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Polycationic calixarene PTX013, a potent cytotoxic agent against tumors and drug resistant cancer

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Summary

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.

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Abbreviations

EC:

Endothelial cell

HUVEC:

Human umbilical vein EC

SAR:

Structural activity relationships

PBS:

Phosphate buffered saline

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Acknowledgements

This work was supported by research grants from the National institute of Health - National Cancer Institute (CA-096090 and CA-76497) and OncoEthix Inc. to KHM. ER and LA-X were supported by OncoEthix Inc., the Foundation Nelia & Amadeo Barleta (FNAB), and the Association pour la Recherche & l’Enseignement en Cancérologie (AAREC).

Conflict of interest

Co-authors K.H. Mayo and J. R. MacDonald have a financial interest in PepTx, a pharmaceutical company that holds license to commercialize the PTX compounds

Author information

Authors and Affiliations

  1. Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA

    Ruud P. M. Dings, Joseph I. Levine & Kevin H. Mayo

  2. Department of Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA

    Joseph I. Levine, Susan G. Brown & Thomas R. Hoye

  3. INSERM U728 and Department of Medical Oncology, Beaujon University Hospital, (AP-HP – PRES Paris 7 Diderot), 100 bd du Général Leclerc, 92110, Paris-Clichy, France

    Lucile Astorgues-Xerri & Eric Raymond

  4. PepTx, Inc., Excelsior, MN, USA

    John R. MacDonald

Authors
  1. Ruud P. M. Dings
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  2. Joseph I. Levine
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  3. Susan G. Brown
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  4. Lucile Astorgues-Xerri
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  5. John R. MacDonald
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  6. Thomas R. Hoye
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  7. Eric Raymond
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  8. Kevin H. Mayo
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Corresponding author

Correspondence to Kevin H. Mayo.

Additional information

Author contribution

Participated in research design:

Ruud P.M. Dings, John R. MacDonald, Thomas R. Hoye, Eric Raymond, and Kevin H. Mayo.

Conducted experiments:

Ruud P.M. Dings, Joseph I. Levine, Susan G. Brown, Lucile Astorgues-Xerri.

Performed data analysis and wrote the paper:

All authors.

RPM Dings and JI Levine contributed equally to this work.

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Dings, R.P.M., Levine, J.I., Brown, S.G. et al. Polycationic calixarene PTX013, a potent cytotoxic agent against tumors and drug resistant cancer. Invest New Drugs 31, 1142–1150 (2013). https://doi.org/10.1007/s10637-013-9932-0

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  • DOI: https://doi.org/10.1007/s10637-013-9932-0

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