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Digalloylresveratrol, a novel resveratrol analog inhibits the growth of human pancreatic cancer cells

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Summary

Digalloylresveratrol (DIG) is a recently synthesized substance aimed to combine the effects of the natural polyphenolic compounds gallic acid and resveratrol, which both are excellent free radical scavengers with anticancer activity. In this study, we investigated the effects of DIG in the human AsPC-1 and BxPC-3 pancreatic adenocarcinoma cell lines. Treatment with DIG dose-dependently attenuated cells in the S phase of the cell cycle and led to a significant depletion of the dATP pool in AsPC-1 cells. The incorporation of 14C-cytidine into nascent DNA of tumor cells was significantly inhibited at all DIG concentrations due to inhibition of ribonucleotide reductase, a key enzyme of DNA synthesis in tumor cells. Furthermore, Erk1/2 became inactivated and moderated p38 phosphorylation reflecting increased replication stress. DIG also activated ATM and Chk2, and induced the phosphorylation and proteasomal degradation of the proto-oncogene Cdc25A, which contributed to cell cycle attenuation. Taken together, DIG is an excellent free radical scavenger, strongly inhibits RR in situ activity, cell cycle progression, and colony formation in AsPC-1 and BxPC-3 cells thus warranting further investigations.

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Acknowledgments

This investigation was supported by the Medical-Scientific Fund of the Mayor of Vienna, grant #09059 to M.F.-S., the “Hochschuljubilaeumsstiftung der Stadt Wien”, grants #H-756/2005 and #H-2498/2011 to T.S. and P.S., respectively, by the Fellinger Cancer Research Association (Fellinger Krebsforschung Gemeinnuetziger Verein) to G.K. as a mission-oriented grant, and by the Herzfelder Family foundation with grants to T.S., P.S., and G.K. The authors also wish to thank Toni Jaeger for preparing the western blotting figures.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria

    Philipp Saiko, Geraldine Graser, Marie-Thérèse Steinmann, Heike Schuster, Monika Fritzer-Szekeres & Thomas Szekeres

  2. Department of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria

    Benedikt Giessrigl & Georg Krupitza

  3. Department of Medicine I, Division of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria

    Andreas Lackner & Michael Grusch

  4. Department of Clinical Pharmacy and Diagnostics, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria

    Walter Jaeger

  5. Laila Impex Research Center, Jawahar Autonagar, Vijayawada, 520 007, India

    Venkateswarlu Somepalli & Trimurtulu Golakoti

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  1. Philipp Saiko
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  2. Geraldine Graser
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  3. Benedikt Giessrigl
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  10. Venkateswarlu Somepalli
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Correspondence to Thomas Szekeres.

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Saiko, P., Graser, G., Giessrigl, B. et al. Digalloylresveratrol, a novel resveratrol analog inhibits the growth of human pancreatic cancer cells. Invest New Drugs 31, 1115–1124 (2013). https://doi.org/10.1007/s10637-013-0009-x

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