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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Photochemical Internalization of Therapeutic Macromolecular Agents: A Novel Strategy to Kill Multidrug-Resistant Cancer Cells

Pål K. Selbo, Anette Weyergang, Anette Bonsted, Stephen G. Bown and Kristian Berg
Journal of Pharmacology and Experimental Therapeutics November 2006, 319 (2) 604-612; DOI: https://doi.org/10.1124/jpet.106.109165
Pål K. Selbo
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Anette Weyergang
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Anette Bonsted
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Stephen G. Bown
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Kristian Berg
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Abstract

Drug resistance is a major problem for chemotherapy. Entrapment of anticancer drugs in endolysosomal compartments or active extrusions by plasma membrane proteins of the ATP-binding cassette (ABC) superfamily are important resistance mechanisms. This study evaluated photochemical internalization (PCI) of membrane-impermeable macromolecules that are not the target of ABC drug pumps for treating multidrug-resistant (MDR) cancer cells. We used the drug-sensitive uterine fibrosarcoma cell line MES-SA and its MDR, P-glycoprotein (P-gp)-overexpressing derivative MES-SA/Dx5 with the photosensitizer disulfonated meso-tetraphenylporphine (TPPS2a) and broad spectrum illumination. The PCI of doxorubicin, the ribosome-inactivating protein gelonin and adenoviral transduction were assessed in both cell lines, together with the uptake and excretion of TPPS2a and of two fluid phase markers easily detectable by fluorescence [lucifer yellow (LY) and fluorescein isothiocyanate (FITC)-dextran], as a model of gelonin uptake. Both cell lines were resistant to PCI of doxorubicin, but equally sensitive to PCI of gelonin, even though the endocytosis rates of LY and FITC-dextran were significantly lower in the MDR cells. In control studies, MES-SA/Dx5 cells were more resistant to photodynamic therapy (TPPS2a + light only). This was not mediated by P-gp, as there were no differences in the uptake and efflux of TPPS2a between the cell lines. After adenoviral infection, PCI enhanced gene delivery in both cell lines. In conclusion, PCI of macromolecular therapeutic agents that are not targets of P-gp is a novel therapeutic strategy to kill MDR cancer cells.

Footnotes

  • This work was supported by grants from The Norwegian Cancer Society (Project C 96138/034), The Norwegian Radium Hospital Research Foundation, and The Norwegian Ministry of Health.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.106.109165.

  • ABBREVIATIONS: MDR, multidrug resistance; ABC, ATP-binding cassette; P-gp, P-glycoprotein; DOX, doxorubicin; PCI, photochemical internalization; TPPS2a, meso-tetraphenylporphine with two sulfonate groups on adjacent phenyl rings; PSS, protonation, sequestration and secretion; FCS, fetal calf serum; LY, lucifer yellow; FITC, fluorescein isothiocyanate; PBS, phosphate-buffered saline; PDT, photodynamic therapy; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; Ad5, adenovirus serotype 5; m.o.i., multiplicity of infection; Dn, light dose resulting in n% kill.

    • Received June 7, 2006.
    • Accepted August 9, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 3
1 Mar 2021
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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Photochemical Internalization of Therapeutic Macromolecular Agents: A Novel Strategy to Kill Multidrug-Resistant Cancer Cells

Pål K. Selbo, Anette Weyergang, Anette Bonsted, Stephen G. Bown and Kristian Berg
Journal of Pharmacology and Experimental Therapeutics November 1, 2006, 319 (2) 604-612; DOI: https://doi.org/10.1124/jpet.106.109165

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Photochemical Internalization of Therapeutic Macromolecular Agents: A Novel Strategy to Kill Multidrug-Resistant Cancer Cells

Pål K. Selbo, Anette Weyergang, Anette Bonsted, Stephen G. Bown and Kristian Berg
Journal of Pharmacology and Experimental Therapeutics November 1, 2006, 319 (2) 604-612; DOI: https://doi.org/10.1124/jpet.106.109165
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