title: Overcoming glutathione S-transferase P1-related cisplatin resistance in osteosarcoma.
abstract: Cisplatin (cis-diamminedichloroplatinum, CDDP) is one of the most used drugs for osteosarcoma chemotherapy. By using a series of CDDP-resistant variants, which were established from the U-2OS and Saos-2 human osteosarcoma cell lines, we found that CDDP resistance was mainly associated with the increase of both the intracellular level and enzymatic activity of glutathione S-transferase P1 (GSTP1). On the basis of these findings, we evaluated the clinical effect of GSTP1 in a series of 34 high-grade osteosarcoma patients and we found that the increased expression of GSTP1 gene was associated with a significantly higher relapse rate and a worse clinical outcome. These indications prompted us to assess the in vitro effectiveness of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), a promising new anticancer agent that is a highly efficient inhibitor of GSTP1. NBDHEX was tested on a panel of 10 human osteosarcoma cell lines and 20 variants of the U-2OS or Saos-2 cell lines that were resistant to CDDP, doxorubicin, or methotrexate. NBDHEX proved to be very active on the vast majority of these cell lines, including those with higher GSTP1 levels and enzymatic activity. Drug combination studies showed that NBDHEX can be used in association with CDDP and provided useful information about the best modality of their combined administration. In conclusion, our findings show that GSTP1 has a relevant effect for both CDDP resistance and clinical outcome of high-grade osteosarcoma and that targeting GSTP1 with NBDHEX may be considered a promising new therapeutic possibility for osteosarcoma patients who fail to respond to conventional chemotherapy.
authors.affiliation: Laboratorio di Ricerca Oncologica, Istituti Ortopedici Rizzoli, Bologna, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Pasello
authors.forename: Francesca
authors.initials: F
authors.lastname: Michelacci
authors.forename: Isabella
authors.initials: I
authors.lastname: Scionti
authors.forename: Claudia Maria
authors.initials: CM
authors.lastname: Hattinger
authors.forename: Monia
authors.initials: M
authors.lastname: Zuntini
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Caccuri
authors.forename: Katia
authors.initials: K
authors.lastname: Scotlandi
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.forename: Massimo
authors.initials: M
authors.lastname: Serra
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology; D002945:Cisplatin / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy* / Q000201:enzymology*; D010069:Oxadiazoles / Q000494:pharmacology; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: C528479:6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol; D000970:Antineoplastic Agents; D010069:Oxadiazoles; D004317:Doxorubicin; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D002945:Cisplatin