Article Text

PDF
Dual antitumour effect of 5-azacytidine by inducing a breakdown of resistance-mediating factors and epigenetic modulation
  1. Sascha Venturelli1,
  2. Alexander Berger1,
  3. Timo Weiland1,
  4. Martina Zimmermann1,
  5. Sabine Häcker2,
  6. Christoph Peter1,
  7. Sebastian Wesselborg1,
  8. Alfred Königsrainer3,
  9. Thomas S Weiss4,
  10. Michael Gregor1,
  11. Simone Fulda2,
  12. Ulrich M Lauer1,
  13. Michael Bitzer1
  1. 1Department of Internal Medicine I, Medical University Hospital, Tuebingen, Germany
  2. 2University Children's Hospital, Ulm University, Ulm, Germany
  3. 3Department of General, Visceral and Transplant Surgery, University Hospital, Tuebingen, Germany
  4. 4Center for Liver Cell Research, University Hospital, Regensburg, Germany
  1. Correspondence to Michael Bitzer, Department of Internal Medicine I, Medical University Hospital, Otfried-Mueller-Str. 10, D-72076 Tuebingen, Germany; michael.bitzer{at}uni-tuebingen.de

Abstract

Background The cytokine tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown promising anticancer activity in early clinical settings by selectively inducing apoptosis in different tumour types. However, some tumour entities such as hepatocellular carcinoma (HCC) display an inherent resistance to TRAIL. A huge effort has been made to unravel strategies for a clinically applicable sensitisation of resistant cancer cells to TRAIL. Reversible epigenetic alterations such as DNA methylation play a major role in development, maintenance and resistance phenomena of tumour cells. Currently, several clinical trials are exploiting the potential of epigenetic drugs, such as 5-azacytidine (5-aza-CR) or 5-aza-2′-deoxycytidine (5-aza-dC) to break primary or secondary resistance phenomena of cancer cells. Therefore, 5-aza-CR and 5-aza-dC were investigated in the context of TRAIL resistance.

Methods Alterations in proliferation, apoptosis, regulatory proteins and toxicity were investigated in TRAIL-resistant hepatoma, and also in renal, colon and pancreatic cancer cells as well as non-transformed human-derived primary hepatocytes, tissue slices isolated from human liver and non-malignant colon cells, all of which had been exposed to demethylating drugs and/or TRAIL.

Results Within hours, 5-aza-CR but not 5-aza-dC sensitised in vitro cultured tumour cells to TRAIL, first by activating caspases, followed by a subsequent induction of apoptosis. This surprisingly rapid sensitisation was confirmed in vivo employing a chorioallantoic membrane assay. As a major mechanism, a 5-aza-CR-induced inhibition of cellular protein synthesis was found which led to a breakdown of tumour-protecting factors such as the antiapoptotic factor FLICE inhibitory protein (FLIP). Importantly, TRAIL and 5-aza-CR did not induce relevant toxicity or apoptosis in primary hepatocytes, liver slices from different human donors and in normal colon cells.

Conclusions Molecular evidence is provided for a novel 5-aza-CR-based translational approach enabling a twofold treatment of apoptosis-resistant tumour entities, not only by an epigenetic reversion of the malignancy-associated phenotype but also by an efficient resensitisation to apoptosis-inducing substances such as TRAIL.

  • Apoptosis
  • cancer
  • hepatobiliary cancer
  • hepatocellular carcinoma
  • liver

Statistics from Altmetric.com

Footnotes

  • Funding This work was supported in part by grants from the Deutsche Forschungsgemeinschaft SFB 773, from the Ministry for Nutrition and Rural Territories and the Ministry for Science, Research and Arts of Baden-Wuerttemberg, Germany (Kap. 0802, Title 98174). The work of SF was funded by the EU (ApopTrain), and SV was supported by a grant from the Interdisciplinary Center of Clinical Research Tuebingen (IZKF).

  • Competing interests None.

  • Ethics approval The work contains material from human subjects (primary cells and tissue slices). The Ethics Committee at Tübingen, Germany, has approved the usage of these materials.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.