title: Modulatory effects of heparin on cellular accumulation and cytotoxicity of doxorubicin in MRP1-overexpressing HL60/doxo cells.
abstract: BACKGROUND
  The overexpression of multidrug resistance protein (MRP1), associated with high levels of intracellular glutathione (GSH), is a well characterized mechanism of multidrug resistance (MDR) in several malignancies. Various chemosensitizers have been used in vitro to modulate the MRP1 activity, but the high toxicity limits their clinical application. Unfractionated heparin (UFH), is frequently used to prevent thrombo-embolic complications in cancer patients. This in vitro study aimed to elucidate the potential role of UFH as a sensitizer in anticancer clinical chemotherapy.
  
  
  METHODS
  The human leukemic doxorubicin-resistant cell line (HL60/doxo), which overexpresses the MRP1 protein was treated with UFH alone or in combination with three different concentrations of doxo. The intracellular accumulation and cytotoxicity of doxo and the cellular GSH content were measured in comparison with the leukotriene LTD4 receptor antagonist, MK571, a specific MRP1 inhibitor.
  
  
  RESULTS
  UFH increased doxo accumulation and cytotoxicity in the HL60/doxo cell line with respect to cells treated with doxo alone. UFH also decreased the cellular GSH content in the HL60/doxo cells with respect to the control, suggesting a potential involvement of UFH in doxo co-transport with GSH.
  
  
  CONCLUSIONS
  Our results demonstrate that UFH modulates MRP1-mediated MDR in HL60/doxo cells expressing high MRP1 levels. These findings suggest a potential clinical application of heparin as an adjuvant to overcome MRP1-mediated drug resistance in cancer patients.
authors.affiliation: Department of Medicine and Aging, School of Medicine and Aging Research Center, Ce. S.I. "Gabriele D'Annunzio" University Foundation, Chieti-Pescara, Italy. aangelini@unich.it
authors.forename: Antonio
authors.initials: A
authors.lastname: Angelini
authors.forename: Giuliano
authors.initials: G
authors.lastname: Ciofani
authors.forename: Giovanna
authors.initials: G
authors.lastname: Baccante
authors.forename: Concetta
authors.initials: C
authors.lastname: Di Febbo
authors.forename: Di Ilio
authors.initials: DI
authors.lastname: Carmine
authors.forename: Franco
authors.initials: F
authors.lastname: Cuccurullo
authors.forename: Ettore
authors.initials: E
authors.lastname: Porreca
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000494:pharmacology; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D018922:HL-60 Cells; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D005978:Glutathione; D006493:Heparin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates; D011804:Quinolines; C059141:verlukast; C421109:multidrug resistance-associated protein 1