Targeting DNA Homologous Repair Proficiency With Concomitant Topoisomerase II and c-Abl Inhibition

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Siddiqui , A , Tumiati , M , Joko , A , Sandholm , J , Roering , P , Aakko , S , Vainionpää , R , Kaipio , K , Huhtinen , K , Kauppi , L , Tuomela , J & Hietanen , S 2021 , ' Targeting DNA Homologous Repair Proficiency With Concomitant Topoisomerase II and c-Abl Inhibition ' , Frontiers in oncology , vol. 11 , 733700 . https://doi.org/10.3389/fonc.2021.733700

Title: Targeting DNA Homologous Repair Proficiency With Concomitant Topoisomerase II and c-Abl Inhibition
Author: Siddiqui, Arafat; Tumiati, Manuela; Joko, Alia; Sandholm, Jouko; Roering, Pia; Aakko, Sofia; Vainionpää, Reetta; Kaipio, Katja; Huhtinen, Kaisa; Kauppi, Liisa; Tuomela, Johanna; Hietanen, Sakari
Contributor: University of Helsinki, Research Programs Unit
University of Helsinki, HUSLAB
University of Helsinki, Medicum
Date: 2021-09-20
Language: eng
Number of pages: 16
Belongs to series: Frontiers in oncology
ISSN: 2234-943X
URI: http://hdl.handle.net/10138/336542
Abstract: Critical DNA repair pathways become deranged during cancer development. This vulnerability may be exploited with DNA-targeting chemotherapy. Topoisomerase II inhibitors induce double-strand breaks which, if not repaired, are detrimental to the cell. This repair process requires high-fidelity functional homologous recombination (HR) or error-prone non-homologous end joining (NHEJ). If either of these pathways is defective, a compensatory pathway may rescue the cells and induce treatment resistance. Consistently, HR proficiency, either inherent or acquired during the course of the disease, enables tumor cells competent to repair the DNA damage, which is a major problem for chemotherapy in general. In this context, c-Abl is a protein tyrosine kinase that is involved in DNA damage-induced stress. We used a low-dose topoisomerase II inhibitor mitoxantrone to induce DNA damage which caused a transient cell cycle delay but allowed eventual passage through this checkpoint in most cells. We show that the percentage of HR and NHEJ efficient HeLa cells decreased more than 50% by combining c-Abl inhibitor imatinib with mitoxantrone. This inhibition of DNA repair caused more than 87% of cells in G2/M arrest and a significant increase in apoptosis. To validate the effect of the combination treatment, we tested it on commercial and patient-derived cell lines in high-grade serous ovarian cancer (HGSOC), where chemotherapy resistance correlates with HR proficiency and is a major clinical problem. Results obtained with HR-proficient and deficient HGSOC cell lines show a 50-85% increase of sensitivity by the combination treatment. Our data raise the possibility of successful targeting of treatment-resistant HR-proficient cancers.
Subject: DNA repair
cell cycle arrest
c-Abl
imatinib
mitoxantrone
TYROSINE KINASE
DAMAGE
BRCA1
ATM
ACTIVATION
MUTATIONS
CANCER
CELLS
PHOSPHORYLATION
MITOXANTRONE
3122 Cancers
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