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Cancer Chemotherapy and Pharmacology

Published in:

01-05-2011 | Original Article

Targeting acute hypoxic cancer cells by doxorubicin-immunoliposomes directed by monoclonal antibodies specific to RON receptor tyrosine kinase

Authors: Sunny Guin, Qi Ma, Snehal Padhye, Yong-Qing Zhou, Hang-Ping Yao, Ming-Hai Wang

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2011

Abstract

Purpose

Hypoxia contributes to acquired drug resistance in various cancer cells. The underlying mechanism is cellular insensitivity regulated by hypoxia-inducible factors (HIF), which impairs drug uptake, transport, and metabolism. The current study determines anti-RON antibody-directed cytotoxicity of doxorubicin (Dox)-immunoliposomes (IL) in hypoxic colon cancer cells.

Methods

Cells were cultured under hypoxia (1% O₂, 5% CO₂, and 96% N₂) for 24 h. Dox-loaded IL were formulated followed by post-insertion of monoclonal antibody Zt/g4 specific to RON. Western blotting was used to detect HIF-1α and RON expression. Cellular uptake of Zt/g4-conjugated IL was determined by confocal and internalization assays. Cell viability was assessed by the MTT assay.

Results

RON and HIF-1α expression were observed in hypoxic colon HCT116 and SW620 cells. Resistance to Dox-induced cytotoxicity was acquired in hypoxic cells with increased IC₅₀ values. However, acquired resistance was attenuated by Zt/g4-directed Dox-IL, which displays increased cytotoxic activities. IL binding and uptake revealed that hypoxic RON expression is functional, which mediates high levels of Zt/g4-Dox-IL binding and cytoplasmic internalization. Zt/g4-Dox-IL is effective in killing hypoxic HCT116 and SW620 cells with reduced IC₅₀ values compared to Dox and pegylated-liposomal Dox. These effects were dependent on hypoxic RON expression. HCC1937 cells with diminished RON expression under hypoxia were insensitive to Zt/g4-Dox-IL-induced cytotoxic effect.

Conclusions

RON expressed by hypoxic colon cancer cells is thus a potential targeting molecule for delivery of chemotherapeutics. The ability of anti-RON mAb to direct Dox-IL cytotoxicity could be developed for attenuating hypoxia-acquired drug resistance in various cancer cells.

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Title: Targeting acute hypoxic cancer cells by doxorubicin-immunoliposomes directed by monoclonal antibodies specific to RON receptor tyrosine kinase
Authors: Sunny Guin
Qi Ma
Snehal Padhye
Yong-Qing Zhou
Hang-Ping Yao
Ming-Hai Wang
Publication date: 01-05-2011
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-010-1408-8

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