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Parthenolide, a Sesquiterpene Lactone, Expresses Multiple Anti-cancer and Anti-inflammatory Activities

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Abstract

Parthenolide, a naturally occurring sesquiterpene lactone derived from feverfew (Tanacetum parthenium), exhibits exceptional anti-cancer and anti-inflammatory properties, making it a prominent candidate for further studies and drug development. In this review, we briefly investigate molecular events and cell-specific activities of this chemical in relation to cytochrome c, nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), signal transduction and activation of transcription (STAT), reactive oxygen species (ROS), TCP, HDACs, microtubules, and inflammasomes. This paper reports that parthenolide shows strong NF-κB- and STAT-inhibition-mediated transcriptional suppression of pro-apoptotic genes. This compound acts both at the transcriptional level and by direct inhibition of associated kinases (IKK-β). Similarly, this review discusses parthenolide-induced ROS-mediated apoptosis of tumor cells via the intrinsic apoptotic signaling pathway. The unique ability of this compound to not harm normal cells but at the same time induce sensitization to extrinsic as well as intrinsic apoptosis signaling in cancer cells provides an important, novel therapeutic strategy for treatment of cancer and inflammation-related disorders.

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REFERENCES

  1. Marles, R.J., L. Pazos-Sanou, C.M. Compadre, J.M. Pezzuto, E. Bloszyk, and J. Arnason. 1995. Sesquiterpene lactones revisited: recent developments in the assessment of biological activities and structure relationships. Recent Advances in Phytochemistry 29: 333–356.

    CAS  Google Scholar 

  2. Smolinski, A.T., and J.J. Pestka. 2005. Comparative effects of the herbal constituent parthenolide (Feverfew) on lipopolysaccharide-induced inflammatory gene expression in murine spleen and liver. Journal of Inflammation 2: 1–6.

    Article  Google Scholar 

  3. Baud, V., and M. Karin. 2009. Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nature Reviews Drug Discovery 8: 33–40.

    Article  PubMed  CAS  Google Scholar 

  4. Karin, M., and Y.B. Beriah. 2000. Phosphorylation meets ubiquitination: the control of NF-[kappa] B activity. Annual Review Immunology 18: 621–663.

    Article  CAS  Google Scholar 

  5. Bernhard, S., N. Matthes, N.H. El Armouche, K. Neubauer, and G. Ramadori. 2001. The bcl, NFκB and p53/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-β or TNF-α on activated hepatic stellate cells. European Journal of Cell Biology 80: 554–561.

    Article  Google Scholar 

  6. Tapia, P.C. 2006. Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise and dietary phytonutrients: "Mitohormesis" for health and vitality. Meidical Hypotheses 66: 832–843.

    Article  CAS  Google Scholar 

  7. Payne, C.M., C. Weber, C.C. Skillicorn, K. Dovrak, H. Bernstein, H. Holubec, et al. 2007. Deoxycholate induces mitochondrial oxidative stress and activates NF-kB through multiple mechanisms in HCT-116 colon epithelial cells. Carcinogenesis 28: 215–222.

    Article  PubMed  CAS  Google Scholar 

  8. Li, N., and M. Karin. 1998. Ionizing radiation and short wavelength UV activate NF-κB through two distinct mechanisms. Proceedings of the National Academy of Sciences 95: 13012–13017.

    Article  CAS  Google Scholar 

  9. Zhang, S., C.N. Ong, and H.M. Shen. 2004. Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells. Cancer Letters 208: 143–153.

    Article  PubMed  CAS  Google Scholar 

  10. Tacchini, L., C. DePonti, E. Matteucci, R. Follis, and M.A. Desiderio. 2004. Hepatocyte growth factor-activated NF-kappaB regulates HIF-1 activity and ODC expression, implicated in survival, differently in different carcinoma cell lines. Carcinogenesis 25: 2089–2100.

    Article  PubMed  CAS  Google Scholar 

  11. Zhao, L.J., Y.H. Xu, and Y. Li. 2009. Effect of parthenolide on proliferation and apoptosis in gastric cancer cell line SGC7901. Journal of Digestive Disorder 10: 172–180.

    Article  CAS  Google Scholar 

  12. Benjamin, H.B., B.K. Kwoka, M.K. Ndubuisia, M. Elofssona, and C.M. Crews. 2001. The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IκB kinase. Chemical Biology 8: 759–766.

    Article  Google Scholar 

  13. Dai, Y., M.L. Guzman, S. Chen, L. Wang, S.K. Yeung, X.Y. Pei, et al. 2010. The NF (nuclear factor)-κB inhibitor parthenolide interacts with histone deacetylase inhibitors to induce MKK7/JNK1-dependent apoptosis in human acute myeloid leukaemia cells. British Journal of Haematology 151: 70–83.

