title: Feasibility study of B16 melanoma therapy using oxidized ATP to target purinergic receptor P2X7.
abstract: The P2X7 receptor is not only involved in cell proliferation, but also acts as an adenosine 5'-triphosphate (ATP)-gated non-selective channel, and its expression is increased in human melanoma. An irreversible antagonist of P2X7, such as oxidized ATP (oxATP), might block P2X7 receptor-mediated ATP release and proliferative signaling. Therefore, we carried out basic studies to test this idea and to examine the feasibility of using oxATP to treat B16 melanoma. We first found that low-pH conditions (mimicking the hypoxia and acidosis commonly seen in solid tumors) induced P2X7 receptor-mediated ATP release from B16 melanoma cells. Then, we compared the proliferation rates of B16 melanoma wild-type cells and B16 P2X7 receptor-knockdown clone (P2X7-KDC) cells in the presence of P2X7 agonists. The proliferation rate, as well as the ATP release, of agonist-treated P2X7-KDC cells was lower than that of agonist-treated wild-type cells. Next, the effect of P2X7 antagonist oxATP on B16 melanoma cell growth was examined in vitro and in vivo. oxATP significantly decreased B16 melanoma cell proliferation in vitro, and also significantly inhibited tumor growth in B16 melanoma-bearing mice. These data indicate that extracellularly released ATP may serve as an intercellular signaling molecule. We propose that the P2X7 receptor is a promising target for treatment of solid tumors.
authors.affiliation: Department of Radiation Biosciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi Chiba, Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Hattori
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ohshima
authors.forename: Shizuka
authors.initials: S
authors.lastname: Seki
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Tsukimoto
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sato
authors.forename: Takato
authors.initials: T
authors.lastname: Takenouchi
authors.forename: Akina
authors.initials: A
authors.lastname: Suzuki
authors.forename: Erina
authors.initials: E
authors.lastname: Takai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitani
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Harada
authors.forename: Shuji
authors.initials: S
authors.lastname: Kojima
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005240:Feasibility Studies; D055785:Gene Knockdown Techniques; D006863:Hydrogen-Ion Concentration; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy / Q000379:methods*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D058486:Receptors, Purinergic P2X7 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; C017199:2',3'-dialdehyde ATP; D000255:Adenosine Triphosphate