Summary
One of the features that differentiate cancer cells is their increased proliferation rate, which creates an opportunity for general anti-tumor therapy directed against the elevated activity of replicative apparatus in tumor cells. Besides DNA synthesis, successful genome replication requires the reparation of the newly synthesized DNA. Malfunctions in reparation can cause fatal injuries in the genome and cell death. Recently we have found that the ultra-short single-stranded deoxyribose polynucleotides of random sequence (ssDNA) effectively inhibit the catalytic activity of DNA polymerase \(\beta\). This effect allowed considering these substances as potential anti-tumor drugs, which was confirmed experimentally both in vitro (using cancer cell cultures) and in vivo (using cancer models in mice). According to the obtained results, ssDNA significantly suppresses cancer development and tumor growth, allowing consideration of them as novel candidates for anti-cancer drugs.
Similar content being viewed by others
Data availability
Data available on request.
References
Gaillard H, García-Muse T, Aguilera A (2015) Replication stress and cancer. Nat Rev Cancer 15(2):276–289. https://doi.org/10.1038/nrc3916
Baillie K, Stirling P (2021) Beyond kinases: Targeting replication stress proteins in cancer therapy. Trends in Cancer 7(5):430–446. https://doi.org/10.1016/j.trecan.2020.10.010
Dobbelstein M, Sørensen C (2015) Exploiting replicative stress to treat cancer. Nat Rev Drug Discov 14(6):405–423. https://doi.org/10.1038/nrd4553
Ali R, Alblihy A, Miligy IM, Alabdullah ML, Alsaleem M, Toss MS, Algethami M, Abdel-Fatah T, Moseley P, Chan S, Mongan NP, Narayan S, Rakha EA, Madhusudan S (2021) Molecular disruption of DNA polymerase β for platinum sensitisation and synthetic lethality in epithelial ovarian cancers. Oncogene 40(14):2496–2508. https://doi.org/10.1038/s41388-021-01710-y
Liu S, Lai Y, Zhao W, Wu M, Zhang Z (2011) Links between DNA polymerase beta expression and sensitivity to bleomycin. Toxicology 281(1–3):63–69. https://doi.org/10.1016/j.tox.2011.01.008
Asagoshi K, Liu Y, Masaoka A, Lan L, Prasad R, Horton JK, Brown AR, hong Wang X, Bdour HM, Sobol RW, Taylor JS, Yasui A, Wilson SH (2010) DNA polymerase β-dependent long patch base excision repair in living cells. DNA Repair 9(2):109–119. https://doi.org/10.1016/j.dnarep.2009.11.002
Beard W, Wilson S (2006) Structure and mechanism of DNA polymerase β. Chem Rev 106(2):361–382. https://doi.org/10.1021/cr0404904
Donigan KA, Sun KW, Nemec AA, Murphy DL, Cong X, Northrup V, Zelterman D, Sweasy JB, (2012) Human polb gene is mutated in high percentage of colorectal tumors. J Biol Chem 287(28):23830–23839. https://doi.org/10.1074/jbc.M111.324947
Martin S, Lord C, Ashworth A (2010) Therapeutic targeting of the DNA mismatch repair pathway. Clin Cancer Res 16(21):5107–5113. https://doi.org/10.1158/1078-0432.CCR-10-0821
Ji S (2012) Molecular Theory of the Living Cell. Springer Science+Business Media, Berlin, Germany
Barakat K, Gajewski M, Tuszynski J (2012) DNA polymerase beta (pol β) inhibitors: A comprehensive overview. Drug Discov Today 17(15–16):913–920. https://doi.org/10.1016/j.drudis.2012.04.008
Ge Z, Gu H, Li Q, Fan C (2018) Concept and development of framework nucleic acids. J Am Chem Soc 140(51):17808–17819. https://doi.org/10.1021/jacs.8b10529
Yuhas S, Laverty D, Lee H, Majumdar A, Greenberg M (2021) Selective inhibition of DNA polymerase β by a covalent inhibitor. J Am Chem Soc 143(21):8099–8107. https://doi.org/10.1021/jacs.1c02453
