Antiproliferative and Cytotoxic Activities

  • Claudia A. Anesini
  • María Rosario Alonso
  • Renzo F. Martino


Cancer is a genetic disease, affecting many people worldwide. Chemotherapy is routinely used for cancer treatment. However, this therapeutic approach is not always effective due to the development of cell resistance and toxic effects. Plants are a reservoir of natural chemicals with chemoprotective potential against cancer and with low adverse effects. While some drugs from natural origin are currently used for cancer treatment, others are being studied. Among the compounds isolated from plants, sesquiterpene lactones are very promising anticancer agents, which are widely being studied in different models of cancer in vitro and in vivo, and some clinical trials are being performed. Sesquiterpene lactones are very attractive compounds to be used as antitumoral therapy due to the diverse mechanisms of action through which they exert their effects. Among such mechanisms are their capacity to interfere with the generation of reactive oxygen species, the epigenetic modulation of gene expression, the targeting of the sarco-/endoplasmic reticulum calcium ATPase pump, and the activation of the NF-kB and the p53 signaling pathways. The latter mechanisms could be important to reduce the development of drug resistance by tumor cells. Sesquiterpene lactones can also inhibit angiogenesis and metastasis.


Cancer Sesquiterpene lactones Mechanism of action In vitro studies In vivo studies Clinical trials 



Anaplastic large cell lymphomas


Acute lymphoblastic leukemia


Acute myeloid leukemia


Acute promyelocytic leukemia


Apoptosis regulator BAX

Bcl- 2

B-cell CLL/lymphoma 2


BH3 interacting domain death agonist


Burkitt lymphoma


Human herpes virus (E′stein-Barr virus) gene


Cysteine aspartate-specific proteases

CCRF-CEM cells

Cellosaurus acute lymphoblastic leukemia cell line


Cellosaurus cell line, a doxorubicin-resistant sub-line derived from drug-sensitive, parental CCRF-CEM cells


Cell division control protein 2


Cellular FLICE-like inhibitory protein


Chronic lymphocytic leukemia


Chronic myeloid leukemia


Proto-oncogene tyrosine-protein kinase


CHOP homologus protein

GADD 153

DNA damage inducible gene 153


Human prostate carcinoma cell line


EGFR/PI3K/Akt signaling pathway


Raji cell line: Epstein Barr virus (EBV)-positive Burkitt lymphoma (BL) cell line


