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Pro-Apoptotic Effects of the Novel Tangeretin Derivate 5-Acetyl-6,7,8,4′-Tetramethylnortangeretin on MCF-7 Breast Cancer Cells

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Abstract

Citrus polymethoxyflavone tangeretin (5,6,7,8,4′-pentamethoxyflavone, TAN) displays multiple biological activities, but previous reports showed that TAN failed to induce MCF-7 human breast cancer cells apoptosis. Herein, we prepared 5-acetyl-6,7,8,4′-tetramethylnortangeretin (5-ATAN), and evaluated its cytotoxicity on MCF-7 cells. 5-ATAN revealed stronger cytotoxicity than that of parent TAN in the growth inhibition of MCF-7 cells. 5-ATAN induced apoptosis via both caspase-independent and -dependent pathways, in which 5-ATAN induced the translocation of apoptosis inducing factor and phosphorylation of H2AX as well as poly (ADP-ribose) polymerase cleavage, caspase-3 activation. However, 5-ATAN did not affect extrinsic markers caspase-8, BID, and FADD. Further, 5-ATAN induced the loss of mitochondrial membrane potential (Δψm) by regulating the Bax/Bcl-2 ratio. Loss of Δψm led to the mitochondrial release of cytochrome c which triggered activation of caspase-9. In conclusion, these data indicate that 5-ATAN plays pro-apoptotic cytotoxic roles in MCF-7 cells through both caspase-dependent intrinsic apoptosis and caspase-independent apoptosis pathways.

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (Grant Nos. 81172837, 81101220), the Tianjin Research Program of Application Foundation and Advanced Technology (Grant Nos. 12JCQNJC08100, 13JCQNJC12200) and Innovative Research Team Grant for Agriculture Product Storage and procession (TD12-5049). We thank Mr. Xiaomeng Xing and Ms. Kaili Lin (Center for SCGE assay). We thank Dr. Chang Xu for providing PARP antibody. We thank Dr. Edward Li (Cell Signaling Technology, Technical Support Specialist) for providing partial element of Supplementary Fig. 2).

Conflict of interest

The authors declare that there are no conflicts of interest.

Author information

Authors and Affiliations

  1. Tianjin Key Laboratory of Food and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, China

    Jinhan Wang, Yitao Duan, Dexian Zhi, Liwen Wang, Haihua Ruan, Kunsheng Zhang & Hui Zhao

  2. Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China

    Jinhan Wang, Guangqiang Li & Qiang Liu

  3. Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China

    Yitao Duan

  4. Department of Hematology and Translation Medicine Centre, Hebei Union University Affiliated Hospital, Tangshan, Hebei, China

    Hongmei Zhang, Lichao Gu & Hui Zhao

  5. Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources Comprehensive Utilization, Huanggang Normal University, Huanggang, Hubei, China

    Shiming Li

  6. Department of Food Science, Rutgers University, New Brunswick, NJ, USA

    Shiming Li & Chi-Tang Ho

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  1. Jinhan Wang
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Correspondence to Shiming Li or Hui Zhao.

Electronic supplementary material

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12013_2014_49_MOESM1_ESM.jpg

Supplementary Fig. 1a Cells treated with 5-ATAN (5, 10 and 20 μM) for 12/24 h and observed under microscope (4×). b DAPI staining of MCF-7 cells treated with different time 5 μM 5-ATAN (20×). c MCF-7 cells were incubated for 6 h in the presence 5 μM 5-ATAN or TAN (5, 20 μM). d MCF-7 cells were incubated for the indicated times in the presence or absence of 5 μM 5-ATAN. The protein levels of Bax and Bcl-2 were analyzed by western blotting. e Effects of caspase inhibitors on cell viability induced by MCF-7 cells were pretreated with various caspase inhibitors at 10 μM for 2 h followed by incubation with 5-ATAN (5 μM) for 24 h. (JPEG 433 kb)

Supplementary Fig. 2a Working model summarizing the mechanism of 5-ATAN induced apoptosis in MCF-7 cells (JPEG 505 kb)

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Wang, J., Duan, Y., Zhi, D. et al. Pro-Apoptotic Effects of the Novel Tangeretin Derivate 5-Acetyl-6,7,8,4′-Tetramethylnortangeretin on MCF-7 Breast Cancer Cells. Cell Biochem Biophys 70, 1255–1263 (2014). https://doi.org/10.1007/s12013-014-0049-7

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