Jia Y, Chen L, Liu J, Li W, Gu H (2021) DNA-catalyzed efficient production of single-stranded DNA nanostructures. Chem 7(4):959–981. https://doi.org/10.1016/j.chempr.2020.12.001
Ding D, Yang C, Lv C, Li J, Tan W (2020) Improving tumor accumulation of aptamers by prolonged blood circulation. Anal Chem 92(5):4108–4114. https://doi.org/10.1021/acs.analchem.9b05878
Ermakov K, Bukhvostov A, Vedenkin A, Stovbun S, Dvornikov A, Kuznetsov D (2019) Ultrashort ssDNA in retinoblastoma patients blood plasma detected by a novel high resolution HPCL technique: A preliminary report. Acta Medica 62(4):170–173. https://doi.org/10.14712/18059694.2020.8
Yang C, Zhao H, Sun Y, Wang C, Geng X, Wang R, Tang L, Han D, Liu J, Tan W (2022) Programmable manipulation of oligonucleotide-albumin interaction for elongated circulation time. Nucleic Acids Res 50(6):3083–3095. https://doi.org/10.1093/nar/gkac156
Stovbun S, Ermakov K, Bukhvostov A, Vedenkin A, Kuznetsov D (2019) A new DNA repair-related platform for pharmaceutical outlook in cancer therapies: Ultrashort single-stranded polynucleotides. Sci Pharm 87(4):25. https://doi.org/10.3390/scipharm87040025
Stovbun S, Vedenkin A, Bukhvostov A, Koroleva L, Silnikov V, Kuznetsov D (2020) L, D-Polydeoxyribonucleotides to provide an essential inhibitory effect on DNA polymerase β of human myeloid leukemia HL60 cells. Biochem Biophys Rep 24. https://doi.org/10.1016/j.bbrep.2020.100835
Good P, Krikos A, Li S, Bertrand E, Lee N, Giver L, Ellington A, Zaia J, Rossi J, Engelke D (1997) Expression of small, therapeutic RNAs in human cell nuclei. Gene Ther 4(1):45–54. https://doi.org/10.1038/sj.gt.3300354
Meyer C, Eydeler K, Magbanua E, Zivkovic T, Piganeau N, Lorenzen I, Grötzinger J, Mayer G, Rose-John S, Hahn U (2012) Interleukin-6 receptor specific RNA aptamers for cargo delivery into target cells. RNA Biol 9(1):67–80. https://doi.org/10.4161/rna.9.1.18062
Wolf C, Rapp A, Berndt N, Staroske W, Schuster M, Dobrick-Mattheuer M, Kretschmer S, König N, Kurth T, Wieczorek D, Kast K, Cardoso MC, Günther C, Lee-Kirsch MA (2016) RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA. Nat Commun 7(1):1–11. https://doi.org/10.1038/ncomms11752
Roy MK, Thalang VN, Trakoontivakorn G, Nakahara K (2004) Mechanism of mahanine-induced apoptosis in human leukemia cells (HL-60). Biochem Pharmacol 67(1):41–51. https://doi.org/10.1016/j.bcp.2003.07.021
Guo R, Liu J, Chai J, Gao Y, Abdel-Rahman M, Xu X (2022) Scorpion peptide smp24 exhibits a potent antitumor effect on human lung cancer cells by damaging the membrane and cytoskeleton In Vivo and In Vitro. Toxins 14(7):438. https://doi.org/10.3390/toxins14070438
Teicher BA (2011) Tumor Models in Cancer Research. Springer Science+Business Media, Berlin, Germany. https://doi.org/10.1007/978-1-60761-968-0
Overwijk W, Restifo N (2001) B16 as a mouse model for human melanoma. Curr Protoc Immunol 20(20):1. https://doi.org/10.1002/0471142735.im2001s39
Graham J (2001) Isolation of Golgi membranes from tissues and cells by differential and density gradient centrifugation. Curr Protoc Cell Biol 10(1):3–9. https://doi.org/10.1002/0471143030.cb0309s10
Kruger NJ (2009) The bradford method for protein quantitation. In: Walker J (ed) The Protein Protocols Handbook, Humana Press. Totowa, NJ
Katoch R (2011) Analytical Techniques in Biochemistry and Molecular Biology. Springer, New York, USA
Ormerod MG (2000) Flow Cytometry. Oxford University Press, Oxford, UK
Veerman A, Pieters R (1990) Drug sensitivity assays in leukaemia and lymphoma. Br J Haematol 74(4):381–384. https://doi.org/10.1111/j.1365-2141.1990.tb06323.x
