Regression of lung and colon cancer xenografts by depleting or inhibiting RLIP76 (Ral-binding protein 1).
Ral-binding protein 1 (RALBP1) is a stress-responsive and stress-protective multispecific transporter of glutathione conjugates (GS-E) and xenobiotic toxins. It is frequently overexpressed in malignant cells and plays a prominent antiapoptotic role selectively in cancer cells through its ability to control cellular concentration of proapoptotic oxidized lipid byproducts. In the absence of chemotherapy, depletion or inhibition of RALBP1 causes regression of syngeneic mouse B16 melanoma. Because RALBP1 transports anthracycline and Vinca alkaloid drugs, as well as GS-E, and because it confers resistance to these drugs, we proposed that depletion or inhibition of RALBP1 should cause regression of human solid tumors that overexpress RALBP1 and augment chemotherapy efficacy. Non-small-cell lung cancer (NSCLC) H358 and H520 and colon SW480 cell lines were used. Cytotoxic synergy between anti-RALBP1 immunoglobulin G (IgG), cis-diammine-dichloroplatinum (II) [CDDP], and vinorelbine was examined in cell culture and xenografts of NSCLC cells. Effects of RALBP1 depletion by antisense were examined in xenografts of NSCLC H358, NSCLC H520, and colon SW480 cells. RALBP1 depletion by phosphorothioate antisense was confirmed and was associated with rapid, complete, and sustained remissions in established s.c. human lung and colon xenografts. RALBP1 inhibition by anti-RALBP1 IgG was equally as effective as antisense and enhanced CDDP-vinorelbine in lung cancer xenografts. These studies show that RALBP1 is a transporter that serves as a key effector function in cancer cell survival and is a valid target for cancer therapy, and confirm that inhibitory modulation of RALBP1 transport activity at the cell surface is sufficient for antitumor effects.
Singhal
Sharad S
SS
Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, Texas 76019, USA.
Singhal
Jyotsana
J
Yadav
Sushma
S
Dwivedi
Seema
S
Boor
Paul J
PJ
Awasthi
Yogesh C
YC
Awasthi
Sanjay
S
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016373:DNA, Antisense / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D014162:Transfection; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine; D023041:Xenograft Model Antitumor Assays
D018528:ATP-Binding Cassette Transporters; D016373:DNA, Antisense; D020690:GTPase-Activating Proteins; D007074:Immunoglobulin G; C095637:RALBP1 protein, human; D014747:Vinblastine; D002945:Cisplatin; D000077235:Vinorelbine