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Enhancement of the Cytotoxicity of Liposomal Ricin by the Carboxylic Ionophore Monensin and the Lysosomotropic Amine NH₄Cl in Chinese Hamster Ovary Cells

Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi, India

Correspondence: Address correspondence to Prahlad C. Ghosh, Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi-110021, India. E-mail:pcghose{at}del6.vsnl.net.in,pcghose{at}gmail.com

Ricin was encapsulated in negatively charged liposomes and its effect on the cytotoxicity was compared with native ricin in Chinese hamster ovarian (CHO) cells. The cytotoxicity of ricin, as measured by a marker protein synthesis (incorporation of ³H-leucine), was reduced markedly (300-fold) following encapsulation in liposomes. Lactose, a potent inhibitor of ricin cytotoxicity, had no effect on the binding, internalization, and cytotoxicity of liposomal ricin, indicating that liposomal ricin enter into mammalian cells by an alternative route, bypassing galactose-mediated endocytic pathway. Both monensin (a carboxylic ionophore) and NH₄Cl (a lysosomotropic amine) markedly enhances the cytotoxicity of liposomal ricin, indicating endocytotic uptake of liposomal ricin. The degree of potentiation of the cytotoxicity of liposomal ricin by both monensin and NH₄Cl was significantly higher (441- and 51-fold) as compared to native ricin (62.5- and 12.5-fold). The extent of exocytosis of free ricin was found to be much higher as compared to liposomal ricin; on the other hand, the extent of degradation of free and liposomal ricin was identical. Consequently, the intracellular level of liposomal ricin was increased to 3.5-fold. This higher level of intracellular liposomal ricin may allow more efficient ricin A-chain release into the cytosol under the influence of NH₄Cl and monensin. Monensin-induced potentiation of liposomal ricin was prevented by brefeldin A, indicating that in the presence of monensin, the liposomal ricin was efficiently routed through the Golgi apparatus en route to the cytosol. Thus, liposomal ricin in combination with monensin may have potential application for selective elimination of malignant cells.

Key Words: Ammonium Chloride • Brefeldin A • CHO Cells • Golgi Apparatus Liposomal Ricin • Monensin • Ricin Cytotoxicity

International Journal of Toxicology, Vol. 25, No. 5, 349-359 (2006)
DOI: 10.1080/10915810600846195


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