Modulating radiation resistance by inhibiting ribonucleotide reductase in cancers with virally or mutationally silenced p53 protein.

Radiation Research
Charles KunosTimothy J Kinsella

Abstract

Therapeutic ionizing radiation damages DNA, increasing p53-regulated ribonucleotide reductase (RNR) activity required for de novo synthesis of the deoxyribonucleotide triphosphates used during DNA repair. This study investigated the pharmacological inhibition of RNR in cells of virally or mutationally silenced p53 cancer cell lines using 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine(R), NSC #663249), a chemotherapeutic radiosensitizer that equally inhibits RNR M2 and p53R2 small subunits. The effects of 3-AP on RNR inhibition and resulting radiosensitization were evaluated in cervical (CaSki, HeLa and C33-a) and colon (RKO, RKO-E6) cancer cells. 3-AP treatment significantly enhanced radiation-related cytotoxicity in cervical and colon cancer cells. 3-AP treatment significantly decreased RNR activity, caused prolonged radiation-induced DNA damage, and resulted in an extended G(1)/S-phase cell cycle arrest in all cell lines. Similar effects were observed in both RKO and RKO-E6 cells, suggesting a p53-independent mechanism of radiosensitization. We conclude that inhibition of ribonucleotide reductase by 3-AP enhances radiation-mediated cytotoxicity independent of p53 regulation by impairing repair processes th...Continue Reading

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Citations

Nov 3, 2010·Current Oncology Reports·Ann H Klopp, Patricia J Eifel
Oct 12, 2012·International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society·Charles A KunosFadi W Abdul-Karim
Feb 11, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Charles A KunosTimothy J Kinsella
Feb 12, 2013·International Journal of Molecular Sciences·Lauren ShunkwilerCharles Kunos
Feb 18, 2012·Future Oncology·Charles A KunosCharles L Hoppel
Jul 24, 2012·International Journal of Radiation Oncology, Biology, Physics·Ludmila Katherine MartinTanios Bekaii-Saab
May 1, 2012·International Journal of Radiation Oncology, Biology, Physics·Charles A KunosJames Brindle
Oct 3, 2013·Expert Opinion on Therapeutic Targets·Jimin ShaoYun Yen
Apr 8, 2011·International Journal of Radiation Oncology, Biology, Physics·Charles A KunosNancy L Oleinick
Jan 17, 2015·International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society·Charles KunosKathleen N Moore
Apr 5, 2013·International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society·Charles A KunosDavid K Gaffney
Nov 24, 2016·Cancer Chemotherapy and Pharmacology·Charles A KunosS Percy Ivy
Jul 13, 2019·Frontiers in Oncology·Charles A KunosSusan Percy Ivy
Oct 20, 2010·Radiation Research·Charles A KunosTimothy J Kinsella
Jun 6, 2018·Frontiers in Oncology·Charles A Kunos, S Percy Ivy
Nov 24, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Yaqiong ZhanYunqing Qiu

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Methods Mentioned

BETA
xenografts
Assay
protein assay
flow cytometry
xenograft

Software Mentioned

WinMDI
ModFit LT
SPSS

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