Tumor Biology

, Volume 36, Issue 8, pp 5971–5977 | Cite as

Combined effects of anticancer drugs and new synthetic α-methylene-δ-lactones on MCF-7 cells

  • Katarzyna Gach
  • Jacek Szymański
  • Dorota Pomorska
  • Angelika Długosz
  • Jakub Modranka
  • Tomasz Janecki
  • Anna Janecka
Research Article


The search for novel drug candidates is a priority goal for cancer therapy. Natural products isolated from plants are often used as valuable leads for the synthesis of analogs with simpler structure. Two synthetic α-methylene-δ-lactones with chroman-2-one skeleton, designated DL-3 and DL-5, exhibiting strong cytotoxic activity against several cancer cell lines, have been tested alone and in combination with well-known anticancer drugs, 5-fluorouracil, oxaliplatin, and taxol, in breast cancer MCF-7 cells. Parthenolide, a plant-derived α-methylene-γ-lactone, was used as a positive control. The effects on cell proliferation, DNA damage, and apoptosis induction were evaluated. Neither of the tested compounds significantly enhanced the effects produced by taxol, but a strong synergistic effect was observed with 5-fluorouracil and oxaliplatin. Only small differences between the actions of both α-methylene-δ-lactones were found. The synergistic effects produced by these compounds in MCF-7 cells were stronger as compared with parthenolide. Our findings show that simple and easy-to-obtain synthetic compounds with α-methylene-δ-lactone motif can potentiate the efficiency of anticancer drugs.


Anticancer drugs Apoptosis Breast cancer Cell proliferation DNA damage α-Methylene-δ-lactones 



This work was financed by the Medical University of Lodz (No. 502-14-191 to KG and No. 503/1-156-02/503-01) and by the Ministry of Science and Higher Education (Project No. N N204 005736).

