1. Department of Hematology, the First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, People's Republic of China
2. Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, People's Republic of China
3. Department of Hematology, Hangzhou First people's hospital, Zhejiang, Hangzhou, China
4. The Children's Hospital Zhejiang University School of Medicine
Background: Apigenin, a flavonoid phytochemical extracted from fruits and vegetables, has shown anti-neoplastic effects in a variety of malignant tumors. DLBCL is the most common type of aggressive lymphoma in adults with a poor prognosis. Small-molecule inhibitors like BTK inhibitors have demonstrated extended period of disease control. Whereas the effects of the synergetic inhibition of the two have not been elucidated.
Methods: We assessed the efficacy of Apigenin alone or combined with Abivertinib to inhibit DLBCL progression. Cell viability was examined using the cell proliferation cell proliferation assay (MTS). Apoptotic cells and cell cycle evaluation were detected by Annexin V-FITC and DNA staining solution respectively. Western blot was used to explore the potential mechanism, and the in vivo effects of the two drugs were performed by a DLBCL xenograft BALB/c nude mice model.
Results: Our results demonstrated that Apigenin can inhibit the proliferation and clone forming of DLBCL cells. Apigenin also induces apoptosis by down-regulating BCL-XL and activating Caspase family. In addition, Apigenin down-regulates cell cycle proteins including CDK2/CDK4/CDK6/CDC2/p-RB to increase G2/M phase arrest. Mechanically, our data demonstrate that Apigenin leads to a significant reduction of the expression of pro-proliferative pathway PI3K/mTOR to inhibit DLBCL cells survival. Moreover, our in vitro and in vivo results show that Apigenin can synergize with Abivertinib, a novel BTK inhibitor, in treating DLBCL visa synergistically inducing apoptosis and inhibiting the p-GS3K-β and its downstream targets.
Conclusions: Collectively, our study suggests that Apigenin exerts improving anti-lymphoma effect of BTK inhibitors and provides hope to targeted therapy of those develop resistance.