title: Kinetic Evaluation of Determinant Factors for Cellular Accumulation of Protoporphyrin IX Induced by External 5-Aminolevulinic Acid for Photodynamic Cancer Therapy.
abstract: Five-aminolevulinic acid (ALA) is a prodrug to generate phototoxic protoporphyrin IX (PPIX) for photodynamic cancer therapy. It remains unclear how PPIX accumulates in cancer cells; therefore, we aimed to clarify determinant factors by assessing ALA uptake, PPIX biosynthesis, conversion of PPIX to heme (ferrochelatase activity), and PPIX efflux, independently, in 10 human cancer cell lines. ALA-induced PPIX accumulation was not correlated with ALA uptake clearance. ALA uptake rates were far greater than maximum conversion rates of ALA to PPIX in the five cell lines, where ALA uptake activity was detected. A negative correlation of PPIX accumulation with ferrochelatase activity was found, but not statistically significant among all cell lines. As PPIX accumulation was restored in MCF-7 and DU145 cells by adding an inhibitor of PPIX efflux transporter BCRP, a compartment model incorporating PPIX synthesis, ferrochelatase activity, and PPIX efflux, was established, and hybrid parameters (π index) calculated using the model were significantly correlated with ALA-induced PPIX accumulation (r = 0.90, p = 0.005). Accordingly, kinetic analyses indicate that ALA-induced PPIX levels are determined by the three processes of PPIX biosynthesis, conversion of PPIX to heme, and PPIX efflux, suggesting that π index is a useful to predict ALA-induced PPIX accumulation.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakanishi
authors.affiliation: Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ogawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yanagihara
authors.affiliation: Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000622:Aminolevulinic Acid / Q000494:pharmacology*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D006418:Heme / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D007700:Kinetics; D061986:MCF-7 Cells; D010778:Photochemotherapy / Q000379:methods; D017319:Photosensitizing Agents / Q000494:pharmacology*; D011524:Protoporphyrins / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D017319:Photosensitizing Agents; D011524:Protoporphyrins; D006418:Heme; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX
keywords: ABC transporter; cancer; metabolism; pharmacodynamics; transport