Antimyeloma Potential of Caffeic Acid Phenethyl Ester and Its Analogues through Sp1 Mediated Downregulation of IKZF1-IRF4-MYC Axis

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2020-12, Vol.83 (12), p.3526-3535
• Main Authors: Murugesan, Alli, Lassalle-Claux, Grégoire, Hogan, Lauren, Vaillancourt, Elise, Selka, Ayyoub, Luiker, Katie, Kim, Min Ji, Touaibia, Mohamed, Reiman, Tony
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - pharmacology; Apoptosis - drug effects; Caffeic Acids - chemistry; Caffeic Acids - pharmacology; Cell Line, Tumor; Down-Regulation; Genes, myc; Humans; Ikaros Transcription Factor - metabolism; Interferon Regulatory Factors - metabolism; Lenalidomide - pharmacology; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Phenylethyl Alcohol - analogs & derivatives; Phenylethyl Alcohol - chemistry; Phenylethyl Alcohol - pharmacology; Sp1 Transcription Factor - metabolism; Structure-Activity Relationship
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.0c00350

Caffeic acid phenethyl ester (CAPE, 2), a natural compound from propolis, is a well-documented antitumor agent with nuclear factor kappa B (NF-κB) inhibitory activity. Key transcription factors regulated by NF-κB, namely, interferon regulatory factor-4 (IRF4) and octameric binding protein-2 (OCT2), are implicated in the tumorigenesis of multiple myeloma (MM), an incurable bone marrow cancer. Adverse effects and resistance to current chemotherapeutics pose a great challenge for MM treatment. Hence, the structure–activity relationships of CAPE (2) and 21 of its analogues were evaluated for their antimyeloma potential. Preclinical evaluation revealed that CAPE (2) and the 3-phenylpropyl (4), 2,5-dihydroxycinnamic acid 3-phenylpropyl ester (17), and 3,4-dihydroxycinnamic ether (22) analogues inhibited human myeloma cell growth. Analogue 4 surpassed CAPE (2) and lenalidomide in showing strong apoptotic effects with a remarkable decrease in IRF4 levels. The analogue 17 exhibited the most potent anti-MM activity. The downregulation of specificity protein 1 (Sp1) and the IKZF1-IRF4-MYC axis by CAPE (2) analogues 4 and 17 revealed their novel mechanism of action. The analogues showed no adverse cytotoxic effects on normal human cells and exhibited appropriate in silico pharmacokinetic properties and drug-likeness. These findings suggest the promising application of CAPE (2) analogues to target Ikaros (IKZF1)/IRF4 addiction, the so-called Achilles heel of myeloma, for better treatment outcomes.