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Int. J. Mol. Sci. 2019, 20(3), 525; https://doi.org/10.3390/ijms20030525

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

1
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region 142290, Russia
2
P. Hertzen Moscow Oncology Research Institute, Ministry of Health, Moscow 125284, Russia
3
Pushchino State Institute of Natural Sciences, Ministry of Education, Pushchino, Moscow Region 142290, Russia
*
Authors to whom correspondence should be addressed.
Received: 13 December 2018 / Revised: 19 January 2019 / Accepted: 24 January 2019 / Published: 27 January 2019
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Abstract

One of the main problems in oncology is the development of drugs that cause the death of cancer cells without damaging normal cells. Another key problem to be solved is to suppress the drug resistance of cancer cells. The third important issue is to provide effective penetration of drug molecules to cancer cells. TRAIL (TNFα-related apoptosis inducing ligand)/Apo2L is a highly selective anticancer agent. However, the recombinant TRAIL protein having high efficiency against cancer cells in vitro was not effective in clinical trials. Recently we have discovered an acquisition of TRAIL resistance by cancer cells in confluent cultures, which is apparently a manifestation of the general phenomenon of multicellular resistance. The aim of this study was to evaluate whether the anticancer effect of the recombinant protein TRAIL in vivo can be improved by the suppression of multicellular TRAIL-resistance using sorafenib and a tumor-penetrating peptide iRGD, c(CRGDKGPDC). The results testified a great increase in the resistance of human fibrosarcoma HT-1080 cells to izTRAIL both in confluent cultures and in spheroids. Sorafenib administered at nontoxic concentration effectively suppressed confluent- or spheroid-mediated TRAIL-resistance of HT-1080 cells in vitro. Sorafenib combined with iRGD significantly improved the anticancer effect of the recombinant protein izTRAIL in HT-1080 human fibrosarcoma grafts in BALB/c nude mice. Consistent with this finding, multicellular TRAIL-resistance may be a reason of inefficacy of izTRAIL alone in vivo. The anticancer effect of the recombinant protein izTRAIL in vivo may be improved in combination with sorafenib, an inhibitor of multicellular TRAIL resistance and iRGD, the tumor-penetrating peptide. View Full-Text
Keywords: TRAIL/Apo2L; multicellular TRAIL-resistance; sorafenib; tumor-penetrating peptide iRGD; HT-1080 human fibrosarcoma cells TRAIL/Apo2L; multicellular TRAIL-resistance; sorafenib; tumor-penetrating peptide iRGD; HT-1080 human fibrosarcoma cells
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Fadeev, R.; Chekanov, A.; Solovieva, M.; Bezborodova, O.; Nemtsova, E.; Dolgikh, N.; Fadeeva, I.; Senotov, A.; Kobyakova, M.; Evstratova, Y.; Yakubovskaya, R.; Akatov, V. Improved Anticancer Effect of Recombinant Protein izTRAIL Combined with Sorafenib and Peptide iRGD. Int. J. Mol. Sci. 2019, 20, 525.

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