title: Shenmai injection enhances the cytotoxicity of chemotherapeutic drugs against colorectal cancers via improving their subcellular distribution.
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.
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Wen-Yue
authors.initials: WY
authors.lastname: Liu
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jing-Wei
authors.initials: JW
authors.lastname: Zhang
authors.affiliation: Department of Digestive Tumor Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210009, China.
authors.forename: Xue-Quan
authors.initials: XQ
authors.lastname: Yao
authors.affiliation: Department of Digestive Tumor Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210009, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ji-Chao
authors.initials: JC
authors.lastname: He
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Pin
authors.initials: P
authors.lastname: Ni
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jia-Li
authors.initials: JL
authors.lastname: Liu
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Qian-Ying
authors.initials: QY
authors.lastname: Chen
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Qing-Ran
authors.initials: QR
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Zang
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Yao
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ya-Zhong
authors.initials: YZ
authors.lastname: Liu
authors.affiliation: Chiatai QingChunbao Pharmaceutical Co Ltd, Hangzhou 310023, China.
authors.forename: Mu-Lan
authors.initials: ML
authors.lastname: Wang
authors.affiliation: Chiatai QingChunbao Pharmaceutical Co Ltd, Hangzhou 310023, China.
authors.forename: Pei-Qiang
authors.initials: PQ
authors.lastname: Shen
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Guang-Ji
authors.initials: GJ
authors.lastname: Wang
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhou
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D004317:Doxorubicin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004338:Drug Combinations; D004357:Drug Synergism; D004365:Drugs, Chinese Herbal / Q000032:analysis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D017239:Paclitaxel / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; C009252:fructus schizandrae, radix ginseng, radix ophiopogonis drug combination; D004317:Doxorubicin; D017239:Paclitaxel