Abstract
Taspine, isolated from Radix et Rhizoma Leonticis has demosntrated potential proctiective effects against cancer. Tas13D, a novel taspine derivative synthetized by structure-based drug design, have been shown to possess interesting biological and pharmacological activities. The current study was designed to evaluate its antiproliferative activity and underlying mechanisms. Antiproliferative activity of tas13D was evaluated by xenograft in athymic mice in vivo, and by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and cell migration assays with human liver cancer (SMMC-7721) cell lines in vitro. Docking between tas13D and VEGFR and EGFR was studied by with a Sybyl/Surflex module. VEGF and EGF and their receptor expression was determined by ELISA and real-time PCR methods, respectively. Our present study showed that tas13D inhibited SMMC-7721 xenograft tumor growth, bound tightly with the active site of kinase domains of EGFR and VEGFR, and reduced SMMC-7721 cell proliferation (IC=34.7 μmol/L) and migration compared to negative controls. VEGF and EGF mRNAs were significantly reduced by tas13D treatment in a dose-dependent manner, along with VEGF and EGF production. The obtained results suggest that tas13D inhibits tumor growth and cell proliferation by inhibiting cell migration, downregulating mRNA expression of VEGF and EGF, and decreasing angiogenic factor production. Tas13D deserves further consideration as a chemotherapeutic agent.
Highlights
Radix et Rhizoma Leonticis (Hong Mao Qi in Chinese, HMQ) is distributed mainly in Shaanxi and Sichuan provinces of China
Our present study showed that tas13D inhibited SMMC-7721 xenograft tumor growth, bound tightly with the active site of kinase domains of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR), and reduced SMMC-7721 cell proliferation (IC=34.7 μmol/L) and migration compared to negative controls
We found that taspine had an inhibitory effect on tumor and angiogenesis, and could interact with VEGFR and EGFR
Summary
Radix et Rhizoma Leonticis (Hong Mao Qi in Chinese, HMQ) is distributed mainly in Shaanxi and Sichuan provinces of China. Taspine (Figure 1a), isolated for the first time from HMQ Radix et Rhizoma Leonticis has many pleiotropic effects such as anti-inflammatory, cell toxin, antivirus, topoisomerase I and II inhibition, (Perdue et al, 1979; Kelly and Xie, 1998; Fayad et al, 2009). We found that taspine had an inhibitory effect on tumor and angiogenesis, and could interact with VEGFR and EGFR. Silico ADME prediction showed that taspine wasn’t a compound with drug-like properties. In order to identify its binding mode with enzyme of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR), we performed a molecular docking study using SYBYL and cell inhibition of target compounds. We found tas13D (Figure 1B) had a better effect on SSMC-7721cell line than taspine
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