LCL161為小分子Smac/DIABLO類似藥具有抑制凋亡抑制蛋白的能力。儘管LCL161近年來已在不同癌症種類中進行臨床一期及二期的試驗，但其確切的分子作用機制仍然不明。此外，LCL161對於較難治癒的乳癌患者像是三重陰性乳癌及陽性雌激素受體-抗他莫西芬類乳癌是否可作為治療藥物目前也未知。因此本篇研究之目的為了解LCL161對於不同亞型乳癌的治療潛力及詳細作用機轉。

在本研究中，從顯微鏡觀察、MTT細胞存活測試、及LDH細胞毒性測試的分析中顯示，我們發現LCL161對於三陰性的MDA-MB-231、MDA-MB-453、管腔A型的MCF7、ZR-75-1、MCF7衍生出之陽性雌激素受體-抗他莫西芬之MCF7-TamC3、MCF-TamR7、MCF-TamR8乳癌細胞都會產生抗增生能力以及不同程度的毒殺能力。在分子層次，西方墨點法分析指出LCL161會在給藥24小時後減少MDA-MB-231, MCF7, MCF7-TamR7, ZR-75-1 and MDA-MB-453乳癌細胞中存活素及凋亡抑制蛋白的表現及增加LC3B-II 及 p62/STSQM1這兩個自嗜作用指標蛋白的表現。然而，在相同的給藥方法下LCL161會增加MDA-MB-231, ZR-75-1 and MDA-MB-453細胞中被切割的凋亡蛋白酶及多ADP 核糖聚合酶蛋白質這兩個內在路徑細胞凋亡指標蛋白的表現量，但這情形並不會出現在MCF7 及MCF7-TamR7中。此外，在MCF7 及MCF-TamR7 中LCL161與凋亡蛋白酶抑制劑Z-VAD-FMK合併使用無法衰減LCL161的作用效果。以上結果顯示LCL161在不同種類乳癌細胞中可能是經由非凋亡蛋白酶所造成的細胞凋亡路徑來引起細胞死亡。由螢光顯微鏡的觀察結果我們也發現LCL161會增加LCB斑點的數量及細胞中溶酶體的形成。除此之外LCL161會與自嗜作用抑制劑奎寧產生協同作用因此我們推論LCL161在乳癌細胞中可能是扮演一個自嗜作用抑制劑的角色。

綜合以上結果，我們的發現顯示LCL161在不同的乳癌細胞中有不同的作用效果。更進一步的研究目前正在進行為的是瞭解LCL161在不同種類乳癌細胞中更詳細的作用機轉，了解這些不同的作用機轉對於未來在特定種類的乳癌標靶藥物應用上可以提供重要的資訊。

LCL161 is a novel small molecule second mitochondrial activator of caspase (SMAC) mimetic that exhibits inhibitor-of-apoptosis proteins (IAPs) inhibitory effects. Despite LCL161 is currently undergoing various Phase I/II clinical trials in patients with different cancer types, its molecular mechanism of actions are still incompletely understood. Furthermore, it is still unclear on whether LCL161 is suitable for use in treating breast cancer patients with difficulty treated subtypes like the triple-negative breast cancer and the estrogen receptor-positive (ER+) hormone therapy resistance breast cancer. The aim of this study was to determine the potency and molecular mechanism of actions of LCL161 in various types of breast cancer cells including the ER+ hormone therapy-resistant breast cancer and the triple-negative metastatic aggressive breast cancer.

Results of the microscopic analysis, MTT cell viability assay and LDH cytotoxicity assay revealed that LCL161 exhibits differential anti-proliferative ef-fects and cytotoxicity in different breast cancer cells. At the molecular level, Western blot analysis revealed that LCL161 decreased the expression of survivin IAPs and increased the conversion of LC3B-II and p62/STSQM1, which is au-tophagy markers, in MDA-MB-231, MCF7, MCF7-TamR7, ZR-75-1 and MDA-MB-453 cells as early as 24 h post-treatment. The same treatment induced the cleavage of caspase-9, caspase-3 and PARP, which are the indicators of intrin-sic apoptosis, in MDA-MB-231, ZR-75-1 and MDA-MB-453 but not in MCF7 and MCF7-TamR7 cells. In addition, co-treatment with the pan-caspase inhibitor, Z-VAD-FMK, could not attenuate the effect of LCL161 in MCF7 and MCF-TamR7 cells, suggesting that LCL161 promotes the death of different breast cancer cells through caspase-independent apoptosis. Moreover, LCL161 increased LC3B puncta and lysosome formation indicated that LCL161 enhance the number of au-tophagosomes in different breast cancer cells subtypes. Also, LCL161 might act as an autophagy inhibitor in breast cancer by having synergic effects with autophagy inhibitor CQ.

Taken together, our findings indicate that LCL161 induced differential cellular effects in different breast cancer subtypes. Further study is underway to get deeper understanding on the differential mechanism of actions of LCL161 in different breast cancer subtypes. Understanding the differential molecular mecha-nism of actions of LCL161 in different breast cancer cells may provide important information for using LCL161 as a therapeutic drug for patients with specific breast cancer subtypes in the future

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