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Caffeic acid phenethyl ester exerts apoptotic and oxidative stress on human multiple myeloma cells

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Summary

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.

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Funding

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.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, 625 Old Peachtree Road NW, Suwanee, GA, 30024-2937, USA

    Elizabeth Hernandez Marin, Hana Paek, Mei Li, Yesung Ban, Marie Katie Karaga, Rangaiah Shashidharamurthy & Xinyu Wang

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  1. Elizabeth Hernandez Marin
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Contributions

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.

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Correspondence to Xinyu Wang.

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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.

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Marin, E.H., Paek, H., Li, M. et al. Caffeic acid phenethyl ester exerts apoptotic and oxidative stress on human multiple myeloma cells. Invest New Drugs 37, 837–848 (2019). https://doi.org/10.1007/s10637-018-0701-y

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