Synthesis, structural characterization, and inhibitory effects of caffeic acid phenethyl ester (CAPE) derivatives on human multiple myeloma cell growth

Location

Suwanee, GA

Start Date

6-5-2025 1:00 PM

End Date

6-5-2025 4:00 PM

Description

INTRODUCTION: Multiple Myeloma (MM) is a hematologic cancer that develops due to the proliferation of malignant plasma cells in bone marrow. The accumulation of MM cells leads to a variety of complications such as anemia, bone disease, and renal damage. Despite advancements in technology and improvements in chemotherapy and stem cell transplantation, MM remains challenging to treat due to its drug resistance and the associated side effects, leading researchers to explore naturally derived compounds as adjuvant with current treatments. Caffeic acid phenethyl ester (CAPE), found in honeybee propolis, has demonstrated various pharmacological properties including anti-cancer effects. Previous studies have reported that CAPE and its derivatives inhibit the growth of MM cells through the induction of apoptosis and oxidative stress. This study investigates the inhibitory effects, mechanisms of action, and structural modifications associated with CAPE Derivatives in MM cell growth.

METHODS: Five new CAPE derivatives were synthesized and characterized. RPMI 8226 (MM) cells were treated with CAPE and these derivatives to evaluate their cytotoxic effects using presto blue assay. Cytotoxic activity of CAPE and its derivatives in the presence of ferroptosis inducer and inhibitor, Erastin and Ferrostatin-1, were also determined to investigate the involvement of ferroptosis. Western blot analysis of RPMI 8226 cell lysates was used to examine the expression of the apoptotic marker, caspase 3, and ferroptosis markers, GPX4 and CHAC1. The structural modification of each CAPE derivative was assessed to identify which modification yields a greater or lesser inhibitory effect on MM cell growth.

RESULTS: CAPE derivatives were evaluated for their effects on RPMI 8226 cell viability, which decreased in a time- and dose-dependent manner. Western blot analysis showed that while CAPE induces apoptosis, it is not the only mechanism of cell death for CAPE derivatives, prompting further investigation into their potential link to ferroptosis. When combined with the ferroptosis inducer, Erastin, a significant reduction in cell viability was observed. In contrast, no significant effect occurred with the ferroptosis inhibitor, Ferrostatin-1. Additionally, Western blot analysis showed a notable decrease in GPX4 expression and increased CHAC1 expression when combined with Erastin. The opposite results were seen when the derivatives were combined with Ferrostatin-1, with an increase in GPX4 expression and a decrease in CHAC1 expression.

DISCUSSION: The results from the experiment confirmed the inhibitory effects of CAPE derivatives on MM RPMI 8226 cells, consistent with findings from previous studies. Ferroptosis induction may serve as the main mechanism behind the inhibitory effects of CAPE derivatives compared to apoptosis induction. The structure-activity relationship of CAPE and its derivatives reveals that replacing the ester group with an amide result in a stronger cell death response, as seen in two derivatives compared to CAPE. These data highlight how structural modifications can either preserve or diminish CAPE's effects, emphasizing the critical role of structural changes in modulating its activity.

Embargo Period

5-19-2025

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May 6th, 1:00 PM May 6th, 4:00 PM

Synthesis, structural characterization, and inhibitory effects of caffeic acid phenethyl ester (CAPE) derivatives on human multiple myeloma cell growth

Suwanee, GA

INTRODUCTION: Multiple Myeloma (MM) is a hematologic cancer that develops due to the proliferation of malignant plasma cells in bone marrow. The accumulation of MM cells leads to a variety of complications such as anemia, bone disease, and renal damage. Despite advancements in technology and improvements in chemotherapy and stem cell transplantation, MM remains challenging to treat due to its drug resistance and the associated side effects, leading researchers to explore naturally derived compounds as adjuvant with current treatments. Caffeic acid phenethyl ester (CAPE), found in honeybee propolis, has demonstrated various pharmacological properties including anti-cancer effects. Previous studies have reported that CAPE and its derivatives inhibit the growth of MM cells through the induction of apoptosis and oxidative stress. This study investigates the inhibitory effects, mechanisms of action, and structural modifications associated with CAPE Derivatives in MM cell growth.

METHODS: Five new CAPE derivatives were synthesized and characterized. RPMI 8226 (MM) cells were treated with CAPE and these derivatives to evaluate their cytotoxic effects using presto blue assay. Cytotoxic activity of CAPE and its derivatives in the presence of ferroptosis inducer and inhibitor, Erastin and Ferrostatin-1, were also determined to investigate the involvement of ferroptosis. Western blot analysis of RPMI 8226 cell lysates was used to examine the expression of the apoptotic marker, caspase 3, and ferroptosis markers, GPX4 and CHAC1. The structural modification of each CAPE derivative was assessed to identify which modification yields a greater or lesser inhibitory effect on MM cell growth.

RESULTS: CAPE derivatives were evaluated for their effects on RPMI 8226 cell viability, which decreased in a time- and dose-dependent manner. Western blot analysis showed that while CAPE induces apoptosis, it is not the only mechanism of cell death for CAPE derivatives, prompting further investigation into their potential link to ferroptosis. When combined with the ferroptosis inducer, Erastin, a significant reduction in cell viability was observed. In contrast, no significant effect occurred with the ferroptosis inhibitor, Ferrostatin-1. Additionally, Western blot analysis showed a notable decrease in GPX4 expression and increased CHAC1 expression when combined with Erastin. The opposite results were seen when the derivatives were combined with Ferrostatin-1, with an increase in GPX4 expression and a decrease in CHAC1 expression.

DISCUSSION: The results from the experiment confirmed the inhibitory effects of CAPE derivatives on MM RPMI 8226 cells, consistent with findings from previous studies. Ferroptosis induction may serve as the main mechanism behind the inhibitory effects of CAPE derivatives compared to apoptosis induction. The structure-activity relationship of CAPE and its derivatives reveals that replacing the ester group with an amide result in a stronger cell death response, as seen in two derivatives compared to CAPE. These data highlight how structural modifications can either preserve or diminish CAPE's effects, emphasizing the critical role of structural changes in modulating its activity.