A Novel Bromophenol Compound from Leathesia nana Inhibits Breast Cancer in a Direct Tumor Killing and Immunotherapy Manner

Abstract

Considering the resistance and toxicity of traditional chemotherapeutic drugs, seeking potential candidate for treating breast cancer effectively is a clinical problem that should be solved urgently. Natural products have attracted extensive attention, owing to their multi-target advantages and low toxicity. In the current study, the effects of XK-81, a novel bromophenol compound extracted from Leathesia nana, on breast cancer, and its underlying mechanisms, were explored. Firstly, data from in vitro experiments indicated that 4T-1, one of common mouse breast cancer cell lines, was a XK-81-susceptible cell line, and ferroptosis was the major death manner in response to XK-81 treatment, which was evidenced by increasing intracellular Fe2+ and ROS level with condensed mitochondrial membrane densities, as well as decreasing the protein expressions of SLC7A11 and GPX4. In vivo, XK-81 suppressed the growth of 4T-1 breast-tumor in both BALB/C mice and zebrafish. Obviously, XK-81 decreased the protein expression of SLC7A11 and GPX4 in tumor tissues, hinting at the occurrence of ferroptosis. Moreover, XK-81 increased CD8+ T cells and NK cells numbers and regulated M1/M2 macrophage ratio in tumor tissues, indicating XK-81’s immunotherapeutic effect. Additionally, the secretions of immune-related cytokines, including TNF-α, IL-1β, and IL-12, were elevated with XK-81 stimulation in RAW 264.7 cells. Intriguingly, compared with doxorubicin-induced heart damage, XK-81 demonstrated the therapeutic advantage of little cardiotoxicity on the heart. XK-81 demonstrated potential antitumor advantage by both directly inducing ferroptosis-mediated death of tumor cells and immunization.

Ferroptosis: a new mechanism of traditional Chinese medicine for cancer treatment

“…Another study showed that XK-81, a metabolite of Leathesia nana (Chordariaceae), decreased SLC7A11 and GPX4 expression and induced ferroptosis in tumor tissues. Moreover, XK-81 improves the function of CD8 + T cells and NK cells while simultaneously increasing the ratio of M1/M2 macrophages ( Sun et al, 2023 ). Albiziabioside A (AlbA), an oleanane triterpenoid saponin, was extracted from the aerial parts of Albizia inundata (Mart.)…”

Natural products as promising modulators of breast cancer immunotherapy

“…It elevated the number of CD8+ T cells and NKs and modulated the ratio of M1/M2 macrophage in tumor tissues. This was combined with an elevation of immune-related cytokines, including IL-12, TNF-α, and IL-1β in a macrophage cell line ( 35 ).…”