Dihydrotanshinone I Inhibits the Lung Metastasis of Breast Cancer by Suppressing Neutrophil Extracellular Traps Formation

Abstract

Breast cancer (BC) is a common female malignancy, worldwide. BC death is predominantly caused by lung metastasis. According to previous studies, Dihydrotanshinone I (DHT), a bioactive compound in Salvia miltiorrhiza Bunge (S. miltiorrhiza), has inhibitory effects on numerous cancers. Here, we investigated the anti-metastatic effect of DHT on BC, where DHT more strongly inhibited the growth of BC cells (MDA-MB-231, 4T1, MCF-7, and SKBR-3) than breast epithelial cells (MCF-10a). Additionally, DHT repressed the wound healing, invasion, and migration activities of 4T1 cells. In the 4T1 spontaneous metastasis model, DHT (20 mg/kg) blocked metastasis progression and distribution in the lung tissue by 74.9%. DHT reversed the formation of neutrophil extracellular traps (NETs) induced by phorbol 12-myristate 13-acetate, as well as ameliorated NETs-induced metastasis. Furthermore, it inhibited Ly6G+Mpo+ neutrophils infiltration and H3Cit expression in the lung tissues. RNA sequencing, western blot, and bioinformatical analysis indicated that TIMP1 could modulate DHT acting on lung metastasis inhibition. The study demonstrated a novel suppression mechanism of DHT on NETs formation to inhibit BC metastasis.

Neutrophil extracellular traps in tumor progression and immunotherapy

“…Moreover, metastasis is a multistep process, including the detachment of cancer cells from the primary tumor, the dissemination of tumor cells to surrounding tissues and distant organs ( 96 ). There is also evidence that NETs result in the metastasis cascade of animal and human tumors ( 97 , 98 ). Epithelial−mesenchymal transition (EMT) is critical for tumor cells to physically disseminate from the primary site, which is the first step in distant metastasis ( 99 ).…”

NETosis: Sculpting tumor metastasis and immunotherapy

“…51 Dihydrotanshinone I (DHT) is an acknowledged bioactive compound from Salvia miltiorrhiza Bunge (S. miltiorrhiza), which enables to prevent pulmonary metastasis of breast cancer via downregulating NET generation. 52…”

“…Epigallocatechin‐3‐gallate (EGCG) is one of the major active components of Tea catechins, which enables to prevent the formation of NETs as well as aggressiveness of colon cancer cells through downregulating signal transducer and activator of transcription 3 (STAT3)/CXCL8 machinery 51 . Dihydrotanshinone I (DHT) is an acknowledged bioactive compound from Salvia miltiorrhiza Bunge (S. miltiorrhiza), which enables to prevent pulmonary metastasis of breast cancer via downregulating NET generation 52 …”

GSK484, an inhibitor of peptidyl arginine deiminase 4, increases the radiosensitivity of colorectal cancer and inhibits neutrophil extracellular traps

“…In the context of tumorigenesis, NETs facilitate cancer metastasis by forming circulating tumor cell clusters, enhancing tumor cell adhesion to the endothelium and potentially increasing tumor cell extravasation 8,9 . Citrullinated histone H3 (H3Cit) is a central player in NET formation 10,11 . NETs have been reported to be involved in CRC development and metastasis 12,13 …”

“…8,9 Citrullinated histone H3 (H3Cit) is a central player in NET formation. 10,11 NETs have been reported to be involved in CRC development and metastasis. 12,13 Peptidyl arginine deiminase (PAD) enzymes are widely distributed in mammals and are closely related to cell development and differentiation.…”