Caffeic acid phenethyl ester exerts apoptotic and oxidative stress on human multiple myeloma cells
Caffeic acid phenethyl ester (CAPE) is a phenolic compound initially identified in bee glue. CAPE is reported to exhibit antitumor activity in many cancer models. However, the effect of CAPE on multiple myeloma (MM) is not well studied. We investigated the anti-myeloma effect of CAPE, and the data showed that CAPE inhibited the growth of human MM cells in a dose (1 ~ 30 μM) and time (24 ~72 h) dependent manner without altering the viability of normal human peripheral blood B cells. Stress and toxicity pathway analysis demonstrated that CAPE, in a dose- and time-related fashion, induced the expression of apoptotic and oxidative stress-response genes including growth arrest and DNA-damage inducible, alpha and gamma (GADD45A and GADD45G) and heme oxygenase-1. Apoptosis of MM cells by CAPE was further confirmed through flow cytometric analysis with up to 50% apoptotic cells induced by 50 μM CAPE within 24 h. Western blot analysis revealed the CAPE-induced activation of apoptosis executioner enzyme caspase-3, and corresponding cleavage of its downstream target poly(ADP-ribose)polymerase (PARP). The oxidative stress caused by CAPE cytotoxicity in MM cells was evaluated through measurement of reactive oxygen species (ROS) level, antioxidant intervention and glutathione depletion. The intracellular ROS level was not elevated by CAPE, but the pretreatment of antioxidant (N-acetyl cysteine) and glutathione synthesis inhibitor (buthionine sulfoximine) suggested that CAPE may cause oxidative stress by decrease of intracellular antioxidant level rather than over production of ROS. These data suggest that CAPE promotes apoptosis through oxidative stress in human multiple myeloma cells.
KeywordsCaffeic acid phenethyl ester Multiple myeloma Cytotoxicity Apoptosis Oxidative stress
Conceived and designed the experiments: XW. Performed the experiments: EM, HP, ML.YB, and MK. Analyzed the data: EM, HP, ML, RS, and XW. Critically reviewed the paper: RS. Wrote the paper: XW.
This work was supported by the American Association of Colleges of Pharmacy (AACP) New Investigator Award and The Center for Chronic Disorders of Aging (CCDA) funding from Philadelphia College of Osteopathic Medicine to XW. It was partly supported by AHA (11SDG5710004) and NIAID (AI128254-01A1) to RS.
Compliance with ethical standards
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
- 3.Bakkus MH, Heirman C, Van Riet I, Van Camp B, Thielemans K (1992) Evidence that multiple myeloma Ig heavy chain VDJ genes contain somatic mutations but show no intraclonal variation. Blood 80(9):2326–2335Google Scholar
- 4.Fonseca R, Barlogie B, Bataille R, Bastard C, Bergsagel PL, Chesi M, Davies FE, Drach J, Greipp PR, Kirsch IR, Kuehl WM, Hernandez JM, Minvielle S, Pilarski LM, Shaughnessy JD Jr, Stewart AK, Avet-Loiseau H (2004) Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res 64(4):1546–1558CrossRefGoogle Scholar
- 5.Chauhan D, Uchiyama H, Urashima M, Yamamoto K, Anderson KC (1995) Regulation of interleukin 6 in multiple myeloma and bone marrow stromal cells. Stem Cells 13(Suppl 2):35–39Google Scholar
- 6.Podar K, Tai YT, Davies FE, Lentzsch S, Sattler M, Hideshima T, Lin BK, Gupta D, Shima Y, Chauhan D, Mitsiades C, Raje N, Richardson P, Anderson KC (2001) Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration. Blood 98(2):428–435CrossRefGoogle Scholar
- 7.Mitsiades CS, Mitsiades NS, Munshi NC, Richardson PG, Anderson KC (2006) The role of the bone microenvironment in the pathophysiology and therapeutic management of multiple myeloma: interplay of growth factors, their receptors and stromal interactions. Eur J Cancer 42(11):1564–1573. https://doi.org/10.1016/j.ejca.2005.12.025 CrossRefGoogle Scholar
- 19.Toyoda T, Tsukamoto T, Takasu S, Shi L, Hirano N, Ban H, Kumagai T, Tatematsu M (2009) Anti-inflammatory effects of caffeic acid phenethyl ester (CAPE), a nuclear factor-kappaB inhibitor, on helicobacter pylori-induced gastritis in Mongolian gerbils. Int J Cancer 125(8):1786–1795. https://doi.org/10.1002/ijc.24586 CrossRefGoogle Scholar
- 22.Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB (2010) Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 49(11):1603–1616. https://doi.org/10.1016/j.freeradbiomed.2010.09.006 CrossRefGoogle Scholar
- 23.Wu J, Omene C, Karkoszka J, Bosland M, Eckard J, Klein CB, Frenkel K (2011) Caffeic acid phenethyl ester (CAPE), derived from a honeybee product propolis, exhibits a diversity of anti-tumor effects in pre-clinical models of human breast cancer. Cancer Lett 308(1):43–53. https://doi.org/10.1016/j.canlet.2011.04.012 CrossRefGoogle Scholar
- 26.Wang X, Stavchansky S, Zhao B, Bynum JA, Kerwin SM, Bowman PD (2008) Cytoprotection of human endothelial cells from menadione cytotoxicity by caffeic acid phenethyl ester: the role of heme oxygenase-1. Eur J Pharmacol 591(1–3):28–35. https://doi.org/10.1016/j.ejphar.2008.06.017 CrossRefGoogle Scholar
- 29.Bynum JA, Wang X, Stavchansky SA, Bowman PD (2017) Time course expression analysis of 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole induction of Cytoprotection in human endothelial cells. Gene Regul Syst Bio 11: https://doi.org/10.1177/1177625017701106
- 33.Ozturk G, Ginis Z, Akyol S, Erden G, Gurel A, Akyol O (2012) The anticancer mechanism of caffeic acid phenethyl ester (CAPE): review of melanomas, lung and prostate cancers. Eur Rev Med Pharmacol Sci 16(15):2064–2068Google Scholar
- 34.Nowsheen S, Yang ES (2012) The intersection between DNA damage response and cell death pathways. Exp Oncol 34(3):243–254Google Scholar