title: Polycationic calixarene PTX013, a potent cytotoxic agent against tumors and drug resistant cancer.
abstract: Previously, we reported on the anti-tumor activities of two designed calix[4]arene-based topomimetics (PTX008 and PTX009) of the amphipathic, angiostatic peptide Anginex. Here, we chemically modified the hydrophobic and hydrophilic faces of PTX008 and PTX009, and discovered new calixarene compounds that are more potent, cytotoxic anti-tumor agents. One of them, PTX013, is particularly effective at inhibiting the growth of several human cancer cell lines, as well as drug resistant cancer cells. Mechanistically, PTX013 induces cell cycle arrest in sub-G1 and G0/G1 phases of e.g. SQ20B cells, a radio-resistant human head and neck carcinoma model. In the syngeneic B16F10 melanoma tumor mouse model, PTX013 (0.5 mg/Kg) inhibits tumor growth by about 50-fold better than parent PTX008. A preliminary pharmacodynamics study strongly suggests that PTX013 exhibits good in vivo exposure and a relatively long half-life. Overall, this research contributes to the discovery of novel therapeutics as potentially useful agents against cancer in the clinic.
authors: Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA.
authors: Ruud P M
authors: RP
authors: Dings
authors: Joseph I
authors: JI
authors: Levine
authors: Susan G
authors: SG
authors: Brown
authors: Lucile
authors: L
authors: Astorgues-Xerri
authors: John R
authors: JR
authors: MacDonald
authors: Thomas R
authors: TR
authors: Hoye
authors: Eric
authors: E
authors: Raymond
authors: Kevin H
authors: KH
authors: Mayo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D047250:Calixarenes / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003603:Cytotoxins / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; D047250:Calixarenes
references: Cancer Lett. 2008 Jul 8;265(2):270-80
references: 18378392
references: Cancer Res. 2005 Jul 15;65(14):6237-44
references: 16024625
references: Bioconjug Chem. 2012 May 16;23(5):993-1002
references: 22463059
references: Cancer Res. 2003 Jan 15;63(2):382-5
references: 12543791
references: J Natl Cancer Inst. 2006 Jul 5;98(13):932-6
references: 16818857
references: Bioconjug Chem. 2010 Jan;21(1):20-7
references: 20020769
references: Int J Hyperthermia. 2010;26(3):256-63
references: 20210610
references: J Med Chem. 2012 Jun 14;55(11):5121-9
references: 22575017
references: Int J Cancer. 2005 Jun 10;115(2):312-9
references: 15688384
references: Int J Hyperthermia. 2011;27(1):42-52
references: 21204622
references: Cancer Lett. 2003 May 8;194(1):55-66
references: 12706859
references: Clin Cancer Res. 2007 Jun 1;13(11):3395-402
references: 17545548
references: Cancer Res. 2009 May 15;69(10):4260-9
references: 19417139
references: Chemistry. 2010 Jun 18;16(23):6728-42
references: 20512821
references: Mol Cell Biol. 2008 Feb;28(3):1114-23
references: 18070926
references: J Biol Chem. 2003 Nov 14;278(46):45746-52
references: 12947097
references: Acc Chem Res. 2007 Oct;40(10):1057-65
references: 17661438
references: Mol Cancer Ther. 2010 May;9(5):1308-17
references: 20406951
references: Biochem J. 2001 Mar 1;354(Pt 2):233-42
references: 11171099
references: J Med Chem. 2006 Dec 28;49(26):7754-65
references: 17181157
references: Cancer Res. 2009 Feb 15;69(4):1259-62
references: 19208831