title: Serum-dependent export of protoporphyrin IX by ATP-binding cassette transporter G2 in T24 cells.
abstract: Accumulation of protoporphyrin IX (PpIX) in cancer cells is a basis of 5-aminolevulinic acid (ALA)-induced photodymanic therapy. We studied factors that affect PpIX accumulation in human urothelial carcinoma cell line T24, with particular emphasis on ATP-binding cassette transporter G2 (ABCG2) and serum in the medium. When the medium had no fetal bovine serum (FBS), ALA induced PpIX accumulation in a time- and ALA concentration-dependent manner. Inhibition of heme-synthesizing enzyme, ferrochelatase, by nitric oxide donor (Noc18) or deferoxamine resulted in a substantial increase in the cellular PpIX accumulation, whereas ABCG2 inhibition by fumitremorgin C or verapamil induced a slight PpIX increase. When the medium was added with FBS, cellular accumulation of PpIX stopped at a lower level with an increase of PpIX in the medium, which suggested PpIX efflux. ABCG2 inhibitors restored the cellular PpIX level to that of FBS(-) samples, whereas ferrochelatase inhibitors had little effects. Bovine serum albumin showed similar effects to FBS. Fluorescence microscopic observation revealed that inhibitors of ABC transporter affected the intracellular distribution of PpIX. These results indicated that ABCG2-mediated PpIX efflux was a major factor that prevented PpIX accumulation in cancer cells in the presence of serum. Inhibition of ABCG2 transporter system could be a new target for the improvement of photodynamic therapy.
authors: Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata, Okayama 700-8558, Japan. togino@md.okayama-u.ac.jp
authors: Tetsuya
authors: T
authors: Ogino
authors: Hirotsugu
authors: H
authors: Kobuchi
authors: Kazuaki
authors: K
authors: Munetomo
authors: Hirofumi
authors: H
authors: Fujita
authors: Masanao
authors: M
authors: Yamamoto
authors: Toshihiko
authors: T
authors: Utsumi
authors: Keiji
authors: K
authors: Inoue
authors: Taro
authors: T
authors: Shuin
authors: Junzo
authors: J
authors: Sasaki
authors: Masayasu
authors: M
authors: Inoue
authors: Kozo
authors: K
authors: Utsumi
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000622:Aminolevulinic Acid / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002417:Cattle; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005294:Ferrochelatase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006418:Heme / Q000096:biosynthesis; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009603:Nitroso Compounds / Q000494:pharmacology; D011524:Protoporphyrins / Q000096:biosynthesis / Q000378:metabolism*; D044967:Serum / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000378:metabolism
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D004791:Enzyme Inhibitors; D007211:Indoles; C093285:NOC 18; D009363:Neoplasm Proteins; D009603:Nitroso Compounds; D011524:Protoporphyrins; D012710:Serum Albumin, Bovine; D006418:Heme; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX; C010522:tryptoquivaline; D005294:Ferrochelatase