title: Inhibitors of intracellular chloride regulation induce cisplatin resistance in canine osteosarcoma cells.
abstract: The objective of this study was to examine the role of ion transport mechanisms in clinical anticancer drug resistance. Reduction in intracellular accumulation of cisplatin is believed to be an early change in cisplatin-resistant cells, and may be dependent on the concentration of intracellular chloride (Cl-) ions and intracellular pH. The primary aim of this study was to describe the modifying effects of NHMA (5-N,N hexamethylene; amiloride), a Na+/H+ antiport inhibitor, and/or SITS (4-acetamido-4';isothiocyanostilbene-2,2'-disulfonic acid), a HCO3-/Cl- transport inhibitor, in bicarbonate-containing or bicarbonate-free media on cisplatin (cis-diamminedichloroplatinum(II); CDDP) toxicity between known cisplatin-sensitive (COS31) and cisplatin-resistant (COS31/rCDDP) canine osteosarcoma cells. This study has shown that cell survival can be influenced by the inhibition of the Na(+)-dependent HCO3-/Cl- exchanger using SITS. The addition of SITS increases the intracellular Cl- concentration in canine osteosarcoma cells cultured in a bicarbonate-containing media. In a bicarbonate-free media, the addition of SITS results in a decrease in the cytotoxic action of cisplatin.
authors.affiliation: Department of Comparative Medicine, University of Tennessee, Knoxville 37901-1071, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Yarbrough
authors.forename: J I
authors.initials: JI
authors.lastname: Merryman
authors.forename: M A
authors.initials: MA
authors.lastname: Barnhill
authors.forename: K A
authors.initials: KA
authors.lastname: Hahn
mesh_terms: D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / Q000494:pharmacology; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D017920:Antiporters / Q000037:antagonists & inhibitors; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D019008:Drug Resistance, Neoplasm; D006863:Hydrogen-Ion Concentration; D007424:Intracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D017920:Antiporters; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides; D017923:Sodium-Hydrogen Exchangers; C057360:5-(N,N-hexamethylene)amiloride; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; D000584:Amiloride; D002945:Cisplatin