title: Rlip76 transports sunitinib and sorafenib and mediates drug resistance in kidney cancer.
abstract: RLIP76 is a stress-responsive membrane protein implicated in the regulation of multiple cellular signaling pathways. It represents the predominant glutathione-conjugate (GS-E) transporter in cells. We have shown that RLIP76 plays a crucial role in defending cancer cells from radiation and chemotherapeutic toxin-mediated apoptosis, and that its inhibition by antibodies or depletion by siRNA or antisense causes apoptosis in a number of cancer cell types. We demonstrated for the first time that the striking anti-neoplastic effects with no evident toxicity in terms of either weight loss or metabolic effects are also demonstrable for the antibody, antisense and siRNA in a renal cell xenografts model of Caki-2 cells (Singhal et al., Cancer Res., 2009, 69: 4244). Present studies were performed to determine if RLIP76 targeting is more broadly applicable in other kidney cancer cell lines, to compare the signaling effects of RLIP76 antisense with kinase inhibitors used in treatment of renal cell carcinoma, and to determine whether kinase inhibitors were substrates for transport by RLIP76. Results of these studies show that sorafenib as well as sunitinib are substrates for transport by RLIP76 thus are competitive inhibitors of GS-E transport. Furthermore, kinase inhibition in the ERK as well as PI3K pathways by RLIP76 depletion is more profound and consistent and is more widely apparent in a number of renal carcinoma cell lines. These studies offer strong support for our overall hypothesis that RLIP76 is an overarching anti-apoptosis mechanism that, if inhibited, can be more broadly effective in the treatment of renal cell carcinoma.
authors.affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. ssinghal@hsc.unt.edu
authors.forename: Sharad S
authors.initials: SS
authors.lastname: Singhal
authors.forename: Archana
authors.initials: A
authors.lastname: Sehrawat
authors.forename: Mukesh
authors.initials: M
authors.lastname: Sahu
authors.forename: Preeti
authors.initials: P
authors.lastname: Singhal
authors.forename: Rit
authors.initials: R
authors.lastname: Vatsyayan
authors.forename: Poorna Chandra
authors.initials: PC
authors.lastname: Rao Lelsani
authors.forename: Sushma
authors.initials: S
authors.lastname: Yadav
authors.forename: Sanjay
authors.initials: S
authors.lastname: Awasthi
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D001557:Benzenesulfonates / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D016373:DNA, Antisense / Q000235:genetics; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000378:metabolism* / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology; D011758:Pyrroles / Q000378:metabolism* / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D000077157:Sorafenib; D000077210:Sunitinib; D014162:Transfection; D047368:Tumor Burden / Q000528:radiation effects
chemical_list: D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D016373:DNA, Antisense; D020690:GTPase-Activating Proteins; D007211:Indoles; D010671:Phenylurea Compounds; D011725:Pyridines; D011758:Pyrroles; C095637:RALBP1 protein, human; D034741:RNA, Small Interfering; C490620:Ralbp1 protein, mouse; D009536:Niacinamide; D004317:Doxorubicin; D000077157:Sorafenib; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000077210:Sunitinib