Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press39210.17650/2313-805X-2021-8-4-75-83RESEARCH ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИStudy of the effect of curcumin on excision DNA repair in U251 glioblastoma multiforme cellsИзучение действия куркумина на эксцизионную репарацию ДНК в клетках U251 мультиформной глиобластомыhttps://orcid.org/0000-0001-9626-6847KushnirT. I.КушнирТ. И.
Russian Federation

Bld. 15, 24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-0154-8604ArnotskayaN. E.АрноцкаяН. Е.
Russian Federation

Bld. 15, 24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0001-7588-1066KudryavtsevI. A.КудрявцевИ. А.
Russian Federation

Bld. 15, 24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-4125-7342MitrofanovA. A.МитрофановА. А.
Russian Federation

Bld. 15, 24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-4160-9598BekyashevA. K.БекяшевА. Х.
Russian Federation

Bld. 15, 24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-4532-4274ZgodaV. G.ЗгодаВ. Г.
Russian Federation

10 Bld. 8, Pogodinskaya St., Moscow 119121

119121 Москва, Погодинская ул., 10, стр. 8

https://orcid.org/0000-0002-0401-9900ShevchenkoV. E.ШевченкоВ. Е.
Russian Federation

Valeriy Evgenievich Shevchenko

Bld. 15, 24 Kashirskoe Shosse, Moscow 115478

Валерий Евгеньевич Шевченко

115478 Москва, Каширское шоссе, 24

vshev2015@yandex.ruN.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава РоссииV.N. Orekhovich Research Institute of Biomedical ChemistryФГБНУ «Научно-исследовательский институт биомедицинской химии им. В.Н. Ореховича»151220218475831812202118122021Copyright ©; 2021, Kushnir T.I., Arnotskaya N.E., Kudryavtsev I.A., Mitrofanov A.A., Bekyashev A.K., Zgoda V.G., Shevchenko V.E.Copyright ©; 2021, Кушнир Т.И., Арноцкая Н.Е., Кудрявцев И.А., Митрофанов А.А., Бекяшев А.Х., Згода В.Г., Шевченко В.Е.2021Kushnir T.I., Arnotskaya N.E., Kudryavtsev I.A., Mitrofanov A.A., Bekyashev A.K., Zgoda V.G., Shevchenko V.E.Кушнир Т.И., Арноцкая Н.Е., Кудрявцев И.А., Митрофанов А.А., Бекяшев А.Х., Згода В.Г., Шевченко В.Е.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/392

Introduction. To a large extent, the resistance of glioblastoma multiforme to genotoxic therapy is associated with a dysregulation of responses to DNA damage and repair. Thus, suppression of DNA repair mechanisms is a priority pathway for increasing the survival rate of glioblastoma multiforme patients. Curcumin enhances the effectiveness of standard chemotherapy drugs, but its effect on DNA repair systems is not well understood.

The study objective – to study the molecular mechanisms of curcumin action on excisional DNA repair in U251 glioblastoma multiforme cells.

Materials and methods. high-resolution proteomic mass spectrometry, cell technologies.

Results. In the proteomes of two types of glioblastoma multiforme cells (control and experiment), a total of 2757 proteins were identified, of which 39 % were differentially expressed. Significant changes have been found in many signaling cascades that play an important role in carcinogenesis.

Conclusion. Curcumin suppressed excisional DNA repair by decreasing the expression of determinants APEX1, MSH6, PARP1. PCNA, POLD1, POLE3, RFC2, RPA.

Введение. В значительной степени резистентность мультиформной глиобластомы к генотоксической терапии связана с нарушением регуляции реакций на повреждение и репарацию ДНК. Таким образом, подавление механизмов репарации ДНК – приоритетный путь для увеличения выживаемости больных с данной патологией. Куркумин повышает эффективность стандартных химиотерапевтических препаратов, однако его воздействие на системы репарации ДНК недостаточно изучено.

Цель исследования – изучение молекулярных механизмов действия куркумина на эксцизионную репарацию ДНК в клетках U251 мультиформной глиобластомы.

Материалы и методы. Протеомная масс-спектрометрия высокого разрешения, клеточные технологии.

Результаты. В протеомах 2 типов клеток мультиформной глиобластомы (контроля и опыта) в целом идентифицированы 2757 белков, из которых 39 % были дифференциально экспрессированными. Обнаружены значительные изменения во многих сигнальных каскадах, играющих большую роль в канцерогенезе.

