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, 292 (1), 48-53

Antitumor Activity of Novel Fluoro-Substituted (-)-epigallocatechin-3-gallate Analogs


Antitumor Activity of Novel Fluoro-Substituted (-)-epigallocatechin-3-gallate Analogs

Huanjie Yang et al. Cancer Lett.


Epidemiological studies support the cancer-preventive effects of green tea and its main constituent (-)-epigallocatechin gallate [(-)-EGCG], however, (-)-EGCG is unstable under physiological conditions. Here we report that two novel fluoro-substituted (-)-EGCG analogs inhibited tumor growth with similar potency to that of Pro-EGCG (1) which has improved potency over parental compound (-)-EGCG in human breast cancer MDA-MB-231 xenografts. MDA-MB-231 tumors treated with each fluoro-substituted (-)-EGCG analog showed proteasome inhibition and apoptotic cell death, suggesting that the proteasome might be one of the cellular targets of fluoro-(-)-EGCGs and that proteasome inhibition is partially responsible for the observed antitumor activity.

Conflict of interest statement

Conflict of Interest

We confirmed that there is no potential conflict of interest regarding submission and publication of our manuscript entitled “The Antitumor Activity of Novel Fluoro-Substituted (−)-epigallocatechin-3-gallate Analogs”. All the authors have read and approved for submission to Cancer Letters.

Conflict of Interest

All the authors confirm that there is no potential conflict of interest regarding this publication.


Figure 1
Figure 1. Antitumor effects of fluoro-substituted EGCG analogs
A, Chemical structures of two novel prodrugs of fluoro-substituted EGCG. The chemical structures of Pro-F-EGCG2, Pro-F-EGCG4 and peracetate-protected EGCG [(Pro-EGCG (1)] were shown. B, Inhibition of MDA-MB-231 tumor growth. Nude mice were s.c. inoculated with human breast cancer MDA-MB-231 cells (5×106). When the tumors were detectable, nude mice were s.c. daily treated with either drug vehicle (n=9), or 50 mg/kg Pro-F-EGCG2 (Pro-F2) (n=9), Pro-F-EGCG4 (Pro-F4) (n=9) or control peracetate-protected EGCG (Pro-E) (n=6), as described in Materials and Methods. By the end of 31 days treatment, mice were euthanized and tumors were weighed. Points, mean of tumor weights; bars, SE. **, p<0.01; *, p<0.05.
Figure 2
Figure 2. Cell death induction by prodrugs of fluoro-substituted EGCGs in MDA-MB-231 tumors
Tumor tissues were treated with vehicle (V) or Pro-F-EGCG2 (Pro-F2) or Pro-F-EGCG4 (Pro-F4). Proteins were extracted from tumor tissues, followed by Western blotting analysis using antibody against PARP (A). The full length of PARP is 116 kDa, while the cleaved form of PARP is 65 kDa. B, tumor tissues were sectioned, followed by TUNEL assay and H&E staining. Pro-F-EGCGs treated tumors showed TUNEL positive cells with brown color and condensed nuclei in H&E staining. Magnifications, ×400.
Figure 3
Figure 3. Inhibition of the proteasome by prodrugs of fluoro-substituted EGCG in MDA-MB-231 tumors
Tumors were treated with vehicle (V) or Pro-F-EGCG2 (Pro-F2) or Pro-F-EGCG4 (Pro-F4) as described in Figure 1 and tissues were used. A, Proteasomal chymotrypsin-like activity assay. Proteins were extracted from tumor tissues and subject to proteasome activity assay using Suc-LLVY substrate for chymotrypsin-like activity, as described in Materials and Methods. Protein level of ubiquitinnated protein and proteasome targets p27 and Bax were analyzed by Western blotting (B). An ubiquitinated form of p27 (70 kDa) was indicated by an arrow. Bax, both p21 and p18 forms were shown. Actin was used as loading control. C, Immunochemistry with p27 antibody. Tumor tissues were sectioned for immunochemistry using p27 antibody. Magnifications, ×400.

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