5-Aminoimidazole-4-Carboxamide Riboside Enhances Effect of Ionizing Radiation in PC3 Prostate Cancer Cells
- Department of Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Leuven (Belgium)
- Department of Radiation Oncology, University of California, Los Angeles, School of Medicine, Los Angeles, CA (United States)
- Division of Experimental Therapy, Netherlands Cancer Institute, Amsterdam (Netherlands)
- Department of Radiation Oncology, University Hospitals Leuven Campus Gasthuisberg, Leuven (Belgium)
Purpose: The nucleoside 5-aminoimidazole-4-carboxamide riboside (AICAR) is a low-energy mimetic and adenosine monophosphate (AMP)-activated protein kinase (AMPK) agonist that can affect the phenotype of malignant cells by diminishing their anabolism. It does this by being converted to 5-aminoimidazole-4-carboxamide ribotide (ZMP), an AMP analog. We combined this promising antineoplastic agent with ionizing radiation in an attempt to increase its efficacy. Methods and Materials: The effect of AICAR on cell proliferation, cell viability, apoptosis, reactive oxygen species production, radiosensitivity, and AMPK activation was determined in the human prostate cancer cell line PC3. To elucidate the radiosensitizing mechanism, clonogenic survival assays in the presence of a drug agonist or antagonist or with small interfering RNA targeting AMPK were done, as well as measurements of ZMP production and double strand break repair. Moreover, immunoblot analysis of the radiation response signaling pathways after AICAR treatment was performed. Results: The incubation of human PC3 prostate cancer cells with AICAR-activated AMPK inhibited cell proliferation, decreased viability, increased apoptosis, and generated reactive oxygen species in a dose- and time-dependent manner. None of these endpoints gave more than additive effects when radiation was added. Radiosensitization was observed but only after 72 hours of treatment with 250 {mu}M AICAR, suggesting that it was independent of AMPK activation. This finding was confirmed by small interfering RNA knockdown of AMPK. The mechanism of radiosensitization was associated with imbalanced deoxynucleotide pools owing to ZMP accumulation after AICAR administration that interfered with DNA repair. Conclusions: Our findings on the favorable interaction between low doses of AICAR and ionizing radiation in PC3 cells could open new perspectives for the clinical use of this or similar compounds. However, additional research is still required to establish the ZMP pathway as being of general applicability.
- OSTI ID:
- 22054523
- Journal Information:
- International Journal of Radiation Oncology, Biology and Physics, Vol. 81, Issue 5; Other Information: Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0360-3016
- Country of Publication:
- United States
- Language:
- English
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