:Plant Extracts; C551631:isoangustone A; D045304:Cytochromes c; D020169:Caspases
Apoptosis; Colorectal cancer; Isoangustone A; Mitochondrial outer membrane permeabilization