Inhibition of Bcl-2 family members sensitises soft tissue leiomyosarcomas to chemotherapy

Abstract

Background:Leiomyosarcoma is an aggressive soft tissue sarcoma with a 5-year survival rate of 15 to 60%. Treatment options for inoperable or metastatic patients are limited owing to frequent resistance of tumours to chemotherapy and radiation. In this study, we hypothesised that antiapoptotic Bcl-2 family proteins might contribute to leiomyosarcoma chemoresistance and therefore inhibition of Bcl-2 family proteins might sensitise leiomyosarcomas to conventional chemotherapy.Methods:Expression of the Bcl-2 family proteins Bcl-xL, Bcl-w and Bcl-2 was investigated using immunohistochemistry on a tissue microarray containing 43 leiomyosarcomas. Furthermore, we investigated whether ABT-737, a potent BH3 mimetic, sensitises leiomyosarcoma cells to doxorubicin treatment in vitro.Results:Seventy-seven per cent, 84% and 42% of leiomyosarcomas demonstrated high expression of Bcl-2, Bcl-xL and Bcl-w, respectively. Single-agent treatment with ABT-737 resulted in a minor reduction of cell viability. However, combination treatment of ABT-737 and doxorubicin revealed synergism in all four cell lines, by inducing apoptosis.Conclusions:In conclusion, Bcl-2 family proteins contribute to soft tissue leiomyosarcoma chemoresistance. Antiapoptotic proteins are highly expressed in leiomyosarcoma of soft tissue, and inhibition of these proteins using a BH3 mimetic increases leiomyosarcoma sensitivity to doxorubicin.

Bcl-xL inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas

“…Notwithstanding this set back, we sought to understand whether the key role of Bcl-x L in Dinaciclib-induced cell death was a particular feature or part of a more general behavior. Other groups have already shown a positive cooperation of BH3-mimetics with CDK inhibitors and anthracyclines 25,30 . So, we tested another commonly used anti-tumor drug in STS therapy: nucleoside analogue Gemcitabine.…”

Bcl-xL inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas

“…Research in STS has also pointed to the suitability of such combinations. Possible combinations for BH3-mimetics include anthracyclines, histone deacetylase inhibitors, tubulin poisons and etoposide (31,(58)(59)(60). Here, we add to the list Dinaciclib and Gemcitabine (Figure 5F) and we point that the major focus should be put in Bcl-x L inhibitors.…”

“…Notwithstanding this set back, we sought to understand whether the key role of Bcl-x L in Dinaciclib-induced cell death was a particular feature or part of a more general behavior. Other groups have already shown a positive cooperation of BH3-mimetics with CDK inhibitors and anthracyclines (26,31). So, we tested another commonly used anti-tumor drug in STS therapy: nucleoside analogue Gemcitabine.…”

High nuclear expression of proteasome activator complex subunit 1 predicts poor survival in soft tissue leiomyosarcomas

“…Tissue microarrays were previously constructed from paraffin embedded formalin fixed tissues using a semi-automated TMA apparatus (TMA Master; 3D Histech, Budapest, Hungary) [ 13 ]. Clinicopathological details were described previously [ 14 ]. In brief, analysed samples include 34 leiomyosarcomas, 14 myxofibrosarcomas, 15 undifferentiated pleomorphic sarcomas, four undifferentiated spindle cell sarcomas, four pleomorphic liposarcomas, two pleomorphic rhabdomyosarcomas, and seven uterine leiomyomas.…”

“…In brief, analysed samples include 34 leiomyosarcomas, 14 myxofibrosarcomas, 15 undifferentiated pleomorphic sarcomas, four undifferentiated spindle cell sarcomas, four pleomorphic liposarcomas, two pleomorphic rhabdomyosarcomas, and seven uterine leiomyomas. Clinicopathological data for the leiomyosarcomas, as described previously [ 14 ], are summarized in Additional file 1 : Table S1. All tumor samples are present at least in triplicates with a diameter of 1.5 mm (a surface area of around 1.767 mm 2 ).…”