Tanshinone-IIA-Based Analogues of Imidazole Alkaloid Act as Potent Inhibitors To Block Breast Cancer Invasion and Metastasis in Vivo

Abstract

Tanshinone-IIA (Tan-IIA), a primary active component extracted from commonly used Chinese herbal, Salvia miltiorrhiza (Danshen), is considered as a potential inhibitor against tumor cell proliferation. However, the potential application of Tan-IIA is hindered by its poor water solubility and low bioavailability. In this work, an imidazole moiety was linked to the skeleton of Tan-IIA to enhance its antitumor activity. A series of Tan-IIA-based analogues TA01–TA12 were synthesized, and their inhibitory activities against the migration and invasion of MDA-MB-231 cells were investigated. All compounds, particularly TA12, markedly inhibited the proliferation, migration, and invasion of MDA-MB-231cells. TA12 also prominently blocked cancer cell metastasis in blood vessels and surrounding tissues in zebrafish xenograft model. Further studies showed that the mechanisms may involve S-phase arrest pathway, which was probably caused by inducing reactive oxygen species production and activating DNA damage. These results indicated that the Tan-IIA-based analogues of imidazole derivates can act as potent antimetastasis agents.

Danshen Improves Survival of Patients With Breast Cancer and Dihydroisotanshinone I Induces Ferroptosis and Apoptosis of Breast Cancer Cells

“…Of the tanshinone family, previous studies have demonstrated that tanshinone IIA could induce apoptosis in both ER-positive and ER-negative breast cancers (Wang et al, 2005; Su and Lin, 2008; Su et al, 2012; Yan et al, 2012; Lin et al, 2013; Fu et al, 2014; Li et al, 2015; Li and Lai, 2017; Lin et al, 2018; Lv et al, 2018; Wu et al, 2018). Tanshinone I also exerts a similar anti-breast cancer effect through apoptosis (Nizamutdinova et al, 2008a; Nizamutdinova et al, 2008b; Gong et al, 2012; Wang et al, 2015).…”

“…These data suggested that danshen may have a clinical protective effect for patients with both ER-positive and ER-negative breast cancer owing to the constituent abietane diterpenes. Moreover, some studies have demonstrated that, in combination with tanshinone IIA, danshen could enhance the chemosensitivity of breast cancer cells to chemotherapy and even overcome drug-resistant cancer (Li and Lai, 2017; Lin et al, 2018; Lv et al, 2018; Wu et al, 2018). Further research to investigate the clinical protective effect of danshen combined with other breast cancer medication is necessary.…”

Clinical significance of high expression of stanniocalcin-2 in hepatocellular carcinoma

“…At the same time, the abnormal expression of tumor related genes, abnormal activation of cell signal transduction, cell proliferation cycle, and cell proliferation cycle were also involved in many aspects [15][16][17]. Cell growth and proliferation in human body are affected and controlled by many factors [18,19]. In particular, cell signaling proteins, growth factors and their receptors, apoptotic proteins and transcription factors, etc, and the changes of these factors are closely related to the occurrence and development of tumor [20,21].…”

Synthesis and Evaluation of the Antitumor Activity of Novel 1-(4-Substituted phenyl)-2-ethyl Imidazole Apoptosis Inducers In Vitro

“…Nutlins-1, which has imidazole as a pharmacophore, displaces recombinant p53 protein from its complex with MDM2 and selectively inhibits MDM2-p53 interaction both in vitro and in vivo [ 15 ]. The antitumor potency of Tanshinone-IIA has been enhanced by the introduction of an imidazole moiety ( Figure 1 , TA12) in order to block cancer cell invasion and metastasis in vivo [ 16 ]. N -phenylimidazole (NMIB) possesses outstanding cytotoxic activity [ 17 ].…”