Email this article In vitro antiproliferative activity and in vivo antitumor effect of 2,21-bis-[2-pyridinyl]methylidene hollongdione Dp-41 (2NK), a novel hollongdione derivative
- Authors: Mikheenko A.M.1,2, Smirnova I.E.3, Babayeva G.A.1,2, Beejaimal J.2, Khan I.I.1,2, Kazakova O.B.3, Pokrovsky V.S.1,2
-
Affiliations:
- Blokhin National Medical Research Center of Oncology
- RUDN University
- Ufa Federal Research Centre of the Russian Academy of Science
- Issue: Vol 30, No 3 (2025)
- Pages: 234-246
- Section: Original Study Articles
- URL: https://ogarev-online.ru/1028-9984/article/view/366005
- DOI: https://doi.org/10.17816/onco691718
- EDN: https://elibrary.ru/RTZOPU
- ID: 366005
Cite item
Open Access
Access granted
Subscription Access
Abstract
BACKGROUND: Natural tetracyclic triterpenes, such as dammarane-type triterpenes, have demonstrated diverse pharmacological activities, including significant anti-inflammatory and antitumor properties, making them promising candidates for novel antitumor agents. However, their limited bioavailability and inadequate effects have driven research into targeted structural modifications to enhance their biological activity.
AIM: This study aimed to evaluate the cytotoxic and antitumor activities of a new arylidene derivative of hollongdione: 2,21-bis-[2-pyridinyl]methylidene hollongdione.
METHODS: The cytotoxicity of the study derivative was evaluated using MTT assay. Flow cytometry was performed to assess cell cycle and apoptotic activities using ADAMII™ LS. The in vivo antitumor effect was evaluated using HCT116 human colon cancer xenograft models in Danio rerio embryos.
RESULTS: 2,21-bis-[2-pyridinyl]methylidene hollongdione Dp-41 (2NK) demonstrated cytotoxic activity in DU145 (0.70 ± 0.03 µM), HCT116 (0.99 ± 0.01 µM), Panc1 (0.20 ± 0.03 µM), and A549 (0.60 ± 0.04 µM) cell cultures. In the HCT116 human colon cancer xenograft model in Danio rerio embryos, it achieved 72% tumor growth inhibition, thus demonstrating antitumor activity.
CONCLUSION: Dp-41 (2NK) exhibited significant antiproliferative activity against prostate, colon, pancreatic, and lung cancer cell lines, as well as against HCT116 human colon cancer xenografts in Danio rerio embryos.
About the authors
Anastasia M. Mikheenko
Blokhin National Medical Research Center of Oncology; RUDN University
Email: amiheenko7@gmail.com
ORCID iD: 0009-0009-2158-3915
Russian Federation, Moscow; Moscow
Irina E. Smirnova
Ufa Federal Research Centre of the Russian Academy of Science
Email: si8081@yandex.ru
ORCID iD: 0000-0001-7176-505X
Cand. Sci. (Chemistry)
Russian Federation, UfaGulyalek A. Babayeva
Blokhin National Medical Research Center of Oncology; RUDN University
Email: babaevagulyalek@gmail.com
ORCID iD: 0000-0001-5781-7925
SPIN-code: 8547-6770
Cand. Sci. (Biology)
Russian Federation, Moscow; MoscowJaunita Beejaimal
RUDN University
Email: jay.beejaimal4@gmail.com
Russian Federation, Moscow
Irina I. Khan
Blokhin National Medical Research Center of Oncology; RUDN University
Email: irinchek05@gmail.com
ORCID iD: 0000-0003-2948-0872
SPIN-code: 6826-7694
Cand. Sci. (Biology)
Russian Federation, Moscow; MoscowOksana B. Kazakova
Ufa Federal Research Centre of the Russian Academy of Science
Email: obf@anrb.ru
ORCID iD: 0000-0002-5606-1588
Dr. Sci. (Chemistry), Professor
Russian Federation, UfaVadim S. Pokrovsky
Blokhin National Medical Research Center of Oncology; RUDN University
Author for correspondence.
