Wogonin induces mitochondrial apoptosis and synergizes with venetoclax in diffuse large B-cell lymphoma.

ABSTRACT

Diffuse large B-cell lymphoma (DLBCL) is among the most aggressive hematological malignancies and patients are commonly treated with combinatorial immunochemotherapies such as R-CHOP. Till now, the prognoses are still variable and unsatisfactory, depending on the molecular subtype and the treatment response. Developing effective and tolerable new agents is always urgently needed, and compounds from a natural source have gained increasing attentions. Wogonin is an active flavonoid extracted from the traditional Chinese herbal medicine Scutellaria baicalensis Georgi and has shown extensive antitumor potentials. However, the therapeutic effect of wogonin on DLBCL remains unknown. Here, we found that treatment with wogonin dose- and time-dependently reduced the viability in a panel of established DLBCL cell lines. The cytotoxicity of wogonin was mediated through apoptosis induction, along with the loss of mitochondrial membrane potential and the downregulation of BCL-2, MCL-1, and BCL-xL. In terms of the mechanism, wogonin inhibited the PI3K and MAPK pathways, as evidenced by the clear decline in the phosphorylation of AKT, GSK3ß, S6, ERK, and P38. Furthermore, the combination of wogonin and the BCL-2 inhibitor venetoclax elicited synergistically enhanced killing effect on DLBCL cells regardless of their molecular subtypes. Finally, administration of wogonin significantly impeded the progression of the DLBCL tumor in a xenograft animal model without obvious side effects. Taken together, the present study suggests a promising potential of wogonin in the treatment of DLBCL patients either as monotherapy or an adjuvant for venetoclax-based combinations.