Endoplasmic reticulum


Extracellular signal-regulated kinase


Histone deacetylase 1


Immortal cell line


Human liver cancer cell line


Histidine nucleotide-binding protein 1


Hodgkin lymphoma


Acute myeloid leukemia


Healthy hematopoietic stem cells

HT 29

Human colorectal adenocarcinoma


Human chronic myeloid leukemia (CML) K562 cells


Human leukemia HL-60 cells


Inhibitor of NF-kB


NF-κB kinase


C-Jun N-terminal kinase

Jun B

Transcription factor of the tyrosine receptor kinase PDGF-Rβ


Leukemic stem cells


Mitogen activated protein kinases


Breast cancer cells


Human breast adenocarcinoma cell line

MDA-MB 435

Melanoma cell line


Human breast cancer cell line


Mouse double minute 2 homolog protein

MIA-PaCa-2 cells

Human pancreatic carcinoma cell lines

MDR P-gp CEM/ADR5000 cells

Multidrug-resistant P-gp over expressing CEM/ADR5000 leukemic cells


Nuclear factor kappa-light-chain-enhancer of activated B cells


Non-Hodgkin lymphoma


Normal fibroblast cell line


Nucleophosmin-anaplastic lymphoma kinase


Protein P21


Protein kinase P-38


Protein P53


Poly-(ADP-ribose) polymerase1


Peripheral blood mononuclear cells


Human prostate grade IV adenocarcinoma cell line


Beta-type platelet-derived growth factor receptor




Protein kinase C alpha


Protein kinase β


Receptor interacting protein kinase 1


Reactive oxygen species


Cellosaurus cell line SW 872, liposarcoma


Cellosaurus cell line SW 982, biphasic synovial sarcoma


Cellosaurus cell line T-671, a human rhabdomyosarcoma


Sarcoplasmic/endoplasmic reticulum


Sarco/endoplasmic reticulum calcium ATPase


Mitochondria-derived activator of caspases


Human hepatocarcinoma cell line


Signal transducer and activator of transcription


Tumor necrosis factor-α


TNF-related apoptosis-inducing ligand


Glioblastoma cell line


Histiocytic lymphoma cell line




Unfolded protein response


Rat breast carcinoma cell line


  1. Adekenov SM (2016) Chemical modification of arglabin and biological activity of its new derivatives. Fitoterapia 110:196–205CrossRefPubMedGoogle Scholar
  2. Anfosso L, Efferth T, Albini A et al (2006) Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins. Pharmacogenomics J 6:269–278CrossRefPubMedGoogle Scholar
  3. Armitage JO (2012) The aggressive peripheral T-cell lymphomas: update on diagnosis, risk stratification and management. Am J Hematol 87:511–519CrossRefPubMedGoogle Scholar
  4. Balunas MJ, Kingborn AD (2005) Drug discovery from medicinal plants. Life Sci 78:431–441CrossRefPubMedGoogle Scholar
  5. Bosio C, Tomasoni G, Martínez R et al (2015) Cytotoxic and apoptotic effects of leptocarpin, a plant-derived sesquiterpene lactone, on human cancer cell lines. Chem Biol Interact 242:415–421CrossRefPubMedGoogle Scholar
  6. Bujnicki T, Wilczek C, Schomburg C et al (2012) Inhibition of Myb-dependent gene expression by the sesquiterpene lactone mexicanin-I. Leukemia 26(4):615–622CrossRefPubMedGoogle Scholar
  7. Carlisi D, D’Anneo A, Angileri L et al (2011) Parthenolide sensitizes hepatocellular carcinoma cells to TRAIL by inducing the expression of death receptors through inhibition of STAT3activation. J Cell Physiol 226:1632–1641CrossRefPubMedGoogle Scholar
  8. Carlisi D, Buttitta G, Di Fiore R et al (2016) Parthenolide and DMAPT exert cytotoxic effects on breast cancer stem-like cells by inducing oxidative stress, mitochondrial dysfunction and necrosis. Cell Death Dis 7(4):e2194CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chabner BA, Amrein PC, Druker BJ et al (2006) Antineoplastic agents. In: Goodman, Gilman’s (eds) The pharmacological basis of the therapeutics, 11th edn. The McGraw-Hill Companies Inc, New York, pp 1731–1755Google Scholar
  10. Chen HH, Zhou HJ, Wu GD et al (2004) Inhibitory effects of artesunate on angiogenesis and on expressions of vascular endothelial growth factor and VEGF receptor KDR/flk-1. Pharmacology 71:1–9CrossRefPubMedGoogle Scholar
  11. Cho JY, Kim AR, Jung JH et al (2004) Cytotoxic and pro-apoptotic activities of cynaropicrin, a sesquiterpene lactone on the viability of leukocyte cancer cell lines. Eur J Pharmacol 492:85–94CrossRefPubMedGoogle Scholar
