| Summary: | 博士 === 長庚大學 === 臨床醫學研究所 === 107 === Chondrosarcoma is the third most common malignant primary bone tumor which does not respond to conventional chemotherapy and is usually treated with surgery. However, for highly undifferentiated chondrosarcoma, chemotherapy and surgical treatment still cannot have a good therapeutic effect. Therefore, there is an urgent need for new therapeutic strategy towards chondrosarcoma. The ubiquitin system affects protein metabolism, which is an important mechanism for cellular biological regulation and tumor physiology. Therefore, anti-tumor drugs can achieve therapeutic effects by intervening in the ubiquitin system. Neddylation is one of the important upstream mechanism in the ubiquitin system, and many tumors were found to have abnormal neddylation expression. MLN4924 is a neural precursor cell expressed developmentally down-regulate 8 (NEDD8) activating enzyme inhibitor. MLN4924 can treat a variety of malignant tumors by inhibiting neddylation, but it has not been studied for chondrosarcoma. Therefore, we first confirmed that higher neddylation activating enzyme 1 (NAE1) expression in two normal chondrosarcoma cell lines than normal chondrocyte cell line. It was subsequently found that MLN4924 has significant proliferation inhibition and cytotoxicity against chondrosarcoma cell lines. It was further discovered that MLN4924 can activate the apoptotic pathway of chondrosarcoma cells to induce apoptosis, decrease the phosphorylation of histone-H3 (Ser10) to cause G2/M cell cycle arrest, increase the phosphorylation of c-Jun N-terminal kinase (JNK), increase expression of inducers of apoptosis associated with endoplasmic reticulum stress, 78-kDa glucose-regulated protein (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP), and increase caspase-4 cleavage to cause endoplasmic reticulum stress. Furthermore, in vivo in mice, MLN4924 significantly inhibited the growth of chondrosarcoma tumors. It was therefore confirmed that the use of MLN4924 to inhibit neddylation is a new therapeutic strategy for chondrosarcoma. Following medical treatment, surgical resection of chondrosarcoma often causes wound pain and poor patient quality of life, but existing painkillers often cause various side effects. So, if there is a long-acting local analgesic drug, the needed dose can be decreased to reduce systemic side effect. The existing topical analgesic drugs have a short duration of action and do not provide sufficient analgesic effects. Therefore, it is desirable to use a drug embedding thermosensitive hydrogel to provide a slow and long-acting release to control post-operative pain. We first conjugated methoxy-poly(ethylene glycol) and poly(lactide-co-glycolide) (mPEG-PLGA) with 2, 2'-Bis (2-oxazolin) (BOX) into diblock copolymer (BOX copolymer) and mixed with various concentration of ketorolac (Keto-hydrogel). In vitro ketorolac can be released for 10 days from Keto-hydrogels and the solution-gel transition of 10 mg / mL (25 wt%) Keto-hydrogel at 26.4 °C was found. The Keto-hydrogel was further compared with the ketorolac solution for the treatment effect of postoperative pain in the rat paw plantar incisional pain model and the in vivo tissue fluid concentration was also determined. Compared with the ketorolac solution group, the concentration of ketorolac was higher in the keto-hydrogel group in the first 18 hours, and keto-hydrogel group also had higher pain threshold, sensory threshold and weight-bearing capacity, significantly reduced tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β expression, while increased vascular endothelial growth factor (VEGF) in the tissue fluid. Further evaluation of tissue morphology showed that epithelial formation and collagen deposition around the wound after keto-hydrogel treatment were better than other groups. Keto-hydrogel has the potential role for pain control after surgical treatment of chondrosarcoma. Collectively, MLN4924 and Keto-hydrogel could be the new therapeutic strategies for chondrosarcoma and postoperative pain treatment.
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