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.
Highlights
Cisplatin is a very active antitumor agent that shows a relevant clinical activity against a wide variety of human solid tumors
Because we have found that the acquisition of CDDP resistance in our experimental models mostly involved glutathione S-transferase P1 (GSTP1)-1 alterations, we evaluated the clinical effect of GSTP1-1 expression in a series of high-grade osteosarcoma patients, and we assessed the in vitro effectiveness of 6-(7nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), a promising new anticancer agent that is a highly efficient inhibitor of GSTP1-1 and can accumulate in tumor cells by avoiding the extrusion mediated by multidrug resistance protein pumps [9,10,11]
The increase in CDDP resistance compared with the parental cell line ranged from 4.0- to 62.5-fold for U-2OS variants and from 7.4- to 112.1-fold for Saos-2 variants
Summary
Cisplatin (cis-diamminedichloroplatinum, CDDP) is a very active antitumor agent that shows a relevant clinical activity against a wide variety of human solid tumors. CDDP is widely used for highgrade osteosarcoma treatment, but despite this, only a small amount of information about the mechanisms that are responsible for resistance to this drug in human osteosarcoma cells has yet been reported [1,2,3,4]. Several mechanisms can be responsible for CDDP resistance, including decreased drug accumulation, increased drug efflux, increased detoxification by glutathione or metallothionein systems, decreased DNA platination, or increased DNA repair [5, 6]. A key factor that severely limits the CDDP cytotoxic efficacy in several human tumors is the activity of cellular glutathione (GSH)related detoxification system. The formation of aquated CDDP is rate limited by its interaction with many endogenous detoxification molecules, among which GSH is the most important and effective [5]. The reaction with GSH is catalyzed by the glutathione S-transferases (GST), a family of enzymes involved in xenobiotic detoxification, the dominant member of which is the GSTP1-1 isoenzyme [7, 8]
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