Liposomes Decorated with Apo2L/TRAIL Overcome Chemoresistance of Human Hematologic Tumor Cells

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• 作者：Diego De Miguel ; Gorka Bas谩帽ez ; Diego S谩nchez ; Patricia Gal谩n Malo ; Isabel Marzo ; Luis Larrad ; Javier Naval ; Juli谩n Pardo ; Alberto Anel ; Luis Martinez-Lostao
• 刊名：Molecular Pharmaceutics
• 出版年：2013
• 出版时间：March 4, 2013
• 年：2013
• 卷：10
• 期：3
• 页码：893-904
• 全文大小：669K
• 年卷期：v.10,no.3(March 4, 2013)
• ISSN：1543-8392

文摘

Human Apo2-ligand/TRAIL is a member of the TNF cytokine superfamily capable of inducing apoptosis on tumor cells while sparing normal cells. Besides its antitumor activity, Apo2L/TRAIL is also implicated in immune regulation. Apo2L/TRAIL is stored inside activated T cells in cytoplasmic multivesicular bodies and is physiologically released to the extracellular medium inserted in the internal membrane vesicles, known as exosomes. In this study we have generated artificial lipid vesicles coated with bioactive Apo2L/TRAIL, which resemble natural exosomes, to analyze their apoptosis-inducing ability on cell lines from hematological tumors. We have tethered Apo2L/TRAIL to lipid vesicles by using a novel Ni²⁺-(N-5-amino-1-carboxylpentyl)-iminodiacetic acid, NTA)-containing liposomal system. This lipidic framework (LUVs-Apo2L/TRAIL) greatly improves Apo2L/TRAIL activity, decreasing by around 14-fold the LC₅₀ on the T-cell leukemia Jurkat. This increase in bioactivity correlated with the greater ability of LUVs-Apo2L/TRAIL to induce caspase-3 activation and is probably due to the increase in local concentration of Apo2L/TRAIL, improving its receptor cross-linking efficiency. More important, liposome-bound Apo2L/TRAIL overcame the resistance to soluble recombinant Apo2L/TRAIL exhibited by tumor cell mutants overexpressing Bcl-x_L or by a Bax and Bak-defective Jurkat cell mutant (Jurkat-shBak) and are also effective against other hematologic tumor cells. Jurkat-Bcl-x_L and Jurkat-shBak cells are resistant to most chemotherapeutic drugs currently used in cancer treatment, and their sensitivity to LUVs-Apo2L/TRAIL could have potential clinical applications.

Keywords:

Apo2L/TRAIL; cancer; liposomes; therapy; chemoresistance