Abstract
Aralia continentalis has been used in Korea as a folk remedy for arthralgia, rheumatism, and inflammation. However, its anti-lymphoma effect remains uncharacterized. Here, we demonstrate that A. continentalis extract and its three diterpenes efficiently kill B-lymphoma cells. Our in vitro and in vivo results suggest that the cytotoxic activities of continentalic acid, a major diterpene from A. continentalis extract, are specific towards cancer cells while leaving normal murine cells and tissues unharmed. Mechanistically, continentalic acid represses the expression of pro-survival Bcl-2 family members, such as Mcl-1 and Bcl-xL. It dissociates the mitochondrial membrane potential, leading to the stimulation of effector caspase 3/7 activities and, ultimately, cell death. Intriguingly, this agent therapeutically synergizes with roflumilast, a pan-PDE4 inhibitor that has been successfully repurposed for the treatment of aggressive B-cell malignancies in recent clinical tests. Our findings unveiled that A. continentalis extract and three of the plant’s diterpenes exhibit anti-cancer activities. We also demonstrate the synergistic inhibitory effect of continentalic acid on the survival of B-lymphoma cells when combined with roflumilast. Taken in conjunction, continentalic acid may hold significant potential for the treatment of B-cell lymphoma.
Highlights
A previous study has shown that HepG2, a liver hepatocellular carcinoma cell line, can be killed by continentalic acid, and our results indicate that this agent has minimal or no effect on normal liver cells/tissues, which suggests that continentalic acid can induce apoptosis in liver cancer cells, leaving normal liver cells/tissues unharmed
Our study shows that continentalic acid, a diterpene from A. continentalis extracts, induces apoptosis via inhibition of pro-survival Bcl-2 family members, especially Mcl1 and Bcl-xL
The agent reduced the expression of anti-apoptotic Bcl-2 family members, disrupted membrane potential (MMP), and stimulated effector caspase 3/7 activities, which leads to apoptosis
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Lymphoma is a blood cancer that develops from B lymphocytes, T lymphocytes, and natural killer cells. It is categorized into Hodgkin’s lymphoma (HL) (10% of cases) and non-Hodgkin’s lymphoma (NHL) (90% of cases).
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