Screening for antineoplastic ionic liquids by targeting RLIP76.

Abstract

e13033 Background: RLIP76 is a stress-responsive multispecific transporter which functions as an anti-apoptotic protein in cancer cells. The targeting of RLIP76 by antibodies, antisense, or siRNA modalities causes complete regression of cancers such as melanoma, colon cancer and lung cancer. We carried out studies to determine whether the ATPase activity of purified recombinant human RLIP76 protein (encoded by RALBP1, chromosome 18p11.22) can be used to screen for novel ionic liquid compounds with antineoplastic activity. Methods: A series of ionic liquid compounds were tested for their ability to inhibit or activate the ATPase activity and doxorubicin transport activity of purified recombinant human RLIP76. The growth inhibitory effects of these compounds were monitored in human non-small cell lung cancer cell line NCI H358, with human aorta vascular smooth muscle cells serving as non-malignant controls. Results: ATPase activation correlated with doxorubicin transport inhibition. More importantly, the antineoplastic activity towards lung cancer cells was also correlated with degree of ATPase activation or transport inhibition. Cytotoxicity towards the non-neoplastic cell line was 1-2 orders of magnitude less than observed for the lung cancer cells, a characteristic of other agents that target RLIP76. The predicted antineoplastic effect was confirmed in H358 xenografts in nude mice. Conclusions: These studies indicate the potential utility of screening for antineoplastic agents using recombinant RLIP76 and also demonstrate antineoplastic activity of a novel ionic liquid compound.