    Article  PubMed  CAS  Google Scholar 

  14. Jenkins, C., S. Hewamana, A. Gilkes, S. Neelakantan, P. Crooks, K. Mills, et al. 2008. Nuclear factor-kappaB as a potential therapeutic target for the novel cytotoxic agent LC-1 in acute myeloid leukaemia. British Journal of Hematology 143: 661–671.

    Article  Google Scholar 

  15. Hewamana, S., T.T. Lin, C. Jenkins, A.K. Burnett, C.T. Jordan, C. Fegan, et al. 2008. The novel nuclear factor-kappaB inhibitor LC-1 is equipotent in poor prognostic subsets of chronic lymphocytic leukemia and shows strong synergy with fludarabine. Clinical Cancer Research 14: 8102–8111.

    Article  PubMed  CAS  Google Scholar 

  16. Marfurt, J., F. Chalfein, P. Prayoga, F. Wabiser, E. Kenangalem, and K.A. Piera. 2011. Ex vivo activity of histone deacetylase inhibitors against multidrug-resistant clinical isolates of Plasmodium falciparum and P. vivax. Antimicrobial Agents and Chemotherapy 55: 96–66.

    Google Scholar 

  17. Lamkanfi, M., and V.M. Dixit. 2009. The inflammasomes. PLoS Pathogen 5: e1000510.

    Article  Google Scholar 

  18. Rajan, J.V., D. Rodriguez, E.A. Miao, and A. Aderem. 2011. The NLRP3 inflammasome detects encephalomyocarditis virus and vesicular stomatitis virus infection. The Journal of Virology 85: 4167–4172.

    Article  CAS  Google Scholar 

  19. Pelegrin, P., and A. Surprenant. 2009. The P2X7 receptor–pannexin connection to dye uptake and IL-1β release. Purinergic Signal 5: 129–137.

    Article  PubMed  CAS  Google Scholar 

  20. Martinon, F., A. Mayor, and J. Tschopp. 2009. The inflammasomes: guardians of the body. Annual Review of Immunology 27: 229–265.

    Article  PubMed  CAS  Google Scholar 

  21. Hornung, V., F. Bauernfeind, A. Halle, E.O. Samstad, H. Kono, K.L. Rock, et al. 2008. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Natural Immunology 9: 847–856.

    Article  CAS  Google Scholar 

  22. Cassel, S.L., S.C. Eisenbarth, S.S. Iyer, J.J. Sadler, O.R. Colegio, L.A. Tephly, et al. 2008. The Nalp3 inflammasome is essential for the development of silicosis. Proceedings of the National Academy of Sciences 105: 9035–9040.

    Article  CAS  Google Scholar 

  23. Martinon, F., V. Petrilli, A. Mayor, A. Tardivel, and J. Tschopp. 2006. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440: 237–241.

    Article  PubMed  CAS  Google Scholar 

  24. Juliana, C., T. Fernandes-Alnemri, J. Wu, P. Datta, L. Solorzano, J.W. Yu, et al. 2010. Anti-inflammatory compounds parthenolide and bay 11-7082 are direct inhibitors of the inflammasome. The Journal of Biological Chemistry 285: 9792–9802.

    Article  PubMed  CAS  Google Scholar 

  25. Dinarello, C.A. 1998. Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist. International Reviews of Immunolology 16: 457–499.

    Article  CAS  Google Scholar 

  26. Steele, A.J., D.T. Jones, K. Ganeshaguru, V.M. Duke, B.C. Yogashangary, J.M. North, et al. 2006. The sesquiterpene lactone parthenolide induces selective apoptosis of B-chronic lymphocytic leukemia cells in vitro. Leukemia 20: 1073–1079.

    Article  PubMed  CAS  Google Scholar 

  27. Herrera, F., V. Martin, J. Rodriguez-Blanco, G. García-Santos, I. Antolín, and C. Rodriguez. 2005. Intracellular redox state regulation by parthenolide. Biochemical and Biophysical Research Communications 332: 321–325.

    Article  PubMed  CAS  Google Scholar 

  28. Hampton, M.B., and S. Orrenius. 1998. Redox regulation of apoptotic cell death. Biofactors 8: 1–5.

    Article  PubMed  CAS  Google Scholar 

  29. Nakshatri, H., S.E. Rice, and P.B. Nakshatri. 2004. Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase. Oncogene 23: 7330–7344.

    Article  PubMed  CAS  Google Scholar 

  30. Winterbourn, C.C., and M.B. Hampton. 2008. Thiol chemistry and specificity in redox signaling. Free Radical Biology and Medicine 45: 549–561.

