Dataset Information

Apigenin and Abivertinib, a novel BTK inhibitor synergize to inhibit diffuse large B-cell lymphoma in vivo and vitro.

ABSTRACT: 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-? 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.

SUBMITTER: Huang S

PROVIDER: S-EPMC7052937 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Activated B-cell-like diffuse large B-cell lymphoma relies on B-cell receptor signaling to drive proliferation and survival. Downstream of the B-cell receptor, the key signaling kinases Bruton's tyrosine kinase and phosphoinositide 3-kinase δ offer opportunities for therapeutic intervention by agents such as ibrutinib, ONO/GS-4059, and idelalisib. Combination therapy with such targeted agents could provide enhanced efficacy due to complimentary mechanisms of action. In this study, we describe both the additive interaction of and resistance mechanisms to idelalisib and ONO/GS-4059 in a model of activated B-cell-like diffuse large B-cell lymphoma. Significant tumor regression was observed with a combination of PI3Kδ and Bruton's tyrosine kinase inhibitors in the mouse TMD8 xenograft. Acquired resistance to idelalisib in the TMD8 cell line occurred by loss of phosphatase and tensin homolog and phosphoinositide 3-kinase pathway upregulation, but not by mutation of PIK3CD. Sensitivity to idelalisib could be restored by combining idelalisib and ONO/GS-4059. Further evaluation of targeted inhibitors revealed that the combination of idelalisib and the phosphoinositide-dependent kinase-1 inhibitor GSK2334470 or the AKT inhibitor MK-2206 could partially overcome resistance. Characterization of acquired Bruton's tyrosine kinase inhibitor resistance revealed a novel tumor necrosis factor alpha induced protein 3 mutation (TNFAIP3 Q143*), which led to a loss of A20 protein, and increased p-IκBα. The combination of idelalisib and ONO/GS-4059 partially restored sensitivity in this resistant line. Additionally, a mutation in Bruton's tyrosine kinase at C481F was identified as a mechanism of resistance. The combination activity observed with idelalisib and ONO/GS-4059, taken together with the ability to overcome resistance, could lead to a new therapeutic option in activated B-cell-like diffuse large B-cell lymphoma. A clinical trial is currently underway to evaluate the combination of idelalisib and ONO/GS-4059 (NCT02457598).

Dataset Information

Apigenin and Abivertinib, a novel BTK inhibitor synergize to inhibit diffuse large B-cell lymphoma in vivo and vitro.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets