Abstract
Shenmai injection (SMI) is a Chinese patent-protected injection, which was mainly made of Red Ginseng and Radix Ophiopogonis and widely used for treating coronary heart disease and tumors by boosting Qi and nourishing Yin. In this study we examined whether SMI could produce direct synergetic effects on the cytoxicity of adriamycin (ADR) and paclitaxel (PTX) in colorectal cancers in vivo and in vitro, and explored the underlying pharmacokinetic mechanisms. BALB/c nude mice with LoVo colon cancer xenografts were intraperitoneally injected with ADR (2 mg·kg−1·3d−1) or PTX (7.5 mg·kg−1·3d−1) with or without SMI (0.01 mL·g−1·d−1) for 13 d. Co-administration of SMI significantly enhanced the chemotherapeutic efficacy of ADR and PTX, whereas administration of SMI alone at the given dosage did not produce visible anti-cancer effects, The chemosensitizing action of SMI was associated with increased concentrations of ADR and PTX in the plasma and tumors. In Caco-2 and LoVo cells in vitro, co-treatment with SMI (2 μL/mL) significantly enhanced the cytotoxicity of ADR and PTX, and resulted in some favorable pharmacokinetic changes in the subcellular distribution of ADR and PTX. In addition, SMI-induced intracellular accumulation of ADR was closely correlated with the increased expression levels of P-glycoprotein in 4 colon cancer cell lines (r2=+0.8558). SMI enhances the anti-cancer effects of ADR and PTX in colon cancers in vivo and in vitro by improving the subcellular distributions of ADR and PTX.
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Acknowledgements
The work is supported by the National Natural Science Foundation of China (No 81573496, 81530098, 81573494); Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics Projects (No BM2012012); Natural Science Foundation of Jiangsu Province (No BK20131308, BK20160076); Open Research Fund of State Key Laboratory of Bioelectronics, Southeast University; China “Creation of New Drugs” Key Technology Projects (No 2015ZX09501001); and Foundation for Innovative Research Groups of the National Natural Science Foundation of China (No 81421005).
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Supplementary information is available on the Acta Pharmacologica Sinica's web site.
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Supplementary Figure S1
Effects of SMI combination treatment on the pathological histology of heart, liver and kidney by HE staining (×200) in LoVo colon cancer xenograft mice. (DOC 1475 kb)
Supplementary Figure S2
P-gp mRNA level in four colon cancer cell lines and the correlation between SMI-induced changes in intracellular ADR accumulation and P-gp gene expression. (DOC 71 kb)
Supplementary Figure S3
Typical fingerprint of Shenmai Injection with 16 characteristic peaks detected by HPLC method. (DOC 35 kb)
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Liu, Wy., Zhang, Jw., Yao, Xq. et al. Shenmai injection enhances the cytotoxicity of chemotherapeutic drugs against colorectal cancers via improving their subcellular distribution. Acta Pharmacol Sin 38, 264–276 (2017). https://doi.org/10.1038/aps.2016.99
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DOI: https://doi.org/10.1038/aps.2016.99
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