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

Mengting Zhao; Xia Jiang; Jingwen Fang; Ye Lin; Youhong Li; Renzhi Pei; Peipei Ye; Ying Lu; Lei Jiang

doi:10.1016/j.phymed.2023.155074

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. Epub 2023 Sep 7.

Authors

Mengting Zhao¹, Xia Jiang¹, Jingwen Fang², Ye Lin², Youhong Li¹, Renzhi Pei³, Peipei Ye³, Ying Lu³, Lei Jiang⁴

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: jianglei@nbu.edu.cn.

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.

MeSH terms

Animals
Chalcones* / pharmacology
Glycogen Synthase Kinase 3 beta
Humans
Kava*
Lymphoma, B-Cell* / drug therapy
Mammals
Mice
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt

Substances

flavokawain B
Chalcones
Glycogen Synthase Kinase 3 beta
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt