Functional mismatch repair and inactive p53 drive sensitization of colorectal cancer cells to irinotecan via the IAP antagonist BV6

  • Maja T. TomicicEmail author
  • Christian Steigerwald
  • Birgit Rasenberger
  • Anamaria Brozovic
  • Markus Christmann
Molecular Toxicology


A common strategy to overcome acquired chemotherapy resistance is the combination of a specific anticancer drug (e.g., topoisomerase I inhibitor irinotecan) together with a putative sensitizer. The purpose of this study was to analyze the cytostatic/cytotoxic response of colorectal carcinoma (CRC) cells to irinotecan, depending on the mismatch repair (MMR) and p53 status and to examine the impact of BV6, a bivalent antagonist of inhibitors of apoptosis c-IAP1/c-IAP2, alone or combined with irinotecan. Therefore, several MSH2- or MSH6-deficient cell lines were complemented for MMR deficiency, or MSH6 was knocked out/down in MMR-proficient cells. Upon irinotecan, MMR-deficient/p53-mutated lines repaired DNA double-strand breaks by homologous recombination less efficiently than MMR-proficient/p53-mutated lines and underwent elevated caspase-9-dependent apoptosis. Opposite, BV6-mediated sensitization was achieved only in MMR-proficient/p53-mutated cells. In those cells, c-IAP1 and c-IAP2 were effectively degraded by BV6, caspase-8 was fully activated, and both canonical and non-canonical NF-κB signaling were triggered. The results were confirmed ex vivo in tumor organoids from CRC patients. Therefore, the particular MMR+/p53mt signature, often found in non-metastasizing (stage II) CRC might be used as a prognostic factor for an adjuvant therapy using low-dose irinotecan combined with a bivalent IAP antagonist.


IAP antagonist Irinotecan Colorectal cancer Mismatch repair p53 NF-κB 



We thank Anna Frumkina for conducting neutral comet assay. The work was financed by Dr. Mildred Scheel Stiftung für Krebsforschung to MTT.

Author contributions

MTT: study design, experimental work, data analysis, paper writing. CS: experimental work. BR: technical assistance, experimental work. AB: contribution to a new model/methodology. MC: discussion and consulting.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

204_2019_2513_MOESM1_ESM.pptx (2.3 mb)
Supplementary material 1 (PPTX 2394 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of ToxicologyUniversity Medical Center MainzMainzGermany
  2. 2.Division of Molecular BiologyRuđer Bošković InstituteZagrebCroatia

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