Aki T, Noritake K, Funakoshi T, Uemura K (2018) Models of chemically induced cell death. In: McQueen C (ed) Comprehensive Toxicology, vol1, 3rd edn, Elsevier Ltd, Amsterdam, The Netherlands. https://doi.org/10.1016/B978-0-12-801238-3.01893-6
Zhang M, Aguilera D, Das C, Vasquez H, Zage P, Gopalakrishnan V, Wolff J (2008) Measuring cytotoxicity: A new perspective on LC50. Anticancer Res 27(1A):35–39
Brezis H, Pazy A (1972) Convergence and approximation of semigroups of nonlinear operators in Banach spaces. J Funct Anal 9(1):63–74. https://doi.org/10.1016/0022-1236(72)90014-6
Wang SY, Lee YL, Lai YH, Chen JJ, Wu WL, Yuann JMP, Su WL, Chuang SM, Hou MH (2012) Spermine attenuates the action of the DNA intercalator, actinomycin D, on DNA binding and the inhibition of transcription and DNA replication. PLoS ONE 7(11). https://doi.org/10.1371/journal.pone.0047101
Wilmanska D, Czyz M, Studzian K, Piestrzeniewicz M, Gniazdowski M (2001) Effects of anticancer drugs on transcription in vitro. Zeitschriftür Naturforschung C 56(9–10):886–891. https://doi.org/10.1515/znc-2001-9-1034
Tuli HS, Sharma AK, Sandhu SS, Kashyap D (2013) Cordycepin: A bioactive metabolite with therapeutic potential. Life Sci 93(23):863–869. https://doi.org/10.1016/j.lfs.2013.09.030
Park Y, Koga Y, Su C, Waterbury AL, Johnny CL, Liau BB (2019) Versatile synthetic route to cycloheximide and analogues that potently inhibit translation elongation. Angew Chem 58(16):5387–5391. https://doi.org/10.1002/anie.201901386
van der Zanden SY, Qiao X, Neefjes J (2021) New insights into the activities and toxicities of the old anticancer drug doxorubicin. FEBS J 288(21):6095–6111. https://doi.org/10.1111/febs.15583
Baranovskiy AG, Babayeva ND, Suwa Y, Gu J, Pavlov YI, Tahirov TH (2014) Structural basis for inhibition of DNA replication by aphidicolin. Nucleic Acids Res 42(22):14013–14021. https://doi.org/10.1093/nar/gku1209
Sabatino RD, Myers TW, Bambara RA (1990) Substrate specificity of the exonuclease associated with calf DNA polymerase ε. Cancer Res 50(17):5340–5344
Bukhvostov AA, Dvornikov AS, Ermakov KV, Kuznetsov DA (2017) Retinoblastoma case: Shall we get a paramagnetic trend in chemotherapy? Arch Cancer Res 5(4):158
Funding
The work was supported by Ministry of Science and Education of Russian Federation, grant number 122040500058-1.
Author information
Authors and Affiliations
Contributions
Authors’ contributions: A Vedenkin – design of experiments, making experiments (in vivo), text writing (initial draft); S. Stovbun – design of experiments, data analysis and discussion; A. Bukhvostov – making experiments (in vitro); D. Zlenko – data analysis, text writing (final text); I. Stovbun – data analysis and discussion; V. Silnikov – chemicals’ synthesis; V. Fursov – making experiments (in vitro)D. Kuznetsov – design of experiments, data analysis.
Corresponding author
Ethics declarations
Ethics approval
This study was accomplished according to European Directive 2010/63/EU on the protection of animals used for scientific purposes. Approval of the research protocol was granted by the Bioethics Committee of the FRCCP RAS (#2021-011).
Conflicts of interest
Author declare no conflict of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Vedenkin, A.S., Stovbun, S.V., Bukhvostov, A.A. et al. Anti-cancer activity of ultra-short single-stranded polydeoxyribonucleotides. Invest New Drugs 41, 153–161 (2023). https://doi.org/10.1007/s10637-023-01333-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10637-023-01333-y