  12. Christensen SB, Skytte DM, Denmeade SR et al (2009) A trojan horse in drug development: targeting of thapsigargins towards prostate cancer cells. Anti Cancer Agents Med Chem 9:276–294CrossRefGoogle Scholar
  13. Cragg GM, Grothaus PG, Newman DJ (2009) Impact of natural products on developing new anti-cancer agents. Chem Rev 109:3012–3043CrossRefPubMedGoogle Scholar
  14. De Ford C, Ulloa JL, Catalán CA et al (2015) The sesquiterpene lactone polymatin B from Smallanthus sonchifolius induces different cell death mechanisms in three cancer cell lines. Phytochemistry 117:332–339. CrossRefPubMedGoogle Scholar
  15. Degos L, Wang ZY (2001) All trans retinoic acid in acute promyelocytic leukemia. Oncogene 20:7140–7145. CrossRefPubMedGoogle Scholar
  16. Del Socorro Jimenez Usuga N, Malafronte N, Osorio Durango EJ et al (2016) Phytochemical investigation of Pseudelephantopus spiralis (Less.) Cronquist. Phytochem Lett 15:256–259CrossRefGoogle Scholar
  17. Denmeade SR, Isaacs JT (2005) The SERCA pump as a therapeutic target: making a ‘smart bomb’ for prostate cancer. Cancer Biol Ther 4:14–22CrossRefPubMedGoogle Scholar
  18. Ferlay J, Soerjomataram I, Dikshit R et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386CrossRefGoogle Scholar
  19. Ghantous A, Gali-Muhtasib H, Vuorela H et al (2010) What made sesquiterpene lactones reach cancer clinical trials? Drug Discov Today 15:668–678CrossRefPubMedGoogle Scholar
  20. Gomes Martins G, dos Reis Lívero FA, Stolf AM et al (2015) Sesquiterpene lactones of Moquiniastrum polymorpha subsp. floccosum have antineoplastic effects in Walker-256 tumor-bearing rats. Chem Biol Interact 228:46–56CrossRefGoogle Scholar
  21. Gopal YN, Chanchorn E, Van Dyke MW (2009) Parthenolide promotes the ubiquitination of MDM2 and activates p53 cellular functions. Mol Cancer Ther 8:552–562CrossRefPubMedGoogle Scholar
  22. Guzman ML, Rossi RM, Karnischky L et al (2005) The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 105:4163–4169CrossRefPubMedPubMedCentralGoogle Scholar
  23. Guzman ML, Rossi RM, Neelakantan S et al (2007) An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood 110:4427–4435CrossRefPubMedPubMedCentralGoogle Scholar
  24. Hoffmann R, von Schwarzenberg K, Lopez-Anton N et al (2011) Helenalin by passes Bcl-2-mediated cell death resistance by inhibiting NF-kappaB and promoting reactive oxygen species generation. Biochem Pharmacol 82:453–463CrossRefPubMedGoogle Scholar
  25. Hopfinger G, Griessl R, Sifft E et al (2012) Novel treatment avenues for peripheral T-cell lymphomas. Expert Opin Drug Discovery 7:1149–1163CrossRefGoogle Scholar
  26. Huang CC, Lo CP, Chiu CY et al (2010) Deoxyelephantopin, a novel multifunctional agent, suppresses mammary tumour growth and lungmetastasis and doubles survival time in mice. Br J Pharmacol 159:856–871CrossRefPubMedPubMedCentralGoogle Scholar
  27. Hung JY, Hsu YL, Ni WC et al (2010) Oxidative and endoplasmic reticulum stress signaling are involved in dehydrocostuslactone-mediated apoptosis in human non-small cell lungcancer cells. Lung Cancer 68:355–365CrossRefPubMedGoogle Scholar
  28. Idris AI, Libouban H, Nyangoga H et al (2009) Pharmacologic inhibitors of IkappaB kinase suppress growth and migration of mammary carcinosarcoma cells in vitro and prevent osteolyticbone metastasis in vivo. Mol Cancer Ther 8:2339–2347CrossRefPubMedGoogle Scholar
  29. Jaffe ES (2009) The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program:523–531. CrossRefGoogle Scholar
  30. JoungYoun U, Miklossy G, Chai X et al (2014) Bioactive sesquiterpene lactones and other compounds isolated from Vernonia cinerea. Fitoterapia 93:194–200CrossRefGoogle Scholar
  31. Kempema AM, Widen JC, Hexum JK et al (2015) Synthesis and antileukemic activities of C1–C10-modifiedparthenolide analogues. Bioorg Med Chem 23:4737–4745CrossRefPubMedPubMedCentralGoogle Scholar
  32. Kiss I, Unger C, Huu CN et al (2015) Lobatin B inhibits NPM/ALK and NF-κB attenuating anaplastic-large cell-lymphomagenesis and lymph endothelial tumour in travasation. Cancer Lett 356:994–1006CrossRefPubMedGoogle Scholar