    Article  PubMed  CAS  Google Scholar 

  31. Lee, H., M.K. Cha, and I.H. Kim. 2000. Activation of thiol-dependent antioxidant activity of human serum albumin by alkaline pH is due to the B-like conformational change. Archives of Biochemistry and Biophysics 380: 309–318.

    Article  PubMed  CAS  Google Scholar 

  32. Pajak, B., B. Gajkowska, and A. Orzechowski. 2008. Molecular basis of parthenolide-dependent proapoptotic activity in cancer cells. Folia Histochemica et Cytobiologica 46: 129–135.

    Article  PubMed  CAS  Google Scholar 

  33. Sun, Y., D.K. St Clair, Y. Xu, P.A. Crooks, and W.H. StClair. 2010. A NADPH oxidase-dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells. Cancer Research 70: 2880–2890.

    Article  PubMed  CAS  Google Scholar 

  34. Zunino, S.J., J.M. Ducore, and D.H. Storms. 2007. Parthenolide induces significant apoptosis and production of reactive oxygen species in high-risk pre-B leukemia cells. Cancer Letters 254: 119–127.

    Article  PubMed  CAS  Google Scholar 

  35. Zhang, S., C.N. Ong, and H.M. Shen. 2004. Involvement of proapoptotic bcl-2 family members in parthenolide-induced mitochondrial dysfunction and apoptosis. Cancer Letters 211: 175–188.

    Article  PubMed  CAS  Google Scholar 

  36. Li, H., H. Zhu, C.J. Xu, and J. Yuan. 1998. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94: 491–501.

    Article  PubMed  CAS  Google Scholar 

  37. Sahler, J., J.J. Bernard, S.L. Spinelli, N. Blumberg, and R.P. Phipps. 2011. The Feverfew plant-derived compound, parthenolide enhances platelet production and attenuates platelet activation through NF-κB inhibition. Thrombosis Research 27: 426–434.

    Article  Google Scholar 

  38. O’Brien, J.J., C.J. Baglole, T.M. Bates, N. Blumberg, C.W. Francis, and R.P. Phipps. 2009. 15-Deoxy-delta12, 14 prostaglandin J2-induced heme oxygenase-1 in megakaryocytes regulates thrombopoiesis. Journal of Thrombosis and Haemostasis 7: 182–189.

    Article  PubMed  Google Scholar 

  39. Weng, S.X., M.H. Sui, S.C. Wang, G. Xu, J. Ma, J. Shan, et al. 2009. Parthenolide inhibits proliferation of vascular smooth muscle cells through induction of G0/G1 phase cell cycle arrest. Journal of Zhejiang University 10: 528–535.

    Article  PubMed  CAS  Google Scholar 

  40. Meyer, T., and U. Vinkemeier. 2007. STAT nuclear translocation: potential for pharmacological intervention. Expert Opinion on Therapeutic Targets 11: 1355–1365.

    Article  PubMed  CAS  Google Scholar 

  41. Carlisi, D., A. D’Anneo, L. Angileri, M. Lauricella, S. Emanuele, A. Santulli, et al. 2011. Parthenolide sensitizes hepatocellular carcinoma cells to trail by inducing the expression of death receptors through inhibition of STAT3 activation. Journal of Cellular Physiololgy 226: 1632–1641.

    Article  CAS  Google Scholar 

  42. Guzman, M.L., R.M. Rossi, L. Karnischky, X. Li, D.R. Peterson, D.S. Howard, et al. 2005. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 105: 4163–4169.

    Article  PubMed  CAS  Google Scholar 

  43. Ganten, T.M., T.L. Haas, J. Sykora, H. Stahl, M.R. Sprick, S.C. Fas, et al. 2004. Enhanced caspase-8 recruitment to and activation at the DISC is critical for sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugs. Cell Death and Differenciation 11: S86–S96.

    Article  CAS  Google Scholar 

  44. Chen, K.F., W.T. Tai, T.H. Liu, H.P. Huang, Y.C. Lin, C.W. Shiau, et al. 2010. Sorafenib overcomes TRAIL resistance of hepatocellular carcinoma cells through the inhibition of STAT3. Clinical Cancer Research 16: 5189–5199.

    Article  PubMed  CAS  Google Scholar 

  45. Sobota, R., M. Szwed, A. Kasza, M. Bugno, and T. Kordula. 2002. Parthenolide Inhibits activation of signal transducers and activators of transcription (STATs) induced by cytokines of the IL-6 family. Biochemical and Biophysical Research Communications 267: 329–333.

    Article  Google Scholar 

  46. Burton, P.R. 1966. A Comparative electron microscopic study of cytoplasmic microtubules and axial unit tubules in a spermatozoon and a protozoan. Journal of Morphology 120: 397–423.