Заключение. Куркумин супрессирует эксцизионную репарацию ДНК, снижая экспрессию детерминант APEX1, MSH6, PARP1. PCNA, POLD1, POLE3, RFC2 и RPA.

curcuminglioblastoma multiformecurcuminproteomeexcision DNA repairmass spectrometryмультиформная глиобластомакуркуминпротеомэксцизионная репарация ДНКмасс-спектрометрияIt is funded under the state budget theme No. 2021-76.Финансируется в рамках госбюджетной темы № 2021-76.Arvold N.D., Reardon D.A. Treatment options and outcomes for glioblastoma in the elderly patient. Clin Interv Aging 2014;9:357–67. DOI: 10.2147/CIA.S44259.Chinnaiyan P., Won M., Wen P.Y. et al. A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: results of NRG Oncology RTOG 0913. Neuro Oncol 2018;20:666–73. DOI: 10.1093/neuonc/nox209.Fabian D., Eibl M.D.P.G.P., Alnahhas I. et al. Treatment of glioblastoma (GBM) with the addition of tumor-treating fields (TTF): a review. Cancers 2019;11:1–12. DOI: 10.3390/cancers11020174.Kocaadam B., Sanlier N. Curcumin, an active component of turmeric (Curcuma longa), and its effects on health. Crit Rev Food Sci Nutr 2015;57(13):2889–95. DOI: 10.1080/10408398.2015.1077195.Kaina B., Christmann M. DNA repair in personalized brain cancer therapy with temozolomide and nitrosoureas. DNA Repair (Amst) 2019;78:128–41. DOI: 10.1016/j.dnarep.2019.04.007.Ferri A., Stagni V., Barilà D. et al. Targeting the DNA damage response to overcome cancer drug resistance in glioblastoma. Int J Mol Sci 2020;21(14):4910. DOI: 10.3390/ijms21144910.Kotha R.R., Luthria D.L. Curcumin: biological, pharmaceutical, nutraceutical, and analytical aspects. Molecules 2019;24(16):2930. DOI: 10.3390/molecules24162930.Luthra P.M., Lal N. Prospective of curcumin, a pleiotropic signaling molecule from Curcuma longa in the treatment of glioblastoma. Eur J Med Chem 2016;109:23–35. DOI: 10.1016/j.ejmech.2015.11.049.Hosseini A., Hosseinzadeh H. Antidotal or protective effects of Curcuma longa (turmeric) and its active ingredient, curcumin, against natural and chemical toxicities: a review. Biomed Pharmacother 2018;99:411–21. DOI: 10.1016/j.biopha.2018.01.072.Amalraj A., Pius A., Gopi S. et al. Biological activities of curcuminoids, other biomolecules from turmeric and their derivatives: a review. J Tradit Complement Med 2016;7(2):205–33. DOI: 10.1016/j.jtcme.2016.05.005.Meng X., Cai J., Liu J. et al. Curcumin increases efficiency of γ-irradiation in gliomas by inhibiting Hedgehog signaling pathway. Cell Cycle 2017;16(12):1181–92. DOI: 10.1080/15384101.2017.1320000.Park K.S., Yoon S.Y., Park S.H. et al. Antimigration and anti-invasion effects of curcumin via suppression of fascin expression in glioblastoma cells. Brain Tumor Res Treat 2019;7(1):16–24. DOI: 10.14791/btrt.2019.7.e28.Maiti P., Scott J., Sengupta D. et al. Curcumin and solid lipid curcumin particles induce autophagy, but inhibit mitophagy and the PI3K-Akt/mTOR pathway in cultured glioblastoma cells. Int J Mol Sci 2019;20(2):399. DOI: 10.3390/ijms20020399.Trotta T., Panaro M.A., Prifti E. et al. Modulation of biological activities in glioblastoma mediated by curcumin. Nutr Cancer 2019;71(8):1241–53. DOI: 10.1080/01635581.2019.1604978.Kushnir T.I., Arnotskaya N.E., Kudryavtsev I.A. et al. The effect of hypoxia on the secretome of human glioblastoma multiforme cells. Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2021;8(1):32–40. (In Russ.). DOI: 10.17650/2313-805X-2021-8-1-32-40.Кушнир Т.И., Арноцкая Н.Е., Кудрявцев И.А. и др. Влияние гипоксии на секретом клеток мультиформной глиобластомы человека. Успехи молекулярной онкологии 2021;8(1):32–40. DOI: 10.17650/2313-805X-2021-8-1-32-40.Bryukhovetskiy A., Shevchenko V., Kovalev S. et al. To the novel paradigm of proteome-based cell therapy of tumors: through comparative proteome mapping of tumor stem cells and tissue-specific stem cells of humans. Cell Transplant 2014;23(1):151–70. DOI: 10.3727/096368914X684907.Gromova O.A., Torshin Y.U., Zgoda V.G. et al. An analysis of the peptide composition of a “light” peptide fraction of Cerebrolysin. S.S. Korsakov Journal of Neurology and Psychiatry 2019;119(8):75–83. (In Russ.). DOI: 10.17116/jnevro201911908175.