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

Abstract

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.

• Authors: Alli Murugesan, Grégoire Lassalle-Claux, Lauren Hogan, Elise Vaillancourt, Ayyoub Selka, Katie Luiker, Min Ji Kim, Mohamed Touaibia, Tony Reiman
• Journal: Journal of natural products (J Nat Prod) Vol. 83 Issue 12 Pg. 3526-3535 (12 24 2020) ISSN: 1520-6025 [Electronic] United States
• PMID: 33210536 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Caffeic Acids
• IKZF1 protein, human
• Interferon Regulatory Factors
• Sp1 Transcription Factor
• Sp1 protein, human
• interferon regulatory factor-4
• Ikaros Transcription Factor
• Lenalidomide
• caffeic acid phenethyl ester
• Phenylethyl Alcohol

Topics

• Angiogenesis Inhibitors (pharmacology)
• Apoptosis (drug effects)
• Caffeic Acids (chemistry, pharmacology)
• Cell Line, Tumor
• Down-Regulation
• Genes, myc
• Humans
• Ikaros Transcription Factor (metabolism)
• Interferon Regulatory Factors (metabolism)
• Lenalidomide (pharmacology)
• Multiple Myeloma (metabolism, pathology)
• Phenylethyl Alcohol (analogs & derivatives, chemistry, pharmacology)
• Sp1 Transcription Factor (metabolism)
• Structure-Activity Relationship