Email: pokrovskiy-vs@rudn.ru
ORCID iD: 0000-0003-4006-9320
SPIN-code: 4552-1226
MD, Dr. Sci. (Medicine), Professor
Russian Federation, Moscow; MoscowReferences
- Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. 2020;71(3):209–249. doi: 10.3322/caac.21660
- DeSantis CE, Lin CC, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2014. CA: A Cancer Journal for Clinicians. 2014;64(4):252–271. doi: 10.3322/caac.21235
- Atanasov AG, Zotchev SB, Dirsch VM; International Natural Product Sciences Taskforce. Natural products in drug discovery: advances and opportunities. Nature Reviews Drug Discovery. 2021;20(3):200–216. doi: 10.1038/s41573-020-00114-z
- Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nature Reviews Cancer. 2013;13(10):714–726. doi: 10.1038/nrc3599
- Newman DJ, Cragg GM. Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019. Journal of Natural Products. 2020;83(3):770–803. doi: 10.1021/acs.jnatprod.9b01285
- Petronelli A, Pannitteri G, Testa U. Triterpenoids as new promising anticancer drugs. Anti-Cancer Drugs. 2009;20(10):880–892. doi: 10.1097/CAD.0b013e328330fd90
- Xu R, Fazio GC, Matsuda SP. On the origins of triterpenoid skeletal diversity. Phytochemistry. 2004;65(3):261–291. doi: 10.1016/j.phytochem.2003.11.014
- Chudzik M, Korzonek-Szlacheta I, Król W. Triterpenes as Potent Cell Growth Modulators. Molecules. 2015;20(5):8790–8826. doi: 10.3390/molecules20011610
- Huang M, Jin J, Zhang H, Wu K. Semisynthesis and cytotoxic evaluation of a series of dammarane-type triterpenoid derivatives. Bioorganic & Medicinal Chemistry Letters. 2018;28(14):2446–2450.
- Smirnova IE, Petrova AV, Fedorova AA, et al. Synthesis and cytotoxiсity of 2-benzilidenes derivatives of dipterocarpol. Izvestiya Ufimskogo nauchnogo tsentra RAN. 2020;(1):36–40. doi: 10.31040/2222-8349-2020-0-1-36-40 EDN: EULUAZ
- Smirnova IE, Petrova AV, Kazakova, O.B. Synthesis and Cytotoxicity of A-Azepanodammaradiene. Chem Nat Compd. 2019;55(5):883–889. doi: 10.1007/s10600-019-02838-w EDN: EWPCDV
- Kazakova OB, Smirnova IE, Medvedeva NI, et al. Hepatoprotective Activity of Betulin and Dipterocarpol Derivatives. Russ J Bioorg Chem. 2019;45(6):558–565 doi: 10.1134/S1068162019050030 EDN: RJTPIM
- Machulkin AE, Uspenskaya AA, Zyk NU, et al. Synthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin E Conjugate. J Med Chem. 2021;64(23):17123–17145. doi: 10.1021/acs.jmedchem.1c01157 EDN: XLFMLK
- Smirnova I, Drăghici G, Kazakova O, et al. Hollongdione arylidene derivatives induce antiproliferative activity against melanoma and breast cancer through pro-apoptotic and antiangiogenic mechanisms. Bioorganic Chemistry. 2022;119:105535. doi: 10.1016/j.bioorg.2021.105535 EDN: JXGPXL
- Smirnova IE, Kazakova OB, Huong DTT, et al. One-pot synthesis of hollongdione from dipterocarpol. Natural Product Communications. 2014;9(10):1417–20. doi: 10.1177/1934578x1400901005 EDN: UFIHEZ
- Westerfield M. The zebrafish book. A guide for the laboratory use of zebrafish (Danio rerio). 4th ed. Univ. of Oregon Press, Eugene; 2000.
- Smirnova IE, Gatilov YV, Bagryanskaya IY. Synthesis and Molecular Structure of Hydroxy and Hydroxyimino Derivatives of Hollongdione. Russ J Org Chem. 2021;57(4):671–674. doi: 10.1134/S1070428021040266 EDN: PZWGGD
- Zhdanov DD, Pokrovsky VS, Pokrovskaya MV, et al. Rhodospirillum rubruml-asparaginase targets tumor growth by a dual mechanism involving telomerase inhibition. Biochem Biophys Res Commun. 2017;492(2):282–288. doi: 10.1016/j.bbrc.2017.08.078 EDN: PRZGDN
- Şoica C, Voicu M, Ghiulai R, et al. Natural Compounds in Sex Hormone-Dependent Cancers: The Role of Triterpenes as Therapeutic Agents. Front Endocrinol (Lausanne). 2021;11:612396. doi: 10.3389/fendo.2020.612396
- Puthongking P, Yongram C, Katekaew S, Sungthong B, Weerapreeyakul N. Dipterocarpol in Oleoresin of Dipterocarpus alatus Attributed to Cytotoxicity and Apoptosis-Inducing Effect. Molecules. 2022;27(10):3187. doi: 10.3390/molecules27103187
- He BC, Gao JL, Luo X, et al. Ginsenoside Rg3 inhibits colorectal tumor growth through the down-regulation of Wnt/ß-catenin signaling. Int J Oncol. 2011;38(2):437–45. doi: 10.3892/ijo.2010.858
- Smirnova I, Drăghici G, Kazakova O, et al. Hollongdione arylidene derivatives induce antiproliferative activity against melanoma and breast cancer through pro-apoptotic and antiangiogenic mechanisms. Bioorg Chem. 2022;119:105535. doi: 10.1016/j.bioorg.2021.105535 EDN: JXGPXL
Supplementary files
