Novel Phosphonium Salt Derivatives Induce DNA Damage and Apoptosis in Cervical Cancer Cells

Article Sidebar

pdf (Русский)
Published: Mar 28, 2025
DOI: https://doi.org/10.18097/BMCRM00254
Keywords:
phosphonium salts; apoptosis; DNA damage; cell cycle

Main Article Content

A.P. Lyubina
Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, 8 Arbuzov str., Kazan, 420088 Russia
A.D. Voloshina
Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, 8 Arbuzov str., Kazan, 420088 Russia
S.K. Amerkhanova
Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, 8 Arbuzov str., Kazan, 420088 Russia
A.S. Sapunova
Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, 8 Arbuzov str., Kazan, 420088 Russia
D.A. Tatarinov
Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, 8 Arbuzov str., Kazan, 420088 Russia
V.F. Mironov
Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, 8 Arbuzov str., Kazan, 420088 Russia

Abstract

This study demonstrates that (Z)-(2-(2-hydroxy-5-chlorophenyl)-2-phenylethenyl)alkyldiphenylphosphonium chlorides exhibit high antitumour activity, comparable to that of the reference drug doxorubicin. The phosphonium salts exhibited reduced toxicity towards conditionally normal cell lines in the majority of cases. The mechanism of action of compound PP8, which contains an octyl radical at the phosphorus atom, on the model cell line M-HeLa included partial cell cycle arrest in the G1 phase, an increased generation of reactive oxygen species, and an induction of mitochondrial apoptosis. These experimental data are supported by the elevated levels of p53, p21, H2A.X and caspase-9 proteins detected by multiplex analysis. The results indicated the occurrence of double-strand DNA breaks under the influence of the studied compound. Therefore, additional structural modifications to enhance the selectivity of the studied compounds will provide a basis for the development of novel effective antitumour agents.

Article Details

How to Cite
Lyubina, A., Voloshina, A., Amerkhanova, S., Sapunova, A., Tatarinov, D., & Mironov, V. (2025). Novel Phosphonium Salt Derivatives Induce DNA Damage and Apoptosis in Cervical Cancer Cells. Biomedical Chemistry: Research and Methods, 8(1), e00254. https://doi.org/10.18097/BMCRM00254
Issue
Vol. 8 No. 1 (2025)
Section
EXPERIMENTAL RESEARCH

