Research Article | OPEN ACCESS
The DNA Repair Key Enzyme Affected by 43Ca2+: A New Platform for Anti-Leukemia Therapies
1Alexander A. Bukhvostov, 2Oleg A. Shatalov, 3Anatoly L. Buchachenko and 3, 4Dmitry A. Kuznetsov
1Department of Pharmacology, School of Pharmacy, I. M. Sechenov Moscow State Medical University, Moscow 129327
2D. Rogachev Federal Research Clinical Center for Pediatric Hematology, Oncology and Immunology, Russian Ministry of Health, Moscow 117997
3N. N. Semenov Institute for Chemical Physics, Russian Academy of Sciences, Moscow 119997
4Department of Medicinal Nanobiotechnologies, N. I. Pirogov Russian National Research Medical University, Moscow 117997, Russia
British Journal of Pharmacology and Toxicology 2014 1:42-48
Received: September 15, 2013 | Accepted: October 06, 2013 | Published: February 20, 2014
Abstract
Human acute myeloblast leukemia HL60 cells over expresses a beta-type DNA polymerase (EC 2.7.7.7) which is found to be operated by Magnetic Isotope Effect (MIE) of Calcium once the Mg2+ ions replaced with the stable 43Ca2+ isotopes inside the enzyme catalytic sites. The isotopes mentioned are the only paramagnetic species of the Calcium isotopic set with a 0.135 natural abundance value and the negative 7/2 nuclear spin providing a nuclear magnetic moment equal to 1.317 Bohr magnetons. As compared to the Mg/40Ca substitution, a 2.25-fold enzyme inhibition has been shown to prove the 43Ca-MIE dependent mode of the catalysis turning down. This 43Ca-promoted enzyme hyper-suppression leads to a residual synthesis of shorted DNA fragments that counts 25-35 nucleotides in length contrasting with the 180-210 n DNA produced by either intact or 40Ca-loaded polymerase. Being occurred simultaneously with a marked MIE-promoted enzyme inhibition, this fact itself makes possible to consider these short (size-invalid) DNA segments hardly efficient in the DNA base-excision repair. The latter is a survival factor in leukemic cells where the DNApol &beta was found over expressed. That confirms a concept considering the DNApol&beta a legitimate target for antitumor agents since its inhibition deprives the malignant cell from a DNA base-excision repair in neoplasma. A possible trend making role of these data for molecular pharmacology of cancers is in a focus.
Keywords:
Acute Myeloblast Leukemia (AML), 40Ca and 43Ca isotopes, DNA polymerase Beta (DNApolB), Magnetic Isotope Effect (MIE), HL-60 cells,
Competing interests
The authors have no competing interests.
Open Access Policy
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Copyright
The authors have no competing interests.
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ISSN (Online): 2044-2467
ISSN (Print): 2044-2459 |
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