Громова О.А., Торшин И.Ю., Згода В.Г. и др. Комплексный протеомный анализ «легкой» пептидной фракции препарата церебролизин. Журнал неврологии и психиатрии им. С.С. Корсакова 2019;119(8):75–83 DOI: 10.17116/jnevro201911908175.Cox J., Hein M.Y., Luber C.A. et al. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol Cell Proteomics 2014;13(9):2513–26. DOI: 10.1074/mcp.M113.031591.Huang D.W., Sherman B.T., Lempicki R.A. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 2009;37(1):1–13. DOI: 10.1093/nar/gkn923.Lee S.Y. Temozolomide resistance in glioblastoma multiforme. Genes Dis 2016;3:198–210. DOI: 10.1016/j.gendis.2016.04.007.Fulton B., Short S.C., James A. et al. PARADIGM-2: two parallel phase I studies of olaparib and radiotherapy or olaparib and radiotherapy plus temozolomide in patients with newly diagnosed glioblastoma, with treatment stratified by MGMT status. Clin Transl Radiat Oncol 2017;8:12–6. DOI: 10.1016/j.ctro.2017.11.003.Xu T., Guo P., He Y. et al. Application of curcumin and its derivatives in tumor multidrug resistance Phytother Res 2020;34(10):2438–58. DOI: 10.1002/ptr.6694.Alexandru O., Georgescu A.M., Ene L. et al. The effect of curcumin on lowpassage glioblastoma cells in vitro. J Cancer Res Ther 2016;12(2):1025–32. DOI: 10.4103/0973-1482.167609.Tomeh M.A., Hadianamrei R., Zhao X. A review of curcumin and its derivatives as anticancer agents. Int J Mol Sci 2019;20(5):1033. DOI: 10.3390/ijms20051033.Rodriguez G.A., Shah A.H., Gersey Z.C. et al. Investigating the therapeutic role and molecular biology of curcumin as a treatment for glioblastoma. Ther Adv Med Oncol 2016;8(4):248–60. DOI: 10.1177/1758834016643518.Stupp R., Mason W.P., van den Bent M.J. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352(10):987–96. DOI: 10.1056/NEJMoa043330.Nakada M., Furuta T., Hayashi Y. et al. The strategy for enhancing temozolomide against malignant glioma. Front Oncol 2012;2:98. DOI: 10.3389/fonc.2012.00098.Atkins R.J., Ng W., Stylli S.S. et al. Repair mechanisms help glioblastoma resist treatment. J Clin Neurosci 2015;22(1):14–20. DOI: 10.1016/j.jocn.2014.09.003.Gu Y., Parker A., Wilson T.M. et al. Human MutY homolog, a DNA glycosylase involved in base excision repair, physically and functionally interacts with mismatch repair proteins humanMutS homolog 2/ humanMutS homolog 6. J Biol Chem 2002;277(13):11135–42. DOI: 10.1074/jbc.M108618200.Xie C., Sheng H., Zhang N. et al. Association of MSH6 mutation with glioma susceptibility, drug resistance and progression. Mol Clin Oncol 2016;5(2):236–40. DOI: 10.3892/mco.2016.907.Pluciennik A., Modrich P. Protein roadblocks and helix discontinuities are barriers to the initiation of mismatch repair. Proc Natl Acad Sci USA 2007;104(31):12709–13. DOI: 10.1073/pnas.0705129104.Longley M.J., Pierce A.J., Modrich P. DNA polymerase delta is required for human mismatch repair in vitro. J Biol Chem 1997;272(16):10917–21. DOI: 10.1074/jbc.272.16.10917.Jiricny J. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol 2006;7(5):335–46. DOI: 10.1038/nrm1907.Jiapaer S., Furuta T., Tanaka S. et al. Potential strategies overcoming the temozolomide resistance for glioblastoma. Neurol Med Chir (Tokyo) 2018;58(10):405–21. DOI: 10.2176/nmc.ra.2018-0141.Li M., Wilson D.M. Human apurinic/ apyrimidinic endonuclease. Antioxid Redox Signal 2014;20(4):678–707. DOI: 10.1089/ars.2013.5492.Erasimus H., Gobin M., Niclou S. et al. DNA repair mechanisms and their clinical impact in glioblastoma. Mutat Res Rev Mutat Res 2016;769:19–35. DOI: 10.1016/j.mrrev.2016.05.005.Matsumoto Y., Kim К., Hurwitz J. et al. Reconstitution of proliferating cell nuclear antigen-dependent repair of apurinic/ apyrimidinic sites with purified human proteins. J Biol Chem 1999;274(47):33703–8. DOI: 10.1074/jbc.274.47.33703.Chen C.C., Juan C.W., Chen K.Y. et al. Upregulation of RPA2 promotes NF-κB activation in breast cancer by relieving the antagonistic function of menin on NF-κB-regulated transcription. Carcinogenesis 2017;38(2):196–206. DOI: 10.1093/carcin/bgw123.