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

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-3ß (GSK3ß), and ribosomal protein S6 (RPS6). Pharmacological blockage of phosphoinositide 3-kinase (PI3K), Akt, or GSK3ß 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.

Platycodin D induces apoptotic cell death through PI3K/AKT and MAPK/ERK pathways and synergizes with venetoclax in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a highly heterogeneous and rapidly progressive hematopoietic neoplasm characterized by frequent relapses and variable prognoses. The development of new treatment options, therefore, is of crucial importance. Platycodin D (PD) is a triterpenoid saponin, extracted from the roots of the traditional Chinese herbal medicine Platycodon grandiflorum (Jacq.) A. DC., which has been reported to exhibit therapeutic potential against a broad range of cancers. Although the effects of PD on AML remain unclear, in the present study, we observed a concentration-dependent reduction in the viability of multiple human AML cell lines in response to treatment with PD. In addition to triggering mitochondria-dependent apoptosis via the upregulation of BAK and BIM, treatment with PD also induced cell cycle arrest at the G0/G1 phase. Western blot analyses revealed marked suppression of the phosphorylation of protein kinase B (AKT), glycogen synthase kinase-3ß, ribosomal protein S6, and extracellular signal-regulated kinase (ERK) by PD, in turn implying the participation of the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK)/ERK pathways. Pre-incubation with LY294002, MK2206, AR-A014418, or U0126 was consistently found to significantly aggravate PD-induced inhibition of viability. Additionally, PD combined with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax elicited synergistically enhanced cytotoxic effects. The anti-leukemic activity of PD was further validated using primary samples from de novo AML patients. Given the results of the present study, PD may be a potent therapeutic candidate for the treatment of AML.

Influence of the hypothalamus-pituitary-gonadal axis reactivation and corresponding surging sex hormones on the amplitude of low-frequency oscillations in early pubertal girls: A resting state fMRI study.

BACKGROUND: There has been a myriad of neuroimaging studies that have suggested that pubertal stages and sex steroid fluctuations contribute to pubertal brain maturation. Investigations on the influence of hypothalamus-pituitary-gonadal (HPG) axis reactivation and the correlated elevated sex hormones on brain maturation have not unraveled these interactions to date. Here, we aimed to explore the impact of the reactivated HPG axis on spontaneous brain activity changes, by analyzing the amplitude of low-frequency fluctuation (ALFF) in developing girls aged 8-11 years old. METHODS: The gonadotropin-releasing hormone (GnRH) stimulation test was used to determine the HPG axis status and categorize subjects into two groups (HPG+ or HPG- group). Intelligence quotient (IQ) and the parent-rated Child Behavior Checklist (CBCL) were used to evaluate cognitive and behavioral performance. Two-sample t-tests were used to compare intergroup differences, the relations between brain areas' activities, age and hormonal levels were conducted by Pearson or Spearman correlation analyses. RESULTS: Compared with the HPG- group, the HPG+ group showed decreased ALFF values in the left superior temporal gyrus (STG) but increased ALFF values in the right superior frontal gyrus (SFG). In addition, in the HPG+ group, prolactin (PRL) levels were positively correlated with ALFF values in the right SFG, and there was significant negative correlation between ALFF values in the left STG and CBCL activities scores. LIMITATIONS: Due to the cross-sectional design of the present study, further study is needed to determine the relationships between age, reawakening of the HPG axis and related sex hormones and spontaneous brain activity change. CONCLUSIONS: These findings suggested that the reactivated HPG axis and elevated PRL level could affect changes in brain activity and this effect may be the neuroendocrine basis of mood, cognition, and social behavior changes in early pubertal girls.