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.

Effect of variation of ABCB1 and GSTP1 on osteosarcoma survival after chemotherapy

“…Our study reported an effective role of GSTP1 in clinical outcome of osteosarcoma patients, which was in line with previous studies (Pasello et al, 2008;Yang et al, 2012;Zhang et al, 2012). Our study suggests that genetic variation of ABCB1 and GSTP1 could play a critical role in the effectiveness of treatment and overall cancer survival.…”

Glutathione S-transferase P1 and DNA Polymorphisms with the Response to Chemotherapy and the Prognosis of Bone Tumor

“…The association between GSTP1, ERCC1 and ERCC2 gene polymorphisms with prognosis of previous studies (Pasello et al, 2008;Pasello et al, 2011;Windsor et al, 2012;Zhang et al, 2012). Zhang et al, in 2012, studies 159 patients with osteosarcoma treated with neoadjuvant chemotherapy and did not find any association of increased risk of death from osteosarcoma among patients with GSTP1 Val/Val genotype .…”

“…Zhang et al, in 2012, studies 159 patients with osteosarcoma treated with neoadjuvant chemotherapy and did not find any association of increased risk of death from osteosarcoma among patients with GSTP1 Val/Val genotype . However, another two studies conducted in Italy reported GSTP1 Val/Val was associated with the outcome of osteosarcoma, and GSTP1 could be considered a promising new therapeutic possibility for osteosarcoma patients (Pasello et al, 2008;Pasello et al, 2011). The inconsistencey of these results may be explained by differences in different ethnicities, source of control, sample size and etc.…”

Synthesis and structure–activity relationship of new cytotoxic agents targeting human glutathione-S-transferases

“…Nevertheless, among these last compounds, 20 and 24 showed an interesting profile, they being among the most effective GSTP1-1 inhibitors (IC 50 ¼ 0.1 mM for The replacement of the 6-hydroxyhexyl chain of 1 with shorter methyl propanoate (25) or ethylacetamido (26) chains, as well as with moieties characterized by insertion of an amide function (27) or carrying a 4-piperidone portion (28,29), yielded compounds with reduced potency against both GSTP1-1 and GSTM2-2. Both the inhibitory activities were promptly restored when a benzyl/tertbutyl carbamate function was added to the methyl propanoate chain (compare 30 and 31 with 25), or by introduction of the highly hydrophobic cyclohexylmethyl (32) or tert-butyl (33) chain at the C4-sulfur atom, providing in these cases compounds more potent than 1 but sharing similar inhibition profile and SIs.…”

“…We have previously demonstrated that GSTP1-1 contributes to osteosarcoma chemoresistance, and that targeting GSTP1-1 with 1 may represent a new therapeutic strategy for the treatment of this poorly responding tumor [18,25,26]. Thus, we evaluated the cytotoxic effect of the new NBD compounds 2e40 on the human osteosarcoma U-2OS cell line (Table 1).…”