Review on effects and mechanisms of plant-derived natural products against breast cancer bone metastasis

Abstract

Bone metastasis is the prevalent form of metastasis in breast cancer, resulting in severe pain, pathological fractures, nerve compression, hypercalcemia, and other complications that significantly impair patients' quality of life. The infiltration and colonization of breast cancer (BC) cells in bone tissue disrupt the delicate balance between osteoblasts and osteoclasts within the bone microenvironment, initiating a vicious cycle of bone metastasis. Once bone metastasis occurs, conventional medical therapy with bone-modifying agents is commonly used to alleviate bone-related complications and improve patients' quality of life. However, the utilization of bone-modifying agents may cause severe drug-related adverse effects. Plant-derived natural products such as terpenoids, alkaloids, coumarins, and phenols have anti-tumor, anti-inflammatory, and anti-angiogenic pharmacological properties with minimal side effects. Certain natural products that exhibit both anti-breast cancer and anti-bone metastasis effects are potential therapeutic agents for breast cancer bone metastasis (BCBM). This article reviewed the effects of plant-derived natural products against BCBM and their mechanisms to provide a reference for the research and development of drugs related to BCBM.

Keywords: Bone metastasis; Breast cancer; Mechanism; Natural products; Signaling pathway.

Fig. 1

The mechanism of breast cancer bone metastasis. EMT causes primary BC cells to acquire a mesenchymal phenotype with migratory and invasive capabilities; in response to cytokines, BC cells undergoing EMT intravasate into the blood vessels and become CTC cells; some of the CTC cells exude from the blood vessels and are transformed into DTC cells; DTC cells enter the bone microenvironment and ultimately colonize the bone through interactions with osteoblasts and osteoclasts. EMT, epithelial-to-mesenchymal transition; MMPs, matrix metalloproteinases; VEGFA, vascular endothelial growth factor A; PTHrP, parathyroid hormone-related peptide; RANKL, receptor activator of NF-κB ligand; TGF-β, transforming growth factor beta.

Fig. 2

The chemical construct of natural products with inhibitory effects on breast cancer bone metastasis.

Fig. 3

Natural products inhibit breast cancer bone metastasis by the RANKL/RANK, PI3K/AKT/mTOR, and TGF-β signaling pathway. AKT, protein kinase B; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa-B; PI3K, phosphoinositide 3-kinase; PTHrP, parathyroid hormone-related peptide; TAK1, transforming growth factor-beta-activated kinase 1; TGF-β, transforming growth factor beta; TRAF6, TNF receptor-associated factor 6.