Chamaejasmenin B, an Inhibitor for Metastatic Outgrowth, Reversed M2-Dominant Macrophage Polarization in Breast Tumor Microenvironment.

Metastasis is a multistep process that depends on the interactions between tumor cells and their microenvironment. Macrophages in the tumor microenvironment show high polarization plasticity and have a paradoxical role in cancer progression. Hijacked by tumor-promoting signals, the polarization status of macrophages was pathologically disturbed and believed to be the decisive mechanism forcing the progression of metastasis. In this study, we explored the immunological activity of Chamaejasmin B (ICJ), a previously proved inhibitor for metastasis, in macrophages from metastatic microenvironment. When intravenously injected of 4T1 cells in mice, ICJ significantly inhibited its metastatic outgrowth. Taking tumor cell and macrophage as a functional integrity, an adoptive transfer model was established in vitro to exclude the direct effect of ICJ on tumor. The findings suggest a dual influence of ICJ on both tumors and macrophages, as indicated by the rebalance of macrophage polarization and suppression of clonogenic potential in tumor cells. Mechanistically, ICJ redirected M2-dominant polarization of tumor-associated macrophage in an IL-4-mTOR-dependent manner. Collectively, our study revealed that ICJ rebalanced macrophage polarization in malignant microenvironment and showed promising effect in suppressing metastatic outgrowth in breast cancer model.

Chamaejasmin B Decreases Malignant Characteristics of Mouse Melanoma B16F0 and B16F10 Cells.

Chamaejasmin B (CHB), a natural biflavone isolated from Stellera chamaejasme L., has been reported to exhibit anti-cancer properties; however, its effect in melanoma cells is not clear. Here, we aimed to investigate the anticancer effect of CHB in mouse melanoma B16F0 and B16F10 cells. We found that CHB significantly suppressed cell proliferation and promoted cell cycle arrest at G0/G1 phase in B16F0 cells; it also induced cell differentiation and increased melanin content by increasing tyrosinase (TYR) activity and mRNA levels of melanogenesis-related genes in B16F0 cells. Meanwhile, wound closure, invasion, and migration of B16F0 and B16F10 cells were dramatically inhibited. Moreover, CHB significantly increased ROS levels and decreased ΔΨm, resulting in B16F0 and B16F10 cell apoptosis. Finally, in vivo studies showed that CHB inhibited tumor growth and induced tumor apoptosis in a mouse xenograft model of murine melanoma B16F0 and B16F10 cells. Overall, CHB decreases malignant characteristics and may be a promising therapeutic agent for malignant melanoma cells via multiple signaling pathways.

Chamaejasmin B exerts anti-MDR effect in vitro and in vivo via initiating mitochondria-dependant intrinsic apoptosis pathway.

Multidrug resistance (MDR) is the main obstacle limiting the efficacy of cancer chemotherapy. Looking for novel anti-MDR agents is an important way to conquer cancer drug resistance. We recently established that chamaejasmin B (CHB), a natural biflavone from Stellera chamaejasme L., is the major active component. However, its anti-MDR activity is still unknown. This study investigated the anti-MDR effect of CHB and the underlying mechanisms. First, it was found that CHB inhibited the growth of both sensitive and resistant cell lines in vitro, and the average resistant factor (RF) of CHB was only 1.26. Furthermore, CHB also displayed favorable anti-MDR activity in KB and KBV200 cancer cells xenograft mice. Subsequent study showed that CHB induced G0/G1 cell cycle arrest as well as apoptosis both in KB and in resistant KBV200 cancer cells. Further studies showed that CHB had no influence on the level of Fas/FasL and activation of procaspase 8. However, CHB-induced apoptosis was dependent on the activation of caspase 9 and caspase 3. Moreover, CHB treatment resulted in the elevation of the Bax/Bcl-2 ratio, attenuation of mitochondrial membrane potential (ΔΨm), and release of cytochrome c and apoptosis-inducing factor from mitochondria into cytoplasm both in KB and KBV200 cells. In conclusion, CHB exhibited good anti-MDR activity in vitro and in vivo, and the underlying mechanisms may be related to the activation of mitochondrial-dependant intrinsic apoptosis pathway. These findings provide a new leading compound for MDR therapy and supply a new evidence for the potential of CHB to be employed in clinical trial of MDR therapy in cancers.