title: Evidence for mitoxantrone-induced block of inwardly rectifying K(+) channels expressed in the osteoclast precursor RAW 264.7 cells differentiated with lipopolysaccharide.
abstract: OBJECTIVE
  Mitoxanthrone (MX) is an anthracenedione antineoplastic agent. Whether this drug and other related compounds have any effects on ion currents in osteoclasts remains largely unclear.
  
  
  METHODS
  In this study, the effects of MX and other related compounds on inwardly rectifying K(+) current (I(K(IR))) were investigated in RAW 264.7 osteoclast precursor cells treated with lipopolysaccharide.
  
  
  RESULTS
  The I(K(IR))in these cells are blocked by BaCl(2) (1 mM). MX (1-100 µM) decreased the amplitude of I(K(IR)) in a concentration-dependent manner with an IC(50) value of 6.4 µM. MX also slowed the time course of I(K(IR)) inactivation elicited by large hyperpolarization. Doxorubicin (10 µM), 17β-estradiol (10 µM) and tertiapin (1 µM) decreased the I(K(IR)) amplitude in these cells. In bafilomycin A(1)-treated cells, MX-mediated block of I(K(IR)) still existed. In cell-attached configuration, when the electrode was filled with MX (10 µM), the activity of inwardly rectifying K(+) (Kir) channels was decreased with no change in single-channel conductance. MX-mediated reduction of channel activity is accompanied by a shortening of mean open time. Under current-clamp conditions, addition of MX resulted in membrane depolarization. Therefore, MX can interact with the Kir channels to decrease the I(K(IR)) amplitude and to depolarize the membrane in these cells.
  
  
  CONCLUSIONS
  The block by this drug of Kir2.1 channels appears to be one of the important mechanisms underlying its actions on the resorptive activity of osteoclasts, if similar results occur in vivo. Targeting at Kir channels may be clinically useful as an adjunctive regimen to anti-cancer drugs (e.g., MX or doxorubicin) in influencing the resorptive activity of osteoclasts.
authors.affiliation: Department of Nursing, Chung Jen College of Nursing, Health Sciences and Management, Chiayi city, Taiwan.
authors.forename: Chung-Lin
authors.initials: CL
authors.lastname: Wang
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Tsai
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017609:Barium Compounds / Q000494:pharmacology; D001514:Bee Venoms / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002712:Chlorides / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008942:Mitoxantrone / Q000494:pharmacology*; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D017609:Barium Compounds; D001514:Bee Venoms; D002712:Chlorides; D008070:Lipopolysaccharides; D024661:Potassium Channels, Inwardly Rectifying; C024986:barium chloride; C029738:tertiapin; D004958:Estradiol; D004317:Doxorubicin; D008942:Mitoxantrone