Bcl-xl as the most promising Bcl-2 family member in targeted treatment of chondrosarcoma

Abstract

Chondrosarcomas are malignant cartilage tumors showing relative resistance to conventional chemo- and radiotherapy. Previous studies showed that chondrosarcoma cells could be sensitized to chemotherapy by inhibiting the Bcl-2 family members Bcl-2, Bcl-xl and Bcl-w using ABT-737. In this study we explored the specific role of Bcl-2 family members to identify the most important player in chondrosarcoma cell survival and chemo resistance. Immunohistochemistry was performed on tissue microarrays containing 137 conventional chondrosarcomas of different grades. Selective inhibition of Bcl-2 (S55746) or Bcl-xl (WEHI-539 or A-1155463) and the combination with doxorubicin or cisplatin was investigated in a panel of 8 chondrosarcoma cell lines using presto blue viability assays and caspase 3/7 glo apoptosis assays. In addition Bcl-2 and Bcl-xl inhibition was investigated in an orthotopic Swarm Rat Chondrosarcoma (SRC) model. Bcl-2 and Bcl-xl were most abundantly expressed in the primary tumors, and expression increased with increasing histological grade. A subset of chondrosarcoma cell lines was sensitive to selective inhibition of Bcl-xl, and synergy was observed with doxorubicin or cisplatin in 3 out of 8 chondrosarcoma cell lines resulting in apoptosis. Conversely, selective inhibition of Bcl-2 was not effective in chondrosarcoma cell lines and could not sensitize to chemotherapy. In vivo, selective inhibition of Bcl-xl, but not Bcl-2 resulted in a decrease in tumor growth rate, even though no sensitization to doxorubicin was observed. These results suggest that among the Bcl-2 family members, Bcl-xl is most important for chondrosarcoma survival. Further research is needed to validate whether single or combination treatment with chemotherapy will be beneficial for chondrosarcoma patients.

Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status

“…Likewise, the synthetic lethal interaction between temozolomide and IDH mutations described in gliomas was not observed in our study [35,36]. Our research group published that the reported synthetic lethal interaction between IDH mutations and Bcl-2, NAMPT, and glutaminase inhibition was absent in chondrosarcoma [11,[37][38][39]. Together, these findings indicate that therapeutic strategies in AML and glioma based on IDH mutation status cannot be directly translated to chondrosarcoma.…”

You Cannot Have Your Synergy and Efficacy Too

“…With several cell lines where synergy was observed, the maximum synergy occurred at intermediate drug, and therefore efficacy, levels (Table 1). For instance, b B was highest at 12.5 mM cisplatin for the cell line SW1353 and at 6.25 mM cisplatin for the cell line L835 [13] (Table 1). Increasing the cisplatin level beyond this value increased efficacy but compromised synergy, reflecting the synergy-efficacy trade-off.…”

“…Finally, we present evidence of the trade-off in anticancer drugs. In a recent study, several chondrosarcoma cell lines resistant to chemotherapy were made sensitive to cisplatin by inhibiting the antiapoptotic protein Bcl-xl using the drug WEHI-539 [13]. Experiments used a fixed level of WEHI-539 and different levels of cisplatin, ranging from 0.39 to 100 mM.…”

Effect of lncRNA‑BC200 on proliferation and migration of liver cancer cells in�vitro and in�vivo

“…The Bcl-2 family is divided into two classes, pro-apoptotic proteins and anti-apoptotic proteins; Bcl-xL is an anti-apoptotic protein, whereas Bcl-xS and Bax are pro-apoptotic proteins (32,33). Singh et al (14) showed that knockout of BC200 increased Bcl-xS protein expression, whereas Bcl-xL protein was not altered significantly.…”