References

  1. Makimbetov, E.K., Salikhar, R.I., Tumanbaev, A.M., Toktanalieva, A.N.,Kerimov, A.D. (2020) Cancer epidemiology in the world. Modern problems ofscience and education, 2, 168-168. DOI
  2. Global cancer burden growing, amidst mounting need for services. RetrievedSeptember 30, 2024, from: https://www.who.int/news/item/01-02-2024-globalcancer-burden-growing--amidst-mounting-need-for-services
  3. Kaprin, A.D., Starinsky, V.V., Shakhzadova, A.O. (2022). Malignantneoplasms in Russia in 2021 (incidence and mortality). Moscow: PA HertsenMoscow Oncology Research Institute–Branch of the National Medical ResearchRadiological Center. 252 p. ISBN 978-5-85502-280-3
  4. Peyraga, G., Ducassou, A., Arnaud, F.X., Lizée, T., Pouédras, J., Moyal, É.(2021). Radiothérapie et toxicité médullaire: actualités et perspectives. Cancer/Radiothérapie, 25(1), 55-61. DOI
  5. Zhu, S., Wang, X., Jiang, H. (2024). Systematic Reversal of Drug Resistancein Cancer. Targets, 2(3), 250-286. DOI
  6. Pawar, A., Korake, S., Pawar, A., Kamble, R. (2023). Delocalized lipophiliccation triphenyl phosphonium: promising molecule for mitochondria targeting.Current Drug Delivery, 20(9), 1217-1223. DOI
  7. Ibrahim, M.K., Haria, A., Mehta, N.V., Degani, M.S. (2023). Antimicrobialpotential of quaternary phosphonium salt compounds: A review. FutureMedicinal Chemistry, 15(22), 2113-2141. DOI
  8. Nissim, M., Lline-Vul, T., Shoshani, S., Jacobi, G., Malka, E., Dombrovsky,A., Banin, E., Margel, S. (2023). Synthesis and Characterization of DurableAntibiofilm and Antiviral Silane-Phosphonium Thin Coatings for Medical andAgricultural Applications. ACS omega, 8(42), 39354-39365. DOI
  9. Tatarinov, D.A., Kuznetsov, D.M., Voloshina, A.D., Lyubina, A.P., Strobykina,A.S., Mukhitova, F.K., Polyancev, F.M., Mironov, V.F. (2016). Synthesis of2-(2-hydroxyaryl) alkenylphosphonium salts from phosphine oxides via ringclosingring-opening approach and their antimicrobial evaluation. Tetrahedron,72(51), 8493-8501. DOI
  10. Terekhova, N.V., Lyubina, A.P., Voloshina, A.D., Sapunova, A.S., Khayarov,K.R., Islamov, D.R., Usachev, K.S., Evtugyn, V.G., Tatarinov, D.A., Mironov,V.F. (2022). Synthesis, biological evaluation and structure-activity relationshipof 2-(2-hydroxyaryl) alkenylphosphonium salts with potency as anti-MRSAagents. Bioorganic Chemistry, 127, 106030. DOI
  11. Rokitskaya, T.I., Terekhova, N.V., Khailova, L.S., Kotova, E.A., Plotnikov,E.Y., Zorov, D.B., Tatarinov, D.A., Antonenko, Y.N. (2019). Zwitterionicprotonophore derived from 2-(2-hydroxyaryl)alkenylphosphonium as anuncoupler of oxidative phosphorylation. Bioconjugate Chemistry, 30(9), 2435-2443. DOI
  12. IC50 Calculator. Retrieved June 11, 2024, from: https://www.aatbio.com/tools/ic50-calculator
  13. Kho, D., MacDonald, C., Johnson, R., Unsworth, C.P., O’Carroll, S.J.,Du Mez, E., Angel, C.E., Graham, E.S. (2015). Application of xCELLigenceRTCA biosensor technology for revealing the profile and window of drugresponsiveness in real time. Biosensors, 5(2), 199-222. DOI
  14. Terekhova, N.V., Tatarinov, D.A., Shaihutdinova, Z.M., Pashirova, T.N.,Lyubina, A.P., Voloshina, A.D., Sapunova, A.S., Zakharova, L.Ya., Mironov, V.F.(2020). Design and synthesis of amphiphilic 2-hydroxybenzylphosphoniumsalts with antimicrobial and antitumor dual action. Bioorganic & MedicinalChemistry Letters, 30(13), 127234. DOI
  15. Chen, Z., Luo, R., Xu, T., Wang, L., Deng, S., Wu, J., Wang, H., Lin, Y.,Bu, M. (2024). Design, synthesis and antitumor effects of lupeol quaternaryphosphonium salt derivatives. Bioorganic & Medicinal Chemistry, 113, 117934. DOI
  16. Abassi, Y.A., Xi, B., Zhang, W., Ye, P., Kirstein, S.L., Gaylord, M.R.,Feinstein, S.C., Wang, X., Xu, X. (2009). Kinetic cell-based morphologicalscreening: prediction of mechanism of compound action and off-target effects.Chemistry & biology, 16(7), 712-723. DOI
  17. Xie, W., Ye, Y., Shen, A., Zhou, L., Lou, Z., Wang, X., & Hu, J. (2008).Evaluation of DNA-targeted anti-cancer drugs by Raman spectroscopy.Vibrational Spectroscopy, 47(2), 119–123. DOI
  18. Bohgaki, T., Bohgaki, M., Hakem, R. (2010). DNA double-strand breaksignaling and human disorders. Genome integrity, 1, 1-14. DOI
  19. Ramazanov, B.R., Khusnutdinov, R.R., Galembikova, A.R., Dunaev, P.D.,Boichuk S.V. Role of p53 protein in activation of ATM- and PARP-mediatedDNA damage repair (DDR) pathways induced by topoisomerase type IIinhibitors. Kazan medical journal, 97(2), 245-249. DOI
  20. Smith, J., Tho, L.M., Xu, N., Gillespie, D.A. (2010). The ATM–Chk2 andATR–Chk1 pathways in DNA damage signaling and cancer. Advances in cancerresearch, 108, 73-112. DOI
  21. Abbas, I., Badran, G., Verdin, A., Ledoux, F., Roumie, M., Guidice, J.M.L.,Courcot, D., Garçon, G. (2019). In vitro evaluation of organic extractablematter from ambient PM2. 5 using human bronchial epithelial BEAS-2B cells:Cytotoxicity, oxidative stress, pro-inflammatory response, genotoxicity, and cellcycle deregulation. Environmental research, 171, 510-522. DOI
  22. Ismail, I.H., Hendzel, M.J. (2008). The γ‐H2A. X: Is it just a surrogatemarker of double‐strand breaks or much more?. Environmental and molecularmutagenesis, 49(1), 73-82. DOI
  23. Craig, A., Scott, M., Burch, L., Smith, G., Ball, K., Hupp, T. (2003).Allosteric effects mediate CHK2 phosphorylation of the p53 transactivationdomain. EMBO reports, 4(8), 787-792. DOI
  24. Loughery, J., Cox, M., Smith, L.M., Meek, D.W. (2014). Critical role forp53-serine 15 phosphorylation in stimulating transactivation at p53-responsivepromoters. Nucleic acids research, 42(12), 7666-7680. DOI
  25. Liebl, M.C., Hofmann, T.G. (2019). Cell fate regulation upon DNA damage:p53 serine 46 kinases pave the cell death road. Bioessays, 41(12), 1900127. DOI
  26. Karimian, A., Ahmadi, Y., Yousefi, B. (2016). Multiple functions of p21 incell cycle, apoptosis and transcriptional regulation after DNA damage. DNArepair, 42, 63-71. DOI
  27. Liebl, M.C., Hofmann, T.G. (2019). Cell fate regulation upon DNA damage:p53 serine 46 kinases pave the cell death road. Bioessays, 41(12), 1900127. DOI
  28. Reczek, C.R., Chandel, N.S. (2017). The two faces of reactive oxygenspecies in cancer. Annual review of cancer biology, 1(1), 79-98. DOI
  29. Sui, X., Wang, J., Zhao, Z., Liu, B., Liu, M., Liu, M., Shi, C., Feng X., Fu Y.,Shi D., Li S., Qi Q., Xian Mo., Zhao, G. (2024). Phenolic compounds induceferroptosis-like death by promoting hydroxyl radical generation in the Fentonreaction. Communications Biology, 7(1), 199. DOI
  30. Wang, Q.Y., Xu, Y.S., Zhang, N.X., Dong, Z.P., Zhao, B.N., Liu, L.C., Lu T.,Wang, Y. (2020). Phenylboronic ester-modified anionic micelles for ROS-stimuliresponse in HeLa cell. Drug Delivery, 27(1), 681-690. DOI