Augmented expression of metallothionein and glutathione S-transferase pi as unfavourable prognostic factors in cisplatin-treated ovarian cancer patients

Abstract

Resistance to cis- or carboplatin represents the principal cause of therapeutic failures in ovarian carcinoma. The phenomenon of resistance to platinum-based drugs is partly related to expression of metallothionein (MT) and of glutathione S-transferase pi (GST-pi), but opinion on the subject is discordant. Documentation of a negative predictive effect of MT and GST-pi expression for the therapy employing platinum-based drugs would permit to select resistant cases in which other therapeutic approaches could be employed. The present study aimed at examining the relation between intensities of MT and GST-pi expressions in ovarian carcinomas and dynamics of the clinical course in the neoplastic disease in a group of cisplatin-treated patients. The analyses were performed on samples of ovarian carcinoma originating from 43 first-look laparotomies (FLLs) and, in 30 cases, from second-look laparotomies (SLL) from the same patients. Immunohistochemical reactions were performed on paraffin sections of studied tumors, using monoclonal antibodies to MT and GST-pi. The calculations showed that in cases with augmented expression of MT, mortality was higher. On the other hand, augmented expression of GST-pi predisposed to more frequent relapses, deaths and progression of the tumor. Kaplan-Meier analysis showed that a significantly shorter survival time was linked to cases of higher expression of MT at FLL and of higher expression of GST-pi at FLL, whereas a shorter progression-free time was manifested by cases with higher expression of GST-pi at FLL. The performed investigations indicate that augmented expressions of MT at FLL and GST-pi at FLL in ovarian cancer represent an unfavourable predictive factor in cisplatin-treated patients.

The role and mechanism of WEE1 on the cisplatin resistance reversal of the HepG2/DDP human hepatic cancer cell line

“…For example, GST can acylate and inactivate cisplatin (16,17). The current study demonstrated that GST levels significantly increased in HepG2/DDP cells and significantly decreased subsequent to WEE1 silencing, suggesting that GST was also involved in WEE1-mediated drug resistance to cisplatin.…”

Effect of miR-155 knockdown on the reversal of doxorubicin resistance in human lung cancer A549/dox cells

“…GST-π is a member of the GST family that is able to catalyze the binding of hydrophobic and A B electrophilic compounds, including cisplatin, with reduced glutathione, causing the former to lose toxicity (28). This represents an additional mechanism of tumor cell resistance to chemotherapeutic drugs (29,30). The current study revealed that the GST-π expression level decreased significantly in A549/dox cells following miR-155 silencing, indicating the involvement of GST-π in miR-155-mediated drug resistance.…”

Metallothionein – overexpression as a highly significant prognostic factor in melanoma: a prospective study on 1270 patients

“…In the last decade, several reports disclosed MT overexpression as a useful prognostic factor for tumour progression and drug resistance in a variety of cancers such as ovarian cancer (Surowiak et al, 2005), renal cell carcinoma (Mitropoulos et al, 2005), breast cancer (Jin et al, 2004), non-small-cell lung carcinomas (Dziegiel et al, 2004), acute lymphoblastic leukaemia (Sauerbrey et al, 1994), pancreatic carcinoma (Ohshio et al, 1996) or carcinoma of the gallbladder (Shukla et al, 1998). Similar results could be found in smaller retrospective studies in melanoma and nonmelanoma skin cancers (Zelger et al, 1993(Zelger et al, , 1994Rossen et al, 1997;Goldmann et al, 1998;Sugita et al, 2001).…”