Conflicts of interest



  1. 1.
    Pati HN, Das U, Sharma RK, Dimmock JR. Cytotoxic thiol alkylators. Mini Rev Med Chem. 2007;7(2):131–9.CrossRefPubMedGoogle Scholar
  2. 2.
    Lee KH, Hall IH, Mar EC, Starnes CO, ElGebaly SA, Waddell TG, et al. Sesquiterpene antitumor agents: inhibitors of cellular metabolism. Science. 1977;196:533–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Zhang S, Ong CN, Shen HM. Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells. Cancer Lett. 2004;208:143–53.CrossRefPubMedGoogle Scholar
  4. 4.
    Janecka A, Wyrębska A, Gach K, Fichna J, Janecki T. Natural and synthetic α-methylenelactones and α- methylenelactams with anticancer potential. Drug Discov Today. 2012;17:561–72.CrossRefPubMedGoogle Scholar
  5. 5.
    Zhang S, Won YK, Ong CN, Shen HM. Anti-cancer potential of sesquiterpene lactones: bioactivity and molecular mechanisms. Curr Med Chem Anticancer Agents. 2005;5:239–49.CrossRefPubMedGoogle Scholar
  6. 6.
    Koprowska K, Czyz M. Molecular mechanisms of parthenolide’s action: old drug with a new face. Postepy Hig Med Dosw (Online). 2010;64:100–14.Google Scholar
  7. 7.
    García-Piñeres AJ, Castro V, Mora G, Schmidt TJ, Strunck E, Pahl HL, et al. Cysteine 38 in p65/NF-kappaB plays a crucial role in DNA binding inhibition by sesquiterpene lactones. J Biol Chem. 2001;276:39713–20.CrossRefPubMedGoogle Scholar
  8. 8.
    Rüngeler P, Castro V, Mora G, Gören N, Vichnewski W, Pahl HL, et al. Inhibition of transcription factor NF-kappaB by sesquiterpene lactones: a proposed molecular mechanism of action. Bioorg Med Chem. 1999;7:2343–52.CrossRefPubMedGoogle Scholar
  9. 9.
    Hung TM, Hung TM, Na M, Dat NT, Ngoc TM, Youn U, et al. Cholinesterase inhibitory and anti-amnesic activity of alkaloids from Corydalis turtschaninovii. J Ethnopharmacol. 2008;119:74–80.CrossRefPubMedGoogle Scholar
  10. 10.
    Wen J, You KR, Lee SY, Song CH, Kim DG. Oxidative stress-mediated apoptosis: the anticancer effect of the sesquiterpene lactone parthenolide. J Biol Chem. 2002;277:38954–64.CrossRefPubMedGoogle Scholar
  11. 11.
    Skalska J, Brookes PS, Nadtochiy SM, Hilchey SP, Jordan CT, Guzman ML, et al. Modulation of cell surface protein free thiols: a potential novel mechanism of action of the sesquiterpene lactone parthenolide. PLoS One. 2009;4:e8115.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Liu Z, Liu S, Xie Z, Pavlovicz RE, Wu J, Chen P, et al. Modulation of DNA methylation by a sesquiterpene lactone parthenolide. J Pharmacol Exp Ther. 2009;329:505–14.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Fonrose X, Ausseil, Soleilhac E, Masson V, David B, Pouny I, et al. Parthenolide inhibits tubulin carboxypeptidase activity. Cancer Res. 2007;67:3371–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Kupchan SM, Hemingway RJ, Werner D, Karim A, McPhail AT, Sim GA. Vernolepin, a novel elemanolide dilactone tumor inhibitor from Vernonia hymenolepis. J Am Chem Soc. 1968;90:3596–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Weinheimer AJ, Chang CWJ, Matson JA. Naturally occurring cembranes. Fortschr Chem Org Naturst. 1979;36:285–387.Google Scholar
  16. 16.
    Modranka J, Albrecht A, Jakubowski R, Krawczyk H, Różalski M, Krajewska U, et al. Synthesis and biological evaluation of α-methylidene-δ-lactones with 3,4-dihydrocoumarin skeleton. Bioorg Med Chem. 2012;20:5017–26.CrossRefPubMedGoogle Scholar
  17. 17.
    Wyrębska A, Gach K, Lewandowska U, Szewczyk K, Hrabec E, Modranka J, et al. Anticancer activity of new synthetic α-methylene-δ-lactones on two breast cancer cell lines. Basic Clin Pharmacol Toxicol. 2013;113:391–400.CrossRefPubMedGoogle Scholar
  18. 18.
    Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55–63.CrossRefPubMedGoogle Scholar
  19. 19.
    Kim SL, Kim SH, Trang KT, Kim IH, Lee SO, Lee ST, et al. Synergistic antitumor effect of 5-fluorouracil in combination with parthenolide in human colorectal cancer. Cancer Lett. 2013;335:479–86.CrossRefPubMedGoogle Scholar
  20. 20.
    Patel NM, Nozaki S, Shortle NH, Bhat-Nakshatri P, Newton TR, Rice S, et al. Paclitaxel sensitivity of breast cancer cells with constitutively active NF-kappaB is enhanced by IkappaBalpha super-repressor and parthenolide. Oncogene. 2000;19:4159–69.CrossRefPubMedGoogle Scholar
  21. 21.
    Zhang D, Qiu L, Jin X, Guo Z, Guo C. Nuclear factor-kappaB inhibition by parthenolide potentiates the efficacy of Taxol in non-small cell lung cancer in vitro and in vivo. Mol Cancer Res. 2009;7:1139–49.CrossRefPubMedGoogle Scholar
  22. 22.
    Fang LJ, Shao XT, Wang S, Lu GH, Xu T, Zhou JY. Sesquiterpene lactone parthenolide markedly enhances sensitivity of human A549 cells to low-dose oxaliplatin via inhibition of NF-kappaB activation and induction of apoptosis. Planta Med. 2010;76:258–64.CrossRefPubMedGoogle Scholar
  23. 23.
    Marchetti P, Galla DA, Russo FP, Ricevuto E, Flati V, Porzio G, et al. Apoptosis induced by oxaliplatin in human colon cancer HCT15 cell line. Anticancer Res. 2004;24:219–26.PubMedGoogle Scholar
  24. 24.
    Wyrębska A, Gach K, Janecka A. Combined effect of parthenolide and various anti-cancer drugs or anti-cancer candidate substances on malignant cells in vitro and in vivo. Mini Rev Med Chem. 2014;14:222–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Aoki Y, Sakogawa K, Hihara J, Emi M, Hamai Y, Kono K, et al. Involvement of ribonucleotide reductase-M1 in 5-fluorouracil-induced DNA damage in esophageal cancer cell lines. Int J Oncol. 2013;42:1951–60.PubMedGoogle Scholar
  26. 26.
    Sweeney CJ, Mehrotra S, Sadaria MR, Kumar S, Shortle NH, Roman Y, et al. The sesquiterpene lactone parthenolide in combination with docetaxel reduces metastasis and improves survival in a xenograft model of breast cancer. Mol Cancer Ther. 2005;4:1004–12.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Katarzyna Gach
    • 1
  • Jacek Szymański
    • 2
  • Dorota Pomorska
    • 1
  • Angelika Długosz
    • 1
  • Jakub Modranka
    • 3
  • Tomasz Janecki
    • 3
  • Anna Janecka
    • 1
  1. 1.Department of Biomolecular Chemistry, Faculty of MedicineMedical University of LodzLodzPoland
  2. 2.Central Scientific Laboratory, Division of Public Health, Faculty of Health SciencesMedical University of LodzLodzPoland
  3. 3.Institute of Organic ChemistryLodz University of TechnologyLodzPoland

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