| Autor: |
Dayan A; The School of Molecular Cell Biology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel., Fleminger G; The School of Molecular Cell Biology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel., Ashur-Fabian O; The Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. osnataf@gmail.com. |
| Jazyk: |
angličtina |
| Zdroj: |
Oncogene [Oncogene] 2019 Jun; Vol. 38 (25), pp. 5050-5061. Date of Electronic Publication: 2019 Mar 14. |
| DOI: |
10.1038/s41388-019-0775-9 |
| Abstrakt: |
Cancer cells frequently exhibit higher levels of reactive oxygen species (ROS) than normal cells and when ROS levels increase beyond a cellular tolerability threshold, cancer cell death is enhanced. The mitochondrial dihydrolipoamide dehydrogenase (DLDH) is an enzyme which produces ROS in association with its oxidoreductive activity and may be thus utilized as an exogenous anticancer agent. As cancer cells often overexpress integrins that recognize RGD-containing proteins, we have bioengineered the human DLDH with RGD motifs (DLDH RGD ) for integrin-mediated drug delivery. The modified protein fully retained its enzyme activity and ROS-production capability. DLDH RGD uptake by cells was shown to depend on the presence of cell-associated integrin αvβ3, as comparatively demonstrated with normal kidney cells (HEK293) transfected with either β1 (αvβ1 positive) or β3 integrins (αvβ3 positive). The interaction with β3 integrins was shown to be competitively inhibited by an RGD peptide. In mice melanoma cells (B16F10), which highly express an endogenous αvβ3 integrin, fast cellular uptake of DLDH RGD which resulted in cell number reduction, apoptosis induction, and a parallel intracellular ROS production was shown. Similar results were obtained with additional human melanoma cell models (A375, WM3314, and WM3682). In contrast, HEK293β3 cells remained intact following DLDH RGD uptake. The high pharmacological safety profile of DLDH RGD has been observed by several modes of administrations in BALB/C or C57Bl/6 mouse strains. Treatments with DLDH RGD in a subcutaneous melanoma mice model resulted in significant tumor inhibition. Our study demonstrated, in vitro and in vivo, the development of a unique platform, which targets cancer cells via integrin-mediated drug delivery of an exogenous ROS-generating drug. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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