Potent CAPE analogs as novel treatment for multiple myeloma

Lauren Hogan (a), Katie Luiker (a), Dr. Mohamed Touaibia (b), Dr. Anthony Reiman (a,c), and Dr. Alli Murugesan (a,c)
(a) Department of Biology, University of New Brunswick
(b) Department of Chemistry and Biochemistry, Université de Moncton
(c) Faculty of Medicine, Dalhousie Medicine New Brunswick

Multiple myeloma is an incurable bone marrow cancer and is the second most common hematological malignancy. Existing therapies yield adverse side effects and many patients display resistance to traditional treatments, which emphasizes the need for developing novel therapeutics for this disease. Caffeic Acid Phenethyl Ester (CAPE), one of the main active components extracted from the propolis of honeybee hives, has been shown to act as a potent NF-kB inhibitor. Since the key transcription factor, interferon regulatory factor 4  (IRF4) involved in myeloma pathobiology is regulated by NF-kB, our study aimed to investigate the anti-myeloma potential of CAPE analogs in vitro using human myeloma cell lines. Structural analogs of CAPE were synthesized and screened for anti-myeloma potential. Myeloma cell lines were treated with varying concentrations of the CAPE analogs. Cell growth inhibition was measured using Prestoblue cell viability assays and half-maximal inhibitory concentration (IC50) was determined. We found the potent CAPE analogs by comparing them with the effect of immunomodulatory drugs (IMiDs) such as Lenalidomide and Pomalidomide, which are widely used to treat myeloma. We have identified two phenpropyl ester analogs that demonstrated significantly higher cell growth inhibition than CAPE and IMiDs. We have investigated the mechanism of action of these potent analogs in our laboratory and revealed the downregulation of several cereblon pathway proteins including IRF4. These findings suggest that potent CAPE analogs have the potential to provide an improved treatment strategy for myeloma.