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A thermally targeted elastin-like polypeptide-doxorubicin conjugate overcomes drug resistance

Gene L Bidwell1, Aisha N Davis, Izabela Fokt

  • 1Department of Biochemistry, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.

Investigational New Drugs
|May 8, 2007
PubMed

Insights

Elastin-like polypeptide (ELP) bound doxorubicin overcomes cancer multidrug resistance by preventing drug efflux. Hyperthermia further enhances ELP-bound doxorubicin

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Multidrug resistance (MDR) in cancer is a significant therapeutic challenge.
  • P-glycoprotein (P-gp) mediated drug efflux is a primary MDR mechanism, particularly for anthracyclines like doxorubicin.
  • Current strategies to overcome MDR include P-gp inhibitors, novel analogs, and drug conjugation.

Purpose of the Study:

  • To evaluate the efficacy of Elastin-like polypeptide (ELP)-bound doxorubicin (Dox) against sensitive and multidrug resistant human carcinoma cells in vitro.
  • To investigate the role of P-gp in doxorubicin resistance and the potential of ELP conjugation to circumvent this efflux mechanism.
  • To explore the synergistic effect of hyperthermia on the cytotoxicity of ELP-bound doxorubicin in resistant cancer cells.

Main Methods:

  • In vitro cytotoxicity assays using sensitive (MES-SA, MCF-7) and multidrug resistant (MES-SA/Dx5, NCI/ADR-RES) human carcinoma cell lines.
  • Assessment of doxorubicin accumulation in cells treated with free vs. ELP-bound doxorubicin.
  • Investigation of the impact of hyperthermia on the efficacy of ELP-bound doxorubicin in resistant cells.

Main Results:

  • Resistant cell lines exhibited significantly higher resistance to free doxorubicin compared to sensitive cell lines (30-70 fold).
  • ELP-bound doxorubicin demonstrated equal cytotoxicity in both sensitive and resistant cell lines, indicating circumvention of P-gp efflux.
  • ELP-bound doxorubicin accumulated within resistant cells, unlike free doxorubicin which was rapidly effluxed.
  • Hyperthermia significantly enhanced the cytotoxicity and apoptosis induced by ELP-bound doxorubicin in resistant cells.

Conclusions:

  • ELP-bound doxorubicin effectively overcomes P-gp mediated multidrug resistance in cancer cells.
  • ELP-Dox conjugates offer a promising strategy to enhance doxorubicin delivery and efficacy in resistant tumors.
  • The combination of ELP-Dox conjugates and hyperthermia presents a potential dual-targeting approach for solid tumors, enhancing therapeutic outcomes.

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