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

Autori
Tomičić, Maja T. ; Steigerwald, Christian ; Rasenberger, Birgit ; Brozović, Anamaria ; Christmann, Markus

Izvornik
Archives of toxicology (0340-5761) 93 (2019), 8; 2265-2277

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
IAP antagonist ; Irinotecan ; Colorectal cancer ; Mismatch repair ; p53 ; NF-κB

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Temeljne medicinske znanosti

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