Breast Cancer Research and Treatment

, Volume 134, Issue 3, pp 1041–1055 | Cite as

Strigolactones: a novel class of phytohormones that inhibit the growth and survival of breast cancer cells and breast cancer stem-like enriched mammosphere cells

  • C. B. Pollock
  • H. Koltai
  • Y. Kapulnik
  • C. Prandi
  • R. I. YardenEmail author
Preclinical Study


Several naturally occurring phytohormones have shown enormous potential in the prevention and treatment of variety of different type of cancers. Strigolactones (SLs) are a novel class of plant hormones produced in roots and regulate new above ground shoot branching, by inhibiting self-renewal of undifferentiated meristem cells. Here, we study the effects of six synthetic SL analogs on breast cancer cell lines growth and survival. We show that SL analogs are able to inhibit proliferation and induce apoptosis of breast cancer cells but to a much lesser extent “non-cancer” lines. Given the therapeutic problem of cancer recurrence which is hypothesized to be due to drug resistant cancer stem cells, we also tested the ability of SL analogs to inhibit the growth of mammosphere cultures that are typically enriched with cancer stem-like cells. We show that SLs are potent inhibitors of self-renewal and survival of breast cancer cell lines grown as mammospheres and even a short exposure leads to irreversible effects on mammosphere dissociation and cell death. Immunoblot analysis revealed that SLs analogs induce activation of the stress response mediated by both P38 and JNK1/2 MAPK modules and inhibits PI3K/AKT activation. Taken together this study indicates that SLs may be promising anticancer agents whose activities may be achieved through modulation of stress and survival signaling pathways.


Plant hormone Strigolactone GR24 Breast cancer Apoptosis Proliferation Mammosphere Cancer stem cell p38 MAPK JNK1/2 





Cancer stem cell


Parts per million


Propidium iodide


Extracellular signal-regulated kinase

p38 MAPK

p38 mitogen-activated protein kinase


Mitogen- and stress-activated protein kinase


Activating transcription factor 2


Protein kinase B


Inhibitory concentration



We gratefully thank Drs. Rebecca Riggins, York Tomita, and Michael Johnson (Lombardi Cancer Centre) for sharing reagents and helpful discussion. We thank the flow cytometry core facility at Lombardi Cancer Center for assistance with the cell cycle analysis. This study was supported by the Department of Defense Breast Program W81XWH-11-1-0190 (RIY) and by the BioBits Project, Regione Piemonte, Italy (CP).

Conflict of interest

The authors declare that there is no conflict of interests.

Supplementary material

10549_2012_1992_MOESM1_ESM.doc (137 kb)
Supplementary material 1 (DOC 137 kb)


