Diosmetin

Wenshen Zhuanggu Formula (WSZG) is an effective traditional Chinese medicine prescription for adjuvantly treating breast cancer (BC) bone metastasis. Four flavonoids (diosmetin, bavachin, corylifolinin and corylin) in WSZG are considered as the main bioactive compounds of preventing bone loss and protecting bone structure. This study aims to develop a sensitive LC-MS/MS method for simultaneous determination of four flavonoids from WSZG in mouse blood and further compare the pharmacokinetic differences between normal and BC mice. A primary BC mouse model was established to explore the bone-protective efficacy of WSZG. The LC-MS/MS method was successfully validated and applied to the pharmacokinetic study of four flavonoids in normal and BC mice after oral administration of WSZG extract at 1.6 g/kg/d dose for 28 days, respectively. There were obvious differences in pharmacokinetic characteristics of four flavonoids between normal and BC states. Compared with normal mice, diosmetin, bavachin, corylifolinin and corylin exhibited more rapid absorption and higher blood exposure with shorter T_max, larger C_max and AUC values in tumor-bearing mice (P < 0.05 or P < 0.01). Besides, bavachin in blood was more slowly eliminated in BC mice than normal mice due to longer T_1/2 and MRT_0-t, while diosmetin showed a opposite result (P < 0.05 or P < 0.01). The discrepancy of these pharmacokinetic behaviors might be attributed to enhanced intestinal permeability and considerable alteration of CYP levels, activities and genotypes endowed by BC states. The results serve to unveil supportive data for clinical application of WSZG in early BC.

Despite the well-established therapeutic benefits of BRAF inhibitors in prolonging progression-free survival (PFS) for melanoma patients with BRAF mutants, their long-term efficacy is often compromised by the emergence of acquired resistance, particularly through compensatory activation of Janus kinase 2/Signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway. Confronting this challenge, concurrent inhibition of Mitogen-activated protein kinase (MAPK) and JAK2/STAT3 pathways offers a novel approach to overcome therapeutic resistance. Diosmetin (DIOS), a naturally occurring flavonoid compound, has a spectrum of bioactivities including antioxidant, anti-infective, and anti-tumor properties. In this study, we explored the antitumor effects of DIOS and evaluated its synergistic potential with BRAF inhibitors in melanoma treatment. Through comprehensive in vitro and in vivo analyses, we demonstrated that DIOS possessed potent antiproliferative effects against melanoma cells and significantly enhanced the antitumor activity of BRAF inhibitors by concurrently suppressing the MAPK and STAT3 pathways. Moreover, DIOS downregulated programmed cell death ligand 1 (PD-L1) expression in melanoma cells, thereby enhancing intratumoral T cell infiltration and activating antitumor immune responses. Collectively, our findings identify DIOS as a multifaceted therapeutic agent with dual-pathway inhibitory activity and immunomodulatory effects, supporting its potential as a clinically translatable adjuvant to BRAF-targeted therapies in BRAF-mutant melanoma.