An in vitro and in vivo investigation of the cytotoxic effects of caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester and bortezomib in multiple myeloma cells

Abstract

IntroductionMultiple myeloma (MM) is a hematologic cancer characterized by uncontrolled monoclonal plasma cell proliferation (1). MM is currently an incurable B-cell malignancy that accounts for nearly 10% of human hematopoietic cancers and 1% of all human cancers (2). Presently, the 2 most effective treatment choices for patients with MM are tandem high-dose chemotherapy followed by autologous stem cell infusion, or allogeneic hematopoietic stem cell transplantation after myeloablative therapy or reduced-intensity conditioning (1). The proteasome inhibitor bortezomib is a novel drug with promising efficacy, even for patients with relapsed refractory MM (3,4). Nevertheless, these choices are not appropriate in all patients, and drug resistance often increases over time. Consequently, there is a need for new treatment options that can augment the effectiveness of current treatments (5,6).Background/aim: In this study, the in vitro and in vivo effectiveness of caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE) in combination with bortezomib, a proteasome inhibitor, was explored in multiple myeloma (MM) cells. Materials and methods:The cytotoxic effects of CAPE and bortezomib were determined by XTT cell proliferation assay. Apoptosis levels were analyzed with annexin V-fluorescein isothiocyanate, nuclear factor kappa beta (NF-κB) was analyzed with electrophoretic mobility-shift assay, and interleukin (IL)-6 levels were analyzed with enzyme-linked immunosorbent assay to evaluate CAPE's mechanism of action. To investigate the in vivo effectiveness of CAPE and bortezomib, an experimental plasmacytoma model was induced in BALB/c mice.Results: Increasing concentrations of CAPE and bortezomib decreased the proliferation of ARH-77 cells in a dose-dependent manner. With doses of CAPE IC50, a significant increase in apoptosis and a significant decrease in IL-6 levels were detected. The NF-κB DNAbinding activity decreased compared to the basal ARH-77 level. The administration of CAPE alone or in combination with bortezomib increased the rate of survival compared to the control group. Conclusion:We think that our study, which is the first to demonstrate the in vitro and in vivo effectiveness of the combined use of CAPE and bortezomib, will be a pioneer for future human applications of CAPE in MM.

Supramolecular Caffeic Acid and Bortezomib Nanomedicine: Prodrug Inducing Reactive Oxygen Species and Inhibiting Cancer Cell Survival

“…We studied how NIH-3T3 fibroblast cells will react to the CAFeB nanomedicine and we found out that it created a slight cytotoxic effect, but due to the inherent lower levels of mitochondrial ROS on normal cells, oxidative stress did not reach apoptotic and necrotic threshold, thus exhibiting a lower cytotoxic effect compared with malignant cells (CT26) ( Figures S4-S6 of Supplementary Materials). Lastly, this study further validated the combinatory effects of CA and BTZ reported by Altayli et al [22], where comprehensive in vivo and in vitro studies were made using a multiple myeloma cell line. However, our nanoparticle formulation can improve the dosing and administration of both CA and BTZ by combining them into a single nanomedicine platform, potentially improving the pharmacokinetic behavior of both molecules once used in vivo.…”

“…BTZ is a synthetic anticancer drug that inhibits NF-κB by binding to the 26S proteasome of cancer cells with high affinity and specificity, thereby resulting in reduced protein degradation tagging and apoptosis [16][17][18][19]. BTZ can complement the use of caffeic acid by virtue of inhibition of the survival mechanism of the cell, while CA creates intracellular DNA and protein damage via the induction of reactive oxygen species (ROS) [20][21][22].…”

Synergistically Anti-Multiple Myeloma Effects: Flavonoid, Non-Flavonoid Polyphenols, and Bortezomib

“…It exerts anti-inflammatory, anti-atherosclerotic, and anti-tumor pharmacological effects [ 33 ]. In addition, caffeic acid, an active component of honeybee propolis, has cytotoxic, apoptosis, and anti-proliferation effects [ 34 ].…”

Polyphenols: Chemoprevention and therapeutic potentials in hematological malignancies

“…These include anti-inflammatory and antioxidative actions ( 81 , 82 ), antidiabetic ( 83 ), and hepatoprotective ( 84 ), and antineoplastic ( 85 , 86 ). Caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE) is reported cytotoxic and anti-proliferative actions on RPMI 8226, H929, U266 and ARH77 cell lines, and also synergises with bortezomib in growth inhibition and reduction of NF-kB binding activity and IL6 levels ( 87 ). In preclinical studies, caffeic acids and its analogues have also been reported to downregulate specificity protein 1 and IKZF1-IRF4-MYC axis in myeloma cells including cell lines resistant to immunomodulatory drugs lenalidomide and pomalidomide ( 88 ).…”