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.

Acute myeloid leukemia (AML) is the most common type of leukemia in adults, accounting for 30% of all adult leukemia cases. While there have been recent improvements in the prognosis of the disease, the prognosis remains grim, and further understanding of AML and the development of new therapeutic agents is critical. This study aimed to investigate the potential interaction between colorectal cancer (CRC) cells and AML cells. Unexpectedly, we found that CRC cell-derived conditioned medium (CM) showed anticancer activities in AML cells by inducing apoptosis and differentiation. Mechanistic studies suggest that these phenotypes are closely associated with the suppression of PI3K/AKT/mTOR and MAPK survival signaling, the upregulation of myeloid differentiation-promoting transcription factors c/EBPα and PU.1, and the augmentation of executioner caspases-3/7. Importantly, bioinformatic analyses of our gene expression profiling data, including that derived from principal component analysis (PCA), volcano plots, boxplots, heat maps, kyoto encyclopedia of genes and genomes (KEGG) pathways, and receiver operating characteristic (ROC) curves, which evaluate gene expression profiling data, provided deeper insight into the mechanism in which CRC-CM broadly modulates apoptosis-, cell cycle arrest-, and differentiation-related gene expression, such as BMF, PLSCR3, CDKN1C, and ID2, among others, revealing the genes that exert anticancer effects in AML cells at the genomic level. Collectively, our data suggest that it may be worthwhile to isolate and identify the molecules with tumor-suppressive effects in the CM, which may help to improve the prognosis of patients with AML.

Patients with pediatric B-cell acute lymphoblastic leukemia (B-ALL) have a high survival rate, yet the prognosis of adults and patients with relapsed/refractory disease is relatively poor. Therefore, it is imperative to develop new therapeutic strategies. Here, we screened 100 plant extracts from South Korean Flora and investigated their anti-leukemic effect using CCRF-SB cells as a B-ALL model. The top cytotoxic extract identified in this screening was the Idesia polycarpa Maxim. branch (IMB), which efficiently inhibited the survival and proliferation of CCRF-SB cells, while having minimal to no impact on normal murine bone marrow cells. Mechanistically, the IMB-induced proapoptotic effect involves the increase of caspase 3/7 activity, which was shown to be associated with the disruption of the mitochondrial membrane potential (MMP) through the reduction in antiapoptotic Bcl-2 family expression. IMB also promoted the differentiation of CCRF-SB cells via the upregulation of the expression of differentiation-related genes, PAX5 and IKZF1. Given that resistance to glucocorticoid (GC) is often found in patients with relapsed/refractory ALL, we investigated whether IMB could restore GC sensitivity. IMB synergized GC to enhance apoptotic rate by increasing GC receptor expression and downmodulating mTOR and MAPK signals in CCRF-SB B-ALL cells. These results suggest that IMB has the potential to be a novel candidate for the treatment of B-ALL.