  1. 1.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917PubMedCrossRefGoogle Scholar
  2. 2.
    Newman DJ, Cragg GM (2004) Advanced preclinical and clinical trials of natural products and related compounds from marine sources. Curr Med Chem 11:1693–1713PubMedGoogle Scholar
  3. 3.
    Skoog F, Strong FM, Miller CO (1965) Cytokinins. Science 148:532–533PubMedCrossRefGoogle Scholar
  4. 4.
    Ishii Y, Sakai S, Honma Y (2003) Cytokinin-induced differentiation of human myeloid leukemia HL-60 cells is associated with the formation of nucleotides, but not with incorporation into DNA or RNA. Biochim Biophys Acta 1643:11–24PubMedCrossRefGoogle Scholar
  5. 5.
    Mlejnek P (2001) Caspase inhibition and N6-benzyladenosine-induced apoptosis in HL-60 cells. J Cell Biochem 83:678–689PubMedCrossRefGoogle Scholar
  6. 6.
    Mlejnek P (2001) Caspase-3 activity and carbonyl cyanide m-chlorophenylhydrazone-induced apoptosis in HL-60. Altern Lab Anim 29:243–249PubMedGoogle Scholar
  7. 7.
    Cohen S, Flescher E (2009) Methyl jasmonate: a plant stress hormone as an anti-cancer drug. Phytochemistry 70:1600–1609PubMedCrossRefGoogle Scholar
  8. 8.
    Goldin N, Arzoine L, Heyfets A, Israelson A, Zaslavsky Z, Bravman T, Bronner V, Notcovich A, Shoshan-Barmatz V, Flescher E (2008) Methyl jasmonate binds to and detaches mitochondria-bound hexokinase. Oncogene 27:4636–4643PubMedCrossRefGoogle Scholar
  9. 9.
    Elia U, Flescher E (2008) PI3K/Akt pathway activation attenuates the cytotoxic effect of methyl jasmonate toward sarcoma cells. Neoplasia 10:1303–1313PubMedGoogle Scholar
  10. 10.
    Oh SY, Kim JH, Park MJ, Kim SM, Yoon CS, Joo YM, Park JS, Han SI, Park HG, Kang HS (2005) Induction of heat shock protein 72 in C6 glioma cells by methyl jasmonate through ROS-dependent heat shock factor 1 activation. Int J Mol Med 16:833–839PubMedGoogle Scholar
  11. 11.
    Clouse SD, Sasse JM (1998) Brassinosteroids: essential regulators of plant growth and development. Annu Rev Plant Physiol Plant Mol Biol 49:427–451PubMedCrossRefGoogle Scholar
  12. 12.
    Steigerova J, Oklestkova J, Levkova M, Rarova L, Kolar Z, Strnad M (2010) Brassinosteroids cause cell cycle arrest and apoptosis of human breast cancer cells. Chem Biol Interact 188:487–496PubMedCrossRefGoogle Scholar
  13. 13.
    Xie X, Yoneyama K (2010) The strigolactone story. Annu Rev Phytopathol 48:93–117PubMedCrossRefGoogle Scholar
  14. 14.
    Akiyama K, Ogasawara S, Ito S, Hayashi H (2010) Structural requirements of strigolactones for hyphal branching in AM fungi. Plant Cell Physiol 51:1104–1117PubMedCrossRefGoogle Scholar
  15. 15.
    Kapulnik Y, Delaux PM, Resnick N, Mayzlish-Gati E, Wininger S, Bhattacharya C, Sejalon-Delmas N, Combier JP, Becard G, Belausov E, Beeckman T, Dor E, Hershenhorn J, Koltai H (2011) Strigolactones affect lateral root formation and root-hair elongation in Arabidopsis. Planta 233:209–216PubMedCrossRefGoogle Scholar
  16. 16.
    Rameau C (2010) Strigolactones, a novel class of plant hormone controlling shoot branching. C R Biol 333:344–349PubMedCrossRefGoogle Scholar
  17. 17.
    Gomez-Roldan V, Fermas S, Brewer PB, Puech-Pages V, Dun EA, Pillot JP, Letisse F, Matusova R, Danoun S, Portais JC, Bouwmeester H, Becard G, Beveridge CA, Rameau C, Rochange SF (2008) Strigolactone inhibition of shoot branching. Nature 455:189–194PubMedCrossRefGoogle Scholar
  18. 18.
    Umehara M, Hanada A, Yoshida S, Akiyama K, Arite T, Takeda-Kamiya N, Magome H, Kamiya Y, Shirasu K, Yoneyama K, Kyozuka J, Yamaguchi S (2008) Inhibition of shoot branching by new terpenoid plant hormones. Nature 455:195–200PubMedCrossRefGoogle Scholar
  19. 19.
    Sharma VK, Fletcher JC (2002) Maintenance of shoot and floral meristem cell proliferation and fate. Plant Physiol 129:31–39PubMedCrossRefGoogle Scholar
  20. 20.
    Koltai H, Dor E, Hershenhorn J, Daniel M, Weininger S, Lekalla S, Shealtiel H, Bhattacharya C, Eliahu E, Resnick N, Barg R, Kapulnik Y (2010) Strigolactones’ effect on root growth and root-hair elongation may be mediated by auxin-efflux carriers. J Plant Growth Regul 29:129–136CrossRefGoogle Scholar
  21. 21.
    Dor E, Joel DM, Kapulnik Y, Koltai H, Hershenhorn J (2011) The synthetic strigolactone GR24 influences the growth pattern of phytopathogenic fungi. Planta 234:419–427PubMedCrossRefGoogle Scholar
  22. 22.
    Bhattacharya C, Bonfante P, Deagostino A, Kapulnik Y, Larini P, Occhiato EG, Prandi C, Venturello P (2009) A new class of conjugated strigolactone analogues with fluorescent properties: synthesis and biological activity. Org Biomol Chem 7:3413–3420PubMedCrossRefGoogle Scholar
  23. 23.
    Mwakaboko AS, Zwanenburg B (2011) Single step synthesis of strigolactone analogues from cyclic keto enols, germination stimulants for seeds of parasitic weeds. Bioorg Med Chem 19:5006–5011PubMedCrossRefGoogle Scholar
  24. 24.
    Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, Wicha MS (2003) In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17:1253–1270PubMedCrossRefGoogle Scholar
  25. 25.
    Prud’homme GJ, Glinka Y, Toulina A, Ace O, Subramaniam V, Jothy S (2010) Breast cancer stem-like cells are inhibited by a non-toxic aryl hydrocarbon receptor agonist. PLoS One 5:e13831PubMedCrossRefGoogle Scholar
  26. 26.
    Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29:4741–4751PubMedCrossRefGoogle Scholar
  27. 27.
    Charafe-Jauffret E, Ginestier C, Iovino F, Wicinski J, Cervera N, Finetti P, Hur MH, Diebel ME, Monville F, Dutcher J, Brown M, Viens P, Xerri L, Bertucci F, Stassi G, Dontu G, Birnbaum D, Wicha MS (2009) Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 69:1302–1313PubMedCrossRefGoogle Scholar
  28. 28.
    Cariati M, Naderi A, Brown JP, Smalley MJ, Pinder SE, Caldas C, Purushotham AD (2008) Alpha-6 integrin is necessary for the tumourigenicity of a stem cell-like subpopulation within the MCF7 breast cancer cell line. Int J Cancer 122:298–304PubMedCrossRefGoogle Scholar
  29. 29.
    Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Hilsenbeck SG, Pavlick A, Zhang X, Chamness GC, Wong H, Rosen J, Chang JC (2008) Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100:672–679PubMedCrossRefGoogle Scholar
  30. 30.
    Jiang F, Qiu Q, Khanna A, Todd NW, Deepak J, Xing L, Wang H, Liu Z, Su Y, Stass SA, Katz RL (2009) Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer. Mol Cancer Res 7:330–338PubMedCrossRefGoogle Scholar
  31. 31.
    Burger PE, Gupta R, Xiong X, Ontiveros CS, Salm SN, Moscatelli D, Wilson EL (2009) High aldehyde dehydrogenase activity: a novel functional marker of murine prostate stem/progenitor cells. Stem Cells 27:2220–2228PubMedCrossRefGoogle Scholar
  32. 32.
    Croker AK, Goodale D, Chu J, Postenka C, Hedley BD, Hess DA, Allan AL (2009) High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability. J Cell Mol Med 13:2236–2252PubMedCrossRefGoogle Scholar
  33. 33.
    Cuadrado A, Nebreda AR (2010) Mechanisms and functions of p38 MAPK signalling. Biochem J 429:403–417PubMedCrossRefGoogle Scholar
  34. 34.
    Saccani S, Pantano S, Natoli G (2002) p38-dependent marking of inflammatory genes for increased NF-kappa B recruitment. Nat Immunol 3:69–75PubMedCrossRefGoogle Scholar
  35. 35.
    Deak M, Clifton AD, Lucocq LM, Alessi DR (1998) Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J 17:4426–4441PubMedCrossRefGoogle Scholar
  36. 36.
    Cargnello M, Roux PP (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75:50–83PubMedCrossRefGoogle Scholar
  37. 37.
    Gum RJ, Young PR (1999) Identification of two distinct regions of p38 MAPK required for substrate binding and phosphorylation. Biochem Biophys Res Commun 266:284–289PubMedCrossRefGoogle Scholar
  38. 38.
    Bhoumik A, Lopez-Bergami P, Ronai Z (2007) ATF2 on the double-activating transcription factor and DNA damage response protein. Pigment Cell Res 20:498–506PubMedCrossRefGoogle Scholar
  39. 39.
    Gong G, Stern HS, Cheng SC, Fong N, Mordeson J, Deng HW, Recker RR (1999) The association of bone mineral density with vitamin D receptor gene polymorphisms. Osteoporos Int 9:55–64PubMedCrossRefGoogle Scholar
  40. 40.
    Woodgett JR (2005) Recent advances in the protein kinase B signaling pathway. Curr Opin Cell Biol 17:150–157PubMedCrossRefGoogle Scholar
  41. 41.
    Scheid MP, Marignani PA, Woodgett JR (2002) Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B. Mol Cell Biol 22:6247–6260PubMedCrossRefGoogle Scholar
  42. 42.
    Shaw M, Cohen P, Alessi DR (1997) Further evidence that the inhibition of glycogen synthase kinase-3beta by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9 and not by dephosphorylation of Tyr-216. FEBS Lett 416:307–311PubMedCrossRefGoogle Scholar
  43. 43.
    Casamayor A, Morrice NA, Alessi DR (1999) Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: identification of five sites of phosphorylation in vivo. Biochem J 342(Pt 2):287–292PubMedCrossRefGoogle Scholar
  44. 44.
    Correze C, Blondeau JP, Pomerance M (2005) p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells. Eur J Endocrinol 153:123–133PubMedCrossRefGoogle Scholar
  45. 45.
    Iyoda K, Sasaki Y, Horimoto M, Toyama T, Yakushijin T, Sakakibara M, Takehara T, Fujimoto J, Hori M, Wands JR, Hayashi N (2003) Involvement of the p38 mitogen-activated protein kinase cascade in hepatocellular carcinoma. Cancer 97:3017–3026PubMedCrossRefGoogle Scholar
  46. 46.
    Chang HL, Wu YC, Su JH, Yeh YT, Yuan SS (2008) Protoapigenone, a novel flavonoid, induces apoptosis in human prostate cancer cells through activation of p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase 1/2. J Pharmacol Exp Ther 325:841–849PubMedCrossRefGoogle Scholar
  47. 47.
    She QB, Chen N, Dong Z (2000) ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation. J Biol Chem 275:20444–20449PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • C. B. Pollock
    • 1
    • 2
  • H. Koltai
    • 3
  • Y. Kapulnik
    • 4
  • C. Prandi
    • 5
  • R. I. Yarden
    • 1
    • 2
    Email author
  1. 1.Department of Human ScienceGeorgetown UniversityWashingtonUSA
  2. 2.Lombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashingtonUSA
  3. 3.Department of Ornamental HorticultureAgricultural Research Organization (ARO), The Volcani CenterBet DaganIsrael
  4. 4.Department of Field Crops and Natural Resources Institute of Plant SciencesAgricultural Research Organization (ARO), The Volcani CenterBet DaganIsrael
  5. 5.Department of ChemistryUniversity TurinTurinItaly

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