Abstract
Osteosarcoma is the most common primary bone malignancy in teenagers and continues to confer a generally poor prognosis due to its highly metastatic potential. Poor solubility in water and instability of curcumin limits its bioavailability for use in the adjuvant situation to improve the prognosis and the long-term survival of patients with osteosarcoma. To further obtain information regarding the apoptosis induced by a new curcumin analog, GO-Y078, in human osteosarcoma cells, flow cytometric analysis, annexin V-FITC/PI apoptosis staining assay, human apoptosis array, and Western blotting were employed. GO-Y078 dose-dependently decreased viabilities of human osteosarcoma U2OS, MG-63, 143B, and Saos-2 cells and induced sub-G1 fraction arrest and apoptosis in U2OS and 143B cells. In addition to the effector caspase 3 and poly adenosine diphosphate-ribose polymerase, GO-Y078 significantly activated both initiators of extrinsic caspase 8 and intrinsic caspase 9, whereas cellular inhibitors of apoptosis 1 (cIAP-1) and X-chromosome-linked IAP (XIAP) in U2OS and 143B cells were significantly repressed. Moreover, GO-Y078 increased phosphorylation of extracellular signal-regulated protein kinases (ERK)1/2, c-Jun N-terminal kinases (JNK)1/2, and p38 in U2OS and 143B cells. Using inhibitors of JNK (JNK-in-8) and p38 (SB203580), GO-Y078′s increases in cleaved caspases 8, 9, and 3 could be expectedly suppressed, but they could not be affected by co-treatment with the ERK inhibitor (U0126). Altogether, GO-Y078 simultaneously induces both apoptotic pathways and cell arrest in U2OS and 143B cells through activating JNK and p38 signaling and repressing IAPs. These findings contribute to a better understanding of the mechanisms responsible for GO-Y078′s apoptotic effects on human osteosarcoma cells.
Highlights
In addition to the suppression of cellular inhibitors of apoptosis 1 (cIAP-1) and X-chromosome-linked inhibitors of apoptosis (IAPs) (XIAP) expressions, we found that GO-Y078 induces apoptosis in U2OS and 143B cells by activating both extrinsic caspase
We intriguingly demonstrated GO-Y0780 s cytotoxicity on U2OS, MG-63, 143B, and Saos-2 cells and used a flow cytometry assay for cell cycle and apoptosis to confirm that GO-Y078 could interfere with the cell cycle at the sub-G1 fraction and induce apoptosis in U2OS and 143B cells
In addition to the suppression of IAPs, we demonstrated that GO-Y078 executes both extrinsic and intrinsic apoptotic signals in U2OS and 143B cells via the activation of the Jun N-terminal kinases (JNK) and p38 pathways
Summary
Osteosarcoma is the most common primary bone cancer in children and adolescents but is accountable for one of the most lethal pediatric malignancies [1,2,3]. As an early metastatic tumor, surgical en bloc resection or amputation of the extensively diseased extremity to achieve a complete radical. Chemotherapy is a cornerstone of treatment for osteosarcoma, so neoadjuvant chemotherapy followed by limb salvage surgery has increased long-term survival rates to approximately 68% recently [4,5]. Potent metastatic lung transfers are still responsible for the unacceptable treatment failures and mortality rates [2,6]. Novel adjuvant agents that target osteosarcoma to cause cell death need to be developed and the precious molecular mechanisms of the cytotoxic activity remain to be elucidated
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