The kava chalcone flavokawain B exerts inhibitory activity and synergizes with BCL-2 inhibition in malignant B-cell lymphoma

  • Phytomedicine. 2023 Nov:120:155074. doi: 10.1016/j.phymed.2023.155074.
Mengting Zhao  1 ,  Xia Jiang  1 ,  Jingwen Fang  2 ,  Ye Lin  2 ,  Youhong Li  1 ,  Renzhi Pei  3 ,  Peipei Ye  3 ,  Ying Lu  3 ,  Lei Jiang  4
Affiliations
  • 1. Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, China; Department of Pathology and Pathogenic Biology, and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, China.
  • 2. Department of Pathology and Pathogenic Biology, and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, China.
  • 3. Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, China.
  • 4. Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, China; Department of Pathology and Pathogenic Biology, and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, China. Electronic address: [email protected].
PMID: 37716033 DOI: 10.1016/j.phymed.2023.155074
Abstract

Background: B-cell lymphoma, which originates from B cells at diverse differentiation stages, is the most common non-Hodgkin lymphoma with tremendous treatment challenges and unsatisfactory clinical outcomes. Flavokawain B (FKB), a naturally occurring chalcone extracted from kava, possesses promising Anticancer properties. However, evidence on the effects of FKB on hematological malignancies, particularly lymphomas, remains scarce.

Purpose: This study aimed to investigate the antilymphoma effect of FKB and its underlying mechanisms.

Study design/methods: Proliferation assays, flow cytometry, and western blotting were employed to determine whether and how FKB affected B-cell lymphoma cell lines in vitro. Xenograft mouse models were established to evaluate the antilymphoma efficacy of FKB in vivo.

Results: FKB reduced the viability of a panel of B-cell lymphoma cell lines in a dose- and time-dependent manner. Mitochondrial Apoptosis was markedly induced by FKB, as evidenced by an increased percentage of annexin V-positive cells, a loss of mitochondrial membrane potential, and cleavage of Caspase-3 and PARP. Moreover, FKB inhibited Bcl-xL expression and synergized with the Bcl-2 Inhibitor ABT-199. Mechanistically, FKB treatment decreased the phosphorylation of Akt, mammalian target of rapamycin (mTOR), glycogen synthase kinase-3β (GSK3β), and ribosomal protein S6 (RPS6). Pharmacological blockage of phosphoinositide 3-kinase (PI3K), Akt, or GSK3β potentiated the activity of FKB, indicating the involvement of the PI3K/Akt cascade in FKB-mediated inhibitory effects. In mouse xenograft models, the intraperitoneal administration of FKB significantly decreased lymphoma growth, accompanied by diminished Mitosis and Ki-67 staining of tumor tissues.

Conclusion: Our data demonstrate the robust therapeutic potential of FKB in the treatment of B-cell lymphoma.

Keywords
ABT-199; Apoptosis; B-cell lymphoma; Flavokawain B.
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