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新藥LCC03，經自噬路徑阻斷前列腺癌細胞成長
Other Title
A novel therapeutic drug, LCC03 efficiently blocks prostate cancer growth through activation of autophagy pathway
Type
thesis
Date Issued
2016-07-07
Author(s)
坂貞儀
Advisor
陳冠州
宋賢穎
Subjects
系所名稱：臨床醫學研究所
Description
學位別：碩士
語文別：英文
指導教授：陳冠州
共同指導教授：宋賢穎
口試委員：蒲永孝;彭瓊琦;廖俊厚
中文關鍵字：自噬作用;去勢抗性前列腺癌，小分子藥物
英文關鍵字：castration-resistant prostate cancer;small molecule drug;autophagy
語文別：英文
指導教授：陳冠州
共同指導教授：宋賢穎
口試委員：蒲永孝;彭瓊琦;廖俊厚
中文關鍵字：自噬作用;去勢抗性前列腺癌，小分子藥物
英文關鍵字：castration-resistant prostate cancer;small molecule drug;autophagy
Abstract
Background: Prostate cancer is one of the most frequently diagnosed noncutaneous malignancy among men worldwide. It was the sixth leading cause of cancer-related deaths among Taiwanese in 2014. Androgen deprivation therapy was the standard treatment for advanced prostate cancer. However, many patients develop metastatic castration resistance prostate cancer (mCRPC), and there is no curable treatment for this stage.
Aim: The aim of this study was to investigate the anti-cancer effect and possible mechanism of a new compound LCC03 in prostate cancer.
Methods: To determine the roles of LCC03 in regulation of cell survival, cell viability assay was conducted by WST-1 assay. After confirming that LCC03 did not have a significant apoptotic effect, we used flow cytometric analysis to observe the mechanism of LCC03, the effects on cell cycle distribution and apoptosis. To examine the effect of LCC03 on the induction of autophagy in AIPC cells, autophagy-related protein expression was determined by Western blotting; TEM assay was performed to further confirm that autophagy could be induced by LCC03. Finally, we used bioluminescence imaging to evaluate the anti-tumor potential of LCC03 on prostate cancer bone metastasis in vivo, and performed IHC staining to directly observe the status of the autophagic protein LC3B in xenograft models.
Results: LCC03 effectively inhibited cell proliferation and induced cell cycle arrest of C4-2 and PC-3 AIPC prostate cancer lines at the range of 0.625-5μM. A massively increased expression of autophagy markers Beclin-1, ATG12-ATG5 conjugate and LC3B but not the apoptosis-related protein was observed in LCC03 treated prostate cancer cells. Autophagic vacuoles staining, as well as TEM assays confirmed the formation of LCC03-induced autophagosome. Moreover, intraperitoneal injection of LCC03 at a dose of 40 mg/kg of body weight significantly suppressed PC-3 tumor growth in mouse bone with no detectable toxicity.
Conclusion: Our results provided the evidence indicating that LCC03 can be served as a novel therapeutic drug for CRPC through activation of autophagy pathway.
Aim: The aim of this study was to investigate the anti-cancer effect and possible mechanism of a new compound LCC03 in prostate cancer.
Methods: To determine the roles of LCC03 in regulation of cell survival, cell viability assay was conducted by WST-1 assay. After confirming that LCC03 did not have a significant apoptotic effect, we used flow cytometric analysis to observe the mechanism of LCC03, the effects on cell cycle distribution and apoptosis. To examine the effect of LCC03 on the induction of autophagy in AIPC cells, autophagy-related protein expression was determined by Western blotting; TEM assay was performed to further confirm that autophagy could be induced by LCC03. Finally, we used bioluminescence imaging to evaluate the anti-tumor potential of LCC03 on prostate cancer bone metastasis in vivo, and performed IHC staining to directly observe the status of the autophagic protein LC3B in xenograft models.
Results: LCC03 effectively inhibited cell proliferation and induced cell cycle arrest of C4-2 and PC-3 AIPC prostate cancer lines at the range of 0.625-5μM. A massively increased expression of autophagy markers Beclin-1, ATG12-ATG5 conjugate and LC3B but not the apoptosis-related protein was observed in LCC03 treated prostate cancer cells. Autophagic vacuoles staining, as well as TEM assays confirmed the formation of LCC03-induced autophagosome. Moreover, intraperitoneal injection of LCC03 at a dose of 40 mg/kg of body weight significantly suppressed PC-3 tumor growth in mouse bone with no detectable toxicity.
Conclusion: Our results provided the evidence indicating that LCC03 can be served as a novel therapeutic drug for CRPC through activation of autophagy pathway.