title: Galactose conjugated platinum(II) complex targeting the Warburg effect for treatment of non-small cell lung cancer and colon cancer.
abstract: Malignant neoplasms exhibit a higher rate of glycolysis than normal cells; this is known as the Warburg effect. To target it, a galactose-conjugated (trans-R,R-cyclohexane-1,2-diamine)-2-chloromalonato-platinum(II) complex (Gal-Pt) was designed, synthesized, and evaluated in five human cancer cell lines and against two different xenograft tumour models. Gal-Pt exhibits much higher aqueous solubility (over 25 times) and improved cytotoxicity than oxaliplatin, especially in human colon (HT29) and lung (H460) cancer cell lines. The safety profile of Gal-Pt was investigated in vivo by exploring the maximum tolerated dose (MTD) and animal mortality rate. The ratios of the animal lethal dosage values to the cytotoxicity in HT29 (LD50/IC50) showed that Gal-Pt was associated with an increased therapeutic index by over 30-fold compared to cisplatin and oxaliplatin. We evaluated in vivo antitumor activity by single agent intravenous treatment comparison studies of Gal-Pt (50 mg/kg as 65% MTD) and cisplatin (3 mg/kg, as 80% MTD) in a H460 lung cancer xenograft model, and with oxaliplatin (7 mg/kg, as 90% MTD) in a HT29 colon cancer xenograft model. The results show that Gal-Pt was more efficacious against H460 than cisplatin, and had superior potency in HT29 cells compared to oxaliplatin under nontoxic dosage conditions. The dependency between cytotoxicity of Gal-Pt and glucose transporters (GLUTs) was investigated by using quercetin as an inhibitor of GLUTs in HT29 cells. The cytotoxic potency of Gal-Pt was highly reduced by the inhibitor, suggesting that the uptake of Gal-Pt was regulated by glucose transporters. The GLUT mediated transportability and cellular uptake of Gal-Pt was also demonstrated using a fluorescent glucose bioprobe in HT29 competition assay.
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wu
authors.affiliation: Affiliated Hospital, Logistics University of the Chinese People's Armed Police Force, No. 220, Cheng-Lin Road, Hedong District, Tianjin 300162, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China.
authors.forename: Ran
authors.initials: R
authors.lastname: Liu
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China.
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Gao
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China.
authors.forename: Menghua
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China.
authors.forename: Pengxing
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Immunology, Laboratory of Immune Micro-environment, Tianjin Medical University, 22, Qi Xiang Tai Road, Heping District, Tianjin 300070, PR China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Department of Medicinal Chemistry, Gudui BioPharma Technology Inc., 5 Lanyuan Road, Huayuan Industrial Park, Tianjin 300384, PR China.
authors.forename: Jinna
authors.initials: J
authors.lastname: Yang
authors.affiliation: Concordia International School, 999 Mingyue Rd., Shanghai 201206, PR China.
authors.forename: Daisy
authors.initials: D
authors.lastname: Zhang-Negrerie
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China. Electronic address: qingzhi@tju.edu.cn.
authors.forename: Qingzhi
authors.initials: Q
authors.lastname: Gao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005690:Galactose / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D051246:Glucose Transport Proteins, Facilitative; D009944:Organoplatinum Compounds; D005690:Galactose
keywords: Antitumor efficacy; Galactose-Pt(II) conjugate; Glucose transporter; Maximum tolerated dose; Warburg effect