骨是乳腺癌每种主要亚型最喜欢的转移部位。缓解与骨转移相关的临床症状的治疗方式包括手术切除、放射和骨靶向治疗，包括双膦酸盐（例如唑来膦酸；ZA）和针对核因子-κB配体受体激活剂的人源化抗体（狄诺塞麦）。然而，骨靶向疗法价格昂贵，并且药代动力学特性差和/或严重的副作用。因此，需要新的策略来治疗骨转移或提高现有骨靶向治疗的有效性。我们之前已经证明异硫氰酸苄酯（BITC）是体外破骨细胞分化和体内骨转移的新型抑制剂。本研究表明，BITC  ZA 组合可协同抑制添加乳腺癌细胞条件培养基诱导的破骨细胞分化。这些作用与多种抗破骨细胞因子水平的显着增加有关，包括干扰素、白细胞介素 (IL)-3、IL-4 和 IL-27。京都基因和基因组百科全书对 BITC 和/或 ZA 处理的细胞的 RNA-seq 数据进行的通路分析显示，通过 BITC  ZA 组合处理，许多通路的基因（例如肌动蛋白细胞骨架、Hippo 信号传导等）下调，但不是单独由 BITC 或单独 ZA 提供。共聚焦显微镜证实，用 BITC  ZA 组合处理 MCF-7 和 MDA-MB-231 细胞后，肌动蛋白细胞骨架严重破坏。这种组合还降低了 yes 相关蛋白的核水平，yes 相关蛋白是 Hippo 信号传导的核心成分。总之，本研究提供了一种预防或治疗乳腺癌骨转移的新组合。© 2023 Wiley periodicals LLC。

Bone is the most favored site for metastasis for each major subtype of breast cancer. Therapeutic modalities for alleviation of clinical symptoms associated with bone metastasis include surgical resection, radiation, and bone-targeted therapies, including bisphosphonates (e.g., zoledronic acid; ZA) and a humanized antibody against receptor activator of nuclear factor-κB ligand (denosumab). However, the bone-targeted therapies are expensive, and have poor pharmacokinetic attributes and/or serious adverse effects. Therefore, novel strategies are needed for treatment of bone metastasis or to increase effectiveness of existing bone-targeted therapies. We have shown previously that benzyl isothiocyanate (BITC) is a novel inhibitor of osteoclast differentiation in vitro and bone metastasis in vivo. The present study shows that BITC + ZA combination synergistically inhibits osteoclast differentiation induced by addition of conditioned media from breast cancer cells. These effects were associated with a significant increase in levels of several antiosteoclastogenic cytokines, including interferons, interleukin (IL)-3, IL-4, and IL-27. Kyoto Encyclopedia of Genes and Genomes pathway analysis of RNA-seq data from BITC and/or ZA-treated cells revealed downregulation of genes of many pathways (e.g., actin cytoskeleton, Hippo signaling, etc.) by treatment with BITC + ZA combination, but not by BITC alone or ZA alone. Confocal microscopy confirmed severe disruption of actin cytoskeleton upon treatment of MCF-7 and MDA-MB-231 cells with the BITC + ZA combination. This combination also decreased the nuclear level of yes-associated protein, a core component of Hippo signaling. In conclusion, the present study offers a novel combination for prevention or treatment of bone metastasis of breast cancer.© 2023 Wiley Periodicals LLC.