Highly water-soluble platinum(ii) complexes as GLUT substrates for targeted therapy: improved anticancer efficacy and transporter-mediated cytotoxic properties

Liu, Pengxing; Lu, Yanhui; Gao, Xiangqian; Liu, Ran; Zhang‐Negrerie, Daisy; Shi, Ying; Wang, Yiqiang; Wang, Songqing; Gao, Qingzhi

doi:10.1039/c3cc38589b

Cited by 84 publications

(59 citation statements)

References 19 publications

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“…On the basis of the cell cycle progression evaluation, both Glu-Pt and oxaliplatin share the same pattern of cell killing and apoptotic induction, therefore, the potent activity observed for glucose-conjugated Glu-Pt may be due to the fact that Glu-Pt can be recognized as substrate of tumor specific glucose transporter (GLUT) for active uptake. This also can be evidenced by the previous study results on the GLUT inhibitor (phlorizin) mediated transport and cytotoxicity dependency evaluation[12].In conclusion, Glu-Pt exhibits a much higher aqueous solubility by a measure of over 150 times, with improved potency in cytotoxicities compared with oxaliplatin. The MTD assessment and efficacy study on L1210 leukemia-bearing DBA/2 mice demonstrated that Glu-Pt shows more favorable safety profiles and superior antitumor efficacy over oxaliplatin.…”

supporting

confidence: 66%

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Glucose conjugated platinum(II) complex: Antitumor superiority to oxaliplatin, combination effect and mechanism of action

Gao

Liu

et al. 2015

European Journal of Medicinal Chemistry

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supporting

confidence: 66%

“…1, is designed as a substrate for tumor specific glucose transporters (GLUTs). Glu-Pt possesses many advantages in comparison with existing platinum anticancer drugs, such as up to 900 mg/mL high water solubility, ease of synthesis and formulation, GLUT dependent and superior cytotoxicity against numbers of human cancer cell lines [12].…”

Section: Introductionmentioning

confidence: 99%

Glucose conjugated platinum(II) complex: Antitumor superiority to oxaliplatin, combination effect and mechanism of action

Gao

Liu

et al. 2015

European Journal of Medicinal Chemistry

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“…Its potency was prevented when human colon cancer (HT29) and breast cancer (MCF7) cells, which overexpress GLUTs, were treated with GLUT inhibitor phlorizin, thus confirming that the uptake and the antiproliferative activity of this compound are mediated by GLUT transporters. 92 …”

Section: Sugar-conjugate Compounds Interacting With Glutsmentioning

confidence: 99%

Anticancer agents interacting with membrane glucose transporters

2016

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The altered metabolism observed in cancer cells generally consists in increased glucose uptake and glycolytic activity. This is associated with an overexpression of glucose transporter proteins (GLUTs), which facilitate glucose uptake across the plasma membrane and play a crucial role in the survival of cancer cells. Therefore GLUTs are considered as suitable targets for the treatment of cancer. Herein we review some of the most relevant GLUT inhibitors that have been recently developed as prospective anticancer agents.

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“…We found that the fluorine substitution has a profound effect on water solubility improvement of the platinum(II) complex [28]. In the present article, we report the comprehensive biological, pharmacological and mechanistic studies on a series of 2-flouromalonato-platinum(II) glycoconjugates using glucose, mannose and galactose as GLUT targeting sugar motif.…”

Section: Introductionmentioning

confidence: 99%

GLUT1-mediated selective tumor targeting with fluorine containing platinum(II) glycoconjugates

Liu

Zhao

et al. 2017

Oncotarget

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Increased glycolysis and overexpression of glucose transporters (GLUTs) are physiological characteristics of human malignancies. Based on the so-called Warburg effect, 18flurodeoxyglucose-positron emission tomography (FDG-PET) has successfully developed as clinical modality for the diagnosis and staging of many cancers. To leverage this glucose transporter mediated metabolic disparity between normal and malignant cells, in the current report, we focus on the fluorine substituted series of glucose, mannose and galactose-conjugated (trans-R,R-cyclohexane-1,2-diamine)-2-flouromalonato-platinum(II) complexes for a comprehensive evaluation on their selective tumor targeting. Besides highly improved water solubility, these sugar-conjugates presented improved cytotoxicity than oxaliplatin in glucose tranporters (GLUTs) overexpressing cancer cell lines and exhibited no cross-resistance to cisplatin. For the highly water soluble glucose-conjugated complex (5a), two novel in vivo assessments were conducted and the results revealed that 5a was more efficacious at a lower equitoxic dose (70% MTD) than oxaliplatin (100% MTD) in HT29 xenograft model, and it was significantly more potent than oxaliplatin in leukemia-bearing DBA/2 mice as well even at equimolar dose levels (18% vs 90% MTD). GLUT inhibitor mediated cell viability analysis, GLUT1 knockdown cell line-based cytotoxicity evaluation, and platinum accumulation study demonstrated that the cellular uptake of the sugar-conjugates was regulated by GLUT1. The higher intrinsic DNA reactivity of the sugar-conjugates was confirmed by kinetic study of platinum(II)-guanosine adduct formation. The mechanistic origin of the antitumor effect of the fluorine complexes was found to be forming the bifunctional Pt-guanine-guanine (Pt-GG) intrastrand cross-links with DNA. The results provide a rationale for Warburg effect targeted anticancer drug design.

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Highly water-soluble platinum(ii) complexes as GLUT substrates for targeted therapy: improved anticancer efficacy and transporter-mediated cytotoxic properties

Cited by 84 publications

References 19 publications

Glucose conjugated platinum(II) complex: Antitumor superiority to oxaliplatin, combination effect and mechanism of action

Glucose conjugated platinum(II) complex: Antitumor superiority to oxaliplatin, combination effect and mechanism of action

Anticancer agents interacting with membrane glucose transporters

GLUT1-mediated selective tumor targeting with fluorine containing platinum(II) glycoconjugates

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