Anticancer effect of AZD2461 PARP inhibitor against colon cancer cells carrying wt or dysfunctional p53
- Department of Experimental Medicine, “Sapienza” University of Rome, Italy. Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti (Italy)
- Department of Radiological, Oncological and Pathological Sciences, “Sapienza” University of Rome, Rome (Italy)
- Department of Radiotherapy, Policlinico Umberto I, “Sapienza” University of Rome, Rome (Italy)
- Department of Neurosciences, Imaging and Clinical Sciences, University “G. D'Annunzio” Chieti (Italy)
Colon cancer is one of the most common cancers, currently treated with traditional chemotherapies or alternative therapies. However, these treatments are still not enough effective and induce several side effects, so that the search of new therapeutic strategies is needed. The use of Poly-(ADP-ribose)-polymerase (PARP) inhibitors, although originally approved against BRCA-1 or BRCA-2 mutated cancers, has been extended, particularly in combination with other treatments, to cure cancers that do not display defects in DNA repair signaling pathways. The role of p53 oncosuppressor in the regulating the outcome of PARP inhibitor treatment remains an open issue. In this study, we addressed this topic by using a well-tolerated PARP 1/2/3 inhibitor, namely AZD2461, against colon cancer cell lines with different p53 status. We found that AZD2461 reduced cell proliferation in wtp53 and p53−/− cancer cells by increasing ROS and DNA damage, while R273H mutant (mut) p53 counteracted these effects. Moreover, AZD2461 improved the reduction of cell proliferation by low dose radiation (IR) in wtp53 cancer cells, in which a down-regulation of BRCA-1 occurred. AZD2461 did not affect cell proliferation of mutp53 colon cancer cells also in combination with low dose radiation, suggesting that only wt p53 or p53 null colon cancer cells could benefit AZD2461 treatment.
- OSTI ID:
- 23195453
- Journal Information:
- Experimental Cell Research, Vol. 408, Issue 2; Other Information: Copyright (c) 2021 Elsevier Inc. All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0014-4827
- Country of Publication:
- United States
- Language:
- English
Similar Records
Structural Basis of Detection and Signaling of DNA Single-Strand Breaks by Human PARP-1
PARP Theranostic Auger Emitters Are Cytotoxic in BRCA Mutant Ovarian Cancer and Viable Tumors from Ovarian Cancer Patients Enable Ex-Vivo Screening of Tumor Response