    Article  Google Scholar 

  47. Fonrose, X., A. Frédéric, E. Soleilhac, B. David, I. Pouny, J.C. Cintrat, et al. 2007. Parthenolide inhibits tubulin carboxypeptidase activity. Cancer Research 67: 3371–3378.

    Article  PubMed  CAS  Google Scholar 

  48. Zhou, J., and P. Giannakakou. 2005. Targeting microtubules for cancer chemotherapy. Current Medicinal Chemistry-Anti-Cancer Agents 5: 65–71.

    Article  PubMed  CAS  Google Scholar 

  49. Mialhe, A., L. Lafanechere, and I. Treilleux. 2001. Tubulin detyrosination is a frequent occurrence in breast cancers of poor prognosis. Cancer Research 61: 5024–5027.

    PubMed  CAS  Google Scholar 

  50. Kato, C., K. Miyazaki, and A. Nakagawa. 2004. Low expression of human tubulin tyrosine ligase and suppressed tubulin tyrosination/detyrosination cycle are associated with impaired neuronal differentiation in neuroblastomas with poor prognosis. International Journal of Cancer 112: 365–375.

    Article  CAS  Google Scholar 

  51. Soucek, K., A. Kamaid, A.D. Phung, L. Kubala, J.C. Bulinski, R.W. Harper, et al. 2006. Normal and prostate cancer cells display distinct molecular profiles of α-tubulin posttranslational modifications. Prostate 66: 954–965.

    Article  PubMed  CAS  Google Scholar 

  52. Lafanechere, L., and D. Job. 2000. The third tubulin pool. Neurochem Research 25: 11–18.

    Article  CAS  Google Scholar 

  53. Akan, I., S. Akan, H. Akca, B. Savas, and T. Ozben. 2005. Multidrug resistance-associated protein 1 (MRP1) mediated vincristine resistance: effects of N-acetylcysteine and Buthionine sulfoximine. Cancer Cell International 5: 22.

    Article  PubMed  Google Scholar 

  54. Heng, H.H., J.B. Stevens, G. Liu, S.W. Bremer, and C.J. Ye. 2004. Imaging genome abnormalities in cancer research. Cell and Chromosomes 5: 22.

    Google Scholar 

  55. Kanda, N., H. Seno, Y. Konda, H. Marusawa, M. Kanai, and T. Nakajima. 2004. STAT3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells. Oncogene 23: 4921–4929.

    Article  PubMed  CAS  Google Scholar 

  56. Wu, C., F. Chen, J.W. Rushing, X. Wang, H.J. Kim, G. Huang, et al. 2006. Antiproliferative activities of parthenolide and golden feverfew extract against three human cancer cell lines. Journal of Medicinal Food 9: 55–61.

    Article  PubMed  CAS  Google Scholar 

  57. Wang, W., M. Adachi, R. Kawamura, H. Sakamoto, T. Hayashi, T. Ishida, et al. 2006. Parthenolide-induced apoptosis in multiple myeloma cells involves reactive oxygen species generation and cell sensitivity depends on catalase activity. Apoptosis 11: 2225–2235.

    Article  PubMed  CAS  Google Scholar 

  58. Gopal, Y.N., T.S. Arora, and M.W. Dyke. 2007. Parthenolide specifically depletes histone deacetylase 1 protein and induces cell death through ataxia telangiectasia mutated. Chemical Biology 14: 813–823.

    Article  CAS  Google Scholar 

  59. Minucci, S., and P.G. Pelicci. 2006. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nature Reviews Cancer 6: 38–51.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Microbiology, School of Medicine and Brain Korea 21 Program, Jeju National University, Jeju, Jeju-Do, South Korea

    Vivek Bhakta Mathema & Young-Sang Koh

  2. Department of Biotechnology, Tribhuvan University, Kathmandu, Nepal

    Balkrishna Chand Thakuri

  3. Laboratory of Green Chemistry, LUT Faculty of Technology, Lappeenranta University of Technology, Patteristonkatu 1, 50110, Mikkeli, Finland

    Mika Sillanpää

  4. Cheju National University, Ara-il-dong 1, Jeju-si, Jeju-do, 690-756, South Korea

    Vivek Bhakta Mathema

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  1. Vivek Bhakta Mathema
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Correspondence to Vivek Bhakta Mathema.

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Mathema, V.B., Koh, YS., Thakuri, B.C. et al. Parthenolide, a Sesquiterpene Lactone, Expresses Multiple Anti-cancer and Anti-inflammatory Activities. Inflammation 35, 560–565 (2012). https://doi.org/10.1007/s10753-011-9346-0

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