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Improved Anticancer Effect of Recombinant Protein izTRAIL Combined with Sorafenib and Peptide iRGD

Roman Fadeev1,2, Alexey Chekanov3,4, Marina Solovieva5

  • 1Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region 142290, Russia. fadeevrs@gmail.com.

International Journal of Molecular Sciences
|January 30, 2019
PubMed

Insights

Multicellular resistance hinders cancer drug effectiveness. Combining TRAIL (TNFα-related apoptosis inducing ligand) with sorafenib and iRGD peptide overcomes this resistance, significantly improving anticancer effects in vivo.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Development

Background:

  • Developing cancer drugs that selectively kill tumor cells without harming normal cells is a major challenge.
  • Overcoming cancer cell drug resistance and ensuring effective drug delivery to tumors are critical unmet needs in oncology.
  • Recombinant TRAIL (TNFα-related apoptosis inducing ligand) protein shows promise as a selective anticancer agent, but its in vivo efficacy is limited by multicellular resistance.

Purpose of the Study:

  • To investigate if combining the recombinant TRAIL protein with sorafenib and the tumor-penetrating peptide iRGD can overcome multicellular TRAIL resistance and enhance anticancer effects in vivo.
  • To evaluate the efficacy of sorafenib in suppressing multicellular TRAIL resistance in cancer cells.
  • To assess the combined effect of sorafenib and iRGD on the therapeutic potential of TRAIL against human fibrosarcoma xenografts.

Main Methods:

  • Assessing the development of TRAIL resistance in human fibrosarcoma HT-1080 cells in confluent cultures and spheroids.
  • Evaluating the ability of sorafenib at non-toxic concentrations to inhibit multicellular TRAIL resistance in vitro.
  • Testing the combined efficacy of recombinant TRAIL (izTRAIL) with sorafenib and iRGD in a mouse model of human fibrosarcoma HT-1080 grafts.

Main Results:

  • Human fibrosarcoma HT-1080 cells exhibited increased resistance to izTRAIL in confluent cultures and spheroids.
  • Sorafenib effectively suppressed TRAIL resistance mediated by confluent or spheroid cancer cells in vitro.
  • The combination of sorafenib and iRGD significantly enhanced the anticancer effect of izTRAIL in HT-1080 fibrosarcoma tumors in mice.

Conclusions:

  • Multicellular resistance is a key factor contributing to the inefficacy of TRAIL alone in vivo.
  • Sorafenib can effectively inhibit multicellular TRAIL resistance.
  • Combining TRAIL with sorafenib and the tumor-penetrating peptide iRGD represents a promising strategy to improve the in vivo anticancer efficacy of TRAIL.
Keywords:
HT-1080 human fibrosarcoma cellsTRAIL/Apo2Lmulticellular TRAIL-resistancesorafenibtumor-penetrating peptide iRGD

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