  33. Kreuger M, Grootjans S, Biavatti MW et al (2012) Sesquiterpene lactones as drugs with multiple targets in cancer treatment: focus on parthenolide. Anti-Cancer Drugs 23(9):883–896PubMedGoogle Scholar
  34. Krysko DV, Vandenabeele P (2009) Part I-molecular mechanisms of phagocytosis of dying cells. In: Krysko DV, Vandenabeele P (eds) Phagocytosis of dying cells from molecular mechanisms to human diseases. Springer, Dordrecht, pp 3–31CrossRefGoogle Scholar
  35. Krysko DV, Brouckaert G, Kalai M et al (2003) Mechanisms of internalization of apoptotic and necrotic L929 cells by amacrophage cell line studied by electron microscopy. J Morphol 258:336–345CrossRefPubMedGoogle Scholar
  36. Kweon SH, Song JH, Kim HJ et al (2015) Induction of human leukemia cell differentiation via PKC/MAPK pathways by arsantin, a sesquiterpene lactone from Artemisia santolina. Arch Pharm Res 38(11):2020–2028. CrossRefPubMedGoogle Scholar
  37. Lee J, Hwangbo C, Lee JJ et al (2010) The sesquiterpene lactone eupatolide sensitizes breast cancer cells to TRAIL through down-regulationof c-FLIP expression. Oncol Rep 23:229–237PubMedGoogle Scholar
  38. Li Y, Zhang Y, Fu M et al (2012) Parthenolide induces apoptosis and lytic cytotoxicity in Epstein-Barr virus-positive Burkitt lymphoma. Mol Med Rep 6:477–482CrossRefPubMedPubMedCentralGoogle Scholar
  39. Li H, Li M, Wang G et al (2016) EM23, a natural sesquiterpene lactone from Elephantopus mollis, induces apoptosis in human myeloid leukemia cells through thioredoxin- and reactive oxygen species-mediated signaling pathways. Front Pharmacol.
  40. Liu Z, Liu S, Xie Z et al (2009) Modulation of DNA methylation by a sesquiterpene lactone parthenolide. J Pharmacol Exp Ther 329:505–514CrossRefPubMedPubMedCentralGoogle Scholar
  41. Liu W, Wang X, Sun J et al (2017) Parthenolide suppresses pancreatic cell growth by autophagy-mediated apoptosis. Onco Targets Ther 10:453–461CrossRefPubMedPubMedCentralGoogle Scholar
  42. Lohberger B, Rinner B, Stuendl N et al (2013) Sesquiterpene lactones downregulate G2/M cell cycle regulator proteins and affect the invasive potential of human soft tissue sarcoma cells. PLoS One 8:1–9CrossRefGoogle Scholar
  43. Mahalingam D, Wilding G, Denmeade S et al (2016) Mipsagargin, a novel thapsigargin-based PSMA-activated prodrug: results of a first-in-man phase I clinical trial in patients with refractory, advanced or metastatic solid tumours. Br J Cancer 114:986–994. CrossRefPubMedPubMedCentralGoogle Scholar
  44. Marin GH, Mansilla E, Ciocchini S et al (2013) Sesquiterpene lactone extract from native American herbs demonstrated antineoplastic activity against non Hodgkin lymphoma cells. Annalen der Chemi Forschung 1(2):50–55Google Scholar
  45. Martino R, Beer MF, Anesini C et al (2015) Sesquiterpene lactones from Ambrosia spp.are active against a murine lymphoma cell line by inducing apoptosis and cell cycle arrest. Toxicol In Vitro 29:1529–1536CrossRefPubMedGoogle Scholar
  46. Merfort I (2011) Perspectives on sesquiterpene lactones in inflammation and cancer. Curr Drug Targets 12:1560–1573CrossRefPubMedGoogle Scholar
  47. Muñoz Acuña U, Shen Q, Ren Y et al (2013) Goyazensolide induces apoptosis in cancer cells in vitro and in vivo. Int J Cancer Res 9(2):36–53. CrossRefGoogle Scholar
  48. Nakase I, Gallis B, Takatani-Nakase T et al (2009) Transferrin receptor-dependent cytotoxicity of artemisinin–transferrin conjugates on prostate cancer cells and induction of apoptosis. Cancer Lett 274:290–298CrossRefPubMedGoogle Scholar
  49. Oh GS, Pae HO, Chung HT et al (2004) Dehydrocostuslactone enhances tumor necrosis factor-alpha-inducedapoptosis of human leukemia HL-60 cells. Immunopharmacol Immunotoxicol 26:163–175CrossRefPubMedGoogle Scholar
  50. Oka D, Nishimura K, Shiba M et al (2007) Sesquiterpene lactone parthenolide suppresses tumor growth in axenograft model of renal cell carcinoma by inhibiting the activation of NF-kappaB. Int J Cancer 120:2576–2581CrossRefPubMedGoogle Scholar
  51. Ordóñez PE, Sharma KK, Bystrom LM et al (2016) Dehydroleucodine, a sesquiterpene lactone from Gynoxys verrucosa, demonstrates cytotoxic activity against Human Leukemia Cells. J Nat Prod 79(4):691–696CrossRefPubMedGoogle Scholar
