Journal
FRONTIERS IN ONCOLOGY
Volume 9, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2019.00438
Keywords
gold(I) N-heterocyclic carbene complex; p53; p21; p73; colorectal cancer; apoptosis
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Funding
- Heidelberg University
- German Academic Exchange Service (DAAD)
- Georg-Lichtenberg fellowship by the State of Lower Saxony
- Bundesministerium fur Bildung und Forschung (BMBF) [FKZ 031A303E, FKZ 01EK1612C]
- Deutsche Forschungsgemeinschaft (DFG) [CH 1690/2-1]
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The tumor suppressor p53 has a diverse mutational profile in human malignancies, which is known to influence the potency of various chemotherapeutics, such as platins and anti-metabolites. However, the impact of the mutations in the TP53 gene (coding for p53) on the anti-cancer efficacy of gold complexes remains incompletely understood. We therefore investigated the anti-tumor properties of a gold(I) N-heterocyclic carbene (NHC) complex-termed MC3-in human colorectal cancer (CRC) cell lines encompassing three different p53 variations: HCT116 wild-type (WT), HCT116 p53(-/-), and HT-29 (mutant; R273H). MC3 treatment induced intracellular reactive oxygen species (ROS) levels, and p21 expression, leading to cell cycle arrest in all cell lines, regardless of their p53 status. The pro-apoptotic response, however, was found to occur in a p53-dependent manner, with WT p53 harboring cells showing the highest responsiveness. Additionally, p73, which was speculated to substitute p53 in p53-deficient cells, was found to be markedly reduced with MC3 treatment in all the cell lines and knocking down its levels did not impact MC3's anti-tumor effects in HCT116 p53(-/-) cells. Collectively, our results suggest that this small molecule has anti-cancer properties in the context of deficient or mutant p53 and may therefore have chemotherapeutic potential for clinical application.
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