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Targeting acute hypoxic cancer cells by doxorubicin-immunoliposomes directed by monoclonal antibodies specific to RON receptor tyrosine kinase.
Cancer Chemother Pharmacol. 2011 May; 67(5):1073-83.CC

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% O(2), 5% CO(2), and 96% N(2)) 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 IC(50) 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 IC(50) 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.

Authors+Show Affiliations

Center for Cancer Biology and Therapeutics, Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1406 Coulter Street, Suite 1117, Amarillo, TX 79106, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20658288

Citation

Guin, Sunny, et al. "Targeting Acute Hypoxic Cancer Cells By Doxorubicin-immunoliposomes Directed By Monoclonal Antibodies Specific to RON Receptor Tyrosine Kinase." Cancer Chemotherapy and Pharmacology, vol. 67, no. 5, 2011, pp. 1073-83.
Guin S, Ma Q, Padhye S, et al. Targeting acute hypoxic cancer cells by doxorubicin-immunoliposomes directed by monoclonal antibodies specific to RON receptor tyrosine kinase. Cancer Chemother Pharmacol. 2011;67(5):1073-83.
Guin, S., Ma, Q., Padhye, S., Zhou, Y. Q., Yao, H. P., & Wang, M. H. (2011). Targeting acute hypoxic cancer cells by doxorubicin-immunoliposomes directed by monoclonal antibodies specific to RON receptor tyrosine kinase. Cancer Chemotherapy and Pharmacology, 67(5), 1073-83. https://doi.org/10.1007/s00280-010-1408-8
Guin S, et al. Targeting Acute Hypoxic Cancer Cells By Doxorubicin-immunoliposomes Directed By Monoclonal Antibodies Specific to RON Receptor Tyrosine Kinase. Cancer Chemother Pharmacol. 2011;67(5):1073-83. PubMed PMID: 20658288.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeting acute hypoxic cancer cells by doxorubicin-immunoliposomes directed by monoclonal antibodies specific to RON receptor tyrosine kinase. AU - Guin,Sunny, AU - Ma,Qi, AU - Padhye,Snehal, AU - Zhou,Yong-Qing, AU - Yao,Hang-Ping, AU - Wang,Ming-Hai, Y1 - 2010/07/25/ PY - 2010/03/31/received PY - 2010/07/11/accepted PY - 2010/7/27/entrez PY - 2010/7/27/pubmed PY - 2011/6/24/medline SP - 1073 EP - 83 JF - Cancer chemotherapy and pharmacology JO - Cancer Chemother Pharmacol VL - 67 IS - 5 N2 - 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% O(2), 5% CO(2), and 96% N(2)) 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 IC(50) 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 IC(50) 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. SN - 1432-0843 UR - https://www.unboundmedicine.com/medline/citation/20658288/Targeting_acute_hypoxic_cancer_cells_by_doxorubicin_immunoliposomes_directed_by_monoclonal_antibodies_specific_to_RON_receptor_tyrosine_kinase_ L2 - https://dx.doi.org/10.1007/s00280-010-1408-8 DB - PRIME DP - Unbound Medicine ER -