Abstract
BackgroundChondrosarcoma is characterized for its lack of response to conventional cytotoxic chemotherapy, propensity for developing lung metastases, and low rates of survival. Research within the field of development and expansion of new treatment options for unresectable or metastatic diseases is of particular priority. Diacerein, a symptomatic slow acting drug in osteoarthritis (SYSADOA), implicates a therapeutic benefit for the treatment of chondrosarcoma by an antitumor activity.MethodsAfter treatment with diacerein the growth behaviour of the cells was analyzed with the xCELLigence system and MTS assay. Cell cycle was examined using flow cytometric analysis, RT-PCR, and western blot analysis of specific checkpoint regulators. The status for phosophorylation of mitogen-activated protein kinases (MAPKs) was analyzed with a proteome profiler assay. In addition, the possible impact of diacerein on apoptosis was investigated using cleaved caspase 3 and Annexin V/PI flow cytometric analysis.ResultsDiacerein decreased the cell viability and the cell proliferation in two different chondrosarcoma cell lines in a dose dependent manner. Flow cytometric analysis showed a classical G2/M arrest. mRNA and protein analysis revealed that diacerein induced a down-regulation of the cyclin B1-CDK1 complex and a reduction in CDK2 expression. Furthermore, diacerein treatment increased the phosphorylation of p38α and p38β MAPKs, and Akt1, Akt2, and Akt 3 in SW-1353, whereas in Cal-78 the opposite effect has been demonstrated. These observations accordingly to our cell cycle flow cytometric analysis and protein expression data may explain the G2/M phase arrest. In addition, no apoptotic induction after diacerein treatment, neither in the Cal-78 nor in the SW-1353 cell line was observed.ConclusionsOur results demonstrate for the first time that the SYSADOA diacerein decreased the viability of human chondrosarcoma cells and induces G2/M cell cycle arrest by CDK1/cyclin B1 down-regulation.
Highlights
Chondrosarcoma is characterized for its lack of response to conventional cytotoxic chemotherapy, propensity for developing lung metastases, and low rates of survival
While an effect on Cal-78 cells could only be observed at a concentration of 300 μM diacerein, causing a complete reduction of cell proliferation, SW-1353 cells demonstrated a higher sensitivity for diacerein illustrated by a considerably reduced cell index at a concentration of 30 and 100 μM
(See figure on previous page.) Fig. 4 Phosphorylation of mitogen-activated protein kinases (MAPKs) under diacerein treatment. a MAPKs phosphorylation of Cal-78 and SW-1353 chondrosarcoma cell lines in percent change after 30 μM diacerein for 24 h. b Western blot analysis confirmed the results of the proteome profiler phospho-MAPK array and showed a significant increase of phospho-Akt and phospho-p38 after the treatment with different concentrations of diacerein in SW-1353 cells, whereas, no significant changes can be observed in the Cal-78 cells
Summary
Chondrosarcoma is characterized for its lack of response to conventional cytotoxic chemotherapy, propensity for developing lung metastases, and low rates of survival. A symptomatic slow acting drug in osteoarthritis (SYSADOA), implicates a therapeutic benefit for the treatment of chondrosarcoma by an antitumor activity. Diacerein represents a symptomatic slow acting drug in osteoarthritis (SYSADOA) from the anthraquinone chemical class and as the general term implicates, efficacy against the symptoms of osteoarthritis (OA) has been demonstrated [1]. Studying the cell proliferation and cell viability characteristics of C28/I2 chondrocytes, strikingly increased concentrations of diacerein significantly decreases cell growth and viability [6]. These observed growth-inhibiting qualities of diacerein, when applied at higher concentrations, might implicate a therapeutic benefit for the treatment of chondrosarcoma [7]. While diacerein has proved to be effective in the treatment of OA, Qin et al described that a diacerein α-aminophosphonate conjugate has anti-proliferative activities on tumor cells [8]
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