Abstract
High grade chondrosarcoma is characterized by its lack of response to conventional cytotoxic chemotherapy, the tendency to develop lung metastases, and low survival rates. Research within the field prioritizes the development and expansion of new treatment options for dealing with unresectable or metastatic diseases. Numerous clinical trials using the proteasome inhibitor bortezomib have shown specific efficacy as an active antitumor agent for treating a variety of solid tumors. However, as of yet the effect of bortezomib on chondrosarcoma has not been investigated. In our study, bortezomib decreased cell viability and proliferation in two different chondrosarcoma cell lines in a time- and dose dependent manner. FACS analysis, mRNA- and protein expression studies illustrated that induction of apoptosis developed through the intrinsic mitochondria-caspase dependent pathway. Furthermore, bortezomib treatment significantly increased expression of the death receptors TRAILR-1 and TRAILR-2 in chondrosarcoma cells. An increased expression of the autophagy markers Atg5/12, Beclin, and LC3BI-II supports the interpretation that bortezomib functions as a trigger for autophagy. Our results demonstrated for the first time that bortezomib reduced viability and proliferation of chondrosarcoma cells, induced apoptosis via the mitochondria-caspase dependent pathway and enhanced death receptor expression and autophagy.
Highlights
Chondrosarcoma denotes a heterogeneous group of neoplasms, comprised of tumor cells that share the common characteristic of producing extracellular matrix components in cartilage tissue [1]
Bortezomib reduces viability and cell proliferation of chondrosarcoma cells After treatment with 0–100 nM bortezomib for 24, 48, and 72 h, cells were measured by the MTS assay (n = 12)
Chondrosarcoma is characterized by its lack of response to conventional cytotoxic chemotherapy, propensity for developing lung metastases, and poor patient survival
Summary
Chondrosarcoma denotes a heterogeneous group of neoplasms, comprised of tumor cells that share the common characteristic of producing extracellular matrix components in cartilage tissue [1]. Influence of Bortezomib on Chondrosarcoma Cells option for intermediate- to high-grade tumors as they are relatively chemo- and radiotherapy resistant, due to their extracellular matrix, low percentage of dividing cells, and poor vascularity [3, 4]. Some types of cancer cells may exploit autophagy to adapt to the hypoxic, nutrient limiting, and metabolically stressful tumor microenvironment, as well as therapeutically induced cell stress or damage [8]. Resistance to chemotherapy-induced apoptosis is one of the most important features of tumor cells, and contributes to tumor recurrence and metastasis. There are significant indications that as a cellprotective mechanism, activation of the autophagy pathway plays an important role in apoptosis resistance [16]
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