Send to

Choose Destination
Cancer Biol Ther. 2016;17(1):48-64. doi: 10.1080/15384047.2015.1108491.

Tangeretin derivative, 5-acetyloxy-6,7,8,4'-tetramethoxyflavone induces G2/M arrest, apoptosis and autophagy in human non-small cell lung cancer cells in vitro and in vivo.

Author information

a Institute of Biomedical Science and Rong Hsing Research Center for Translational Medicine, National Chung-Hsing University , Taichung , Taiwan.
b Hubei Key Laboratory for Processing and Application of Catalytic Materials, Huanggang Normal University , Hubei , China.
c Department of Food Science , Rutgers University , New Brunswick , NJ , USA.
d Tungs' Taichung MetroHarbor Hospital , Taichung , Taiwan.
e Institute of Bioinformatics and Structural Biology and Department of Medical Sciences, National Tsing Hua University , Hsinchu , Taiwan.
f Division of Thoracic Surgery, Department of Surgery, Changhua Christian Hospital and Institute of Medicine, Chung Shan Medical University , Taichung , Taiwan.
g Department of Food Science , National Pingtung University of Science and Technology , Pingtung , Taiwan.


Tangeretin, a major phytochemicals in tangerine peels--an important Chinese herb, has been found to have anti-carcinogenic properties. To improve bioavailability and increase potency of tangeretin, its derivative, 5-acetyloxy-6,7,8,4'-tetramethoxyflavone (5-AcTMF), has been synthesized and shown potent inhibition of proliferation activity against human breast and leukemia cancer cell lines. In this study, we have further investigated the anticancer effects of 5-AcTMF on CL1-5 non-small cell lung cancer cells (NSCLC) both in vitro and in vivo and demonstrated that 5-AcTMF effectively inhibited cancer cell proliferation, induced G2/M-phase arrest associated with cdc2 and CDC25c and increased in the apoptotic cells associated with caspase activation, down regulation of Bcl-2, XIAP and Survivn, inducing release of cytochrome c into the cytosol and disruption of mitochondrial membrane potential. We also found that 5-AcTMF treatment of CL1-5 activated autophagy, indicated by triggered autophagosome formation and increased LC3-II levels and formation of LC3 puncta. Moreover, we also found that 5-AcTMF lowered phophoatidylinositol 3-kinase/AKT/mTOR signaling pathway. Over-expression of AKT by AKT cDNA transfection decreased 5-AcTMF mediated apoptosis and autophagy, supporting the induction of apoptosis and autophagy by inhibition of AKT pathway. In an animal study, 5-AcTMF effectively delayed tumor growth in a nude mouse model of CL1-5 xenografts without observed adverse effect. Immunohistochemistry Analysis indicated that 5-AcTMF induced CL1-5 cell apoptosis and autophagy in vivo. Taken together, these data demonstrate that 5-AcTMF is a novel small molecule agent that can inhibit NSCLC cell proliferation, and induce G(2)/M phase arrest and via the mitochondrial apoptotic pathway and autophagy.


5-Acetyloxy-6,7,8,4′-tetramethoxyflavone; AKT; apoptosis; autophagy; G2/M arrest; non-small cell lung cancer cell

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Taylor & Francis Icon for PubMed Central
Loading ...
Support Center