  52. Quynh D NT, Christensen SB (2015). Thapsigargin, Origin, Chemistry, Structure-Activity Relationships and Prodrug Development. Curr Pharm Des. 21(38):5501–5517CrossRefGoogle Scholar
  53. Ralstin MC, Gage EA, Yip-Schneider MT et al (2006) Parthenolide cooperates with NS398 to inhibit growth of humanhepatocellular carcinoma cells through effects on apoptosis and G0-G1 cellcycle arrest. Mol Cancer Res 4:387–399CrossRefPubMedGoogle Scholar
  54. Rozenblat S, Grossman S, Bergman M et al (2008) Induction of G2/M arrest and apoptosis by sesquiterpene lactones inhuman melanoma cell lines. Biochem Pharmacol 75:369–382CrossRefPubMedGoogle Scholar
  55. Saeed M, Jacob S, Sandjo LP et al (2015) Cytotoxicity of the sesquiterpene lactones neoambrosin and damsin from Ambrosia maritime against multidrug-resistant cancer cells. Front Pharmacol 6:267. CrossRefPubMedPubMedCentralGoogle Scholar
  56. Shukla N, Freeman N, Gadsdon P et al (2001) Thapsigargin inhibits angiogenesis in the rat isolated aorta:studies on the role of intracellular calcium pools. Cardiovasc Res 49:681–689CrossRefPubMedGoogle Scholar
  57. Singh NP, Panwar VK (2006) Case report of a pituitary macro adenoma treated with artemether. Integr Cancer Ther 5:391–394CrossRefPubMedGoogle Scholar
  58. Sturgeon CM, Craig K, Brown C et al (2005) Modulation of the G2 cell cycle checkpoint by sesquiterpene lactones psilostachyins A and C isolated from the common ragweed Ambrosia artemisiifolia. Planta Med 71(10):938–943CrossRefPubMedGoogle Scholar
  59. Sun Y, St Clair DK, Xu Y et al (2010) A NADPH oxidase dependent redox signaling pathway mediates the selective radio sensitization effect of parthenolide in prostate cancer cells. Cancer Res 70:2880–2890CrossRefPubMedPubMedCentralGoogle Scholar
  60. Sweeney CJ, Mehrotra S, Sadaria MR et al (2005) The sesquiterpene lactone parthenolide in combination with docetaxel reduces metastasis and improves survival in a xenograft model of breast cancer. Mol Cancer Ther 4:1004–1012CrossRefPubMedGoogle Scholar
  61. Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820CrossRefPubMedPubMedCentralGoogle Scholar
  62. Villagomez R, Rodrigo GC, Collado IG et al (2013) Multiple anticancer effects of damsin and coronopilin isolated from Ambrosia arborescens on cell cultures. Int J Anticancer Res 33:3799–3806Google Scholar
  63. Wang GW, Qin JJ, Cheng XR et al (2014) Inula sesquiterpenoids: structural diversity, cytotoxicity and anti-tumor activity. Expert Opin Investig Drugs 23(3):317–345. CrossRefPubMedGoogle Scholar
  64. World Health Organization (WHO) (2005) Preventing chronic diseases: a vital investment. Geneva: WHO Global report. Accessed 14 Aug 2017
  65. World Health Organization (WHO) (2017) Accessed 14 Aug 2017
  66. Yang YJ, Yao J, Jin X et al (2016) Sesquiterpenoids and tirucallane triterpenoids from the roots of Scorzonera divaricata. Phytochemistry 124:86–98CrossRefPubMedGoogle Scholar
  67. Yip-Schneider MT, Nakshatri H, Sweeney CJ et al (2005) Parthenolide and sulindac cooperate to mediate growth suppression and inhibit the nuclear factor-kB pathway in pancreatic carcinoma cells. Mol Cancer Ther 4:587–594CrossRefPubMedGoogle Scholar
  68. Zeisig BB, Kulasekararaj AG, Mufti GJ et al (2012) Snap shot: acute myeloid leukemia. Cancer Cell 22:691–698. CrossRefGoogle Scholar
  69. Zhang C, Lu T, Wang GD et al (2016) Costunolide, an active sesquiterpene lactone, induced apoptosis via ROS-mediated ER stress and JNK pathway in human U2OS cells. Biomed Pharmacother 80:253–259CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Claudia A. Anesini
    • 1
    • 2
  • María Rosario Alonso
    • 1
    • 2
  • Renzo F. Martino
    • 3
  1. 1.Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Farmacología, Cátedra de FarmacognosiaBuenos AiresArgentina
  2. 2.CONICET – Universidad de Buenos Aires, Instituto de Química y Metabolismo del Fármaco (IQUIMEFA)Buenos AiresArgentina
  3. 3.Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología y Biotecnología, Cátedra de InmunologíaBuenos AiresArgentina

Personalised recommendations