PO.ET05.01 · 实验与分子治疗
GEM144（一种POLA1-HDAC11双重抑制剂）在结直肠癌模型中的作用机制
Mechanism of action of GEM144, a POLA1-HDAC11 dual inhibitor, in colorectal cancer models
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景与目的：结直肠癌（CRC）的发生和进展受调控细胞存活和上皮-间质转化（EMT）的复杂分子网络所支配。这种恶性肿瘤仍是全球癌症相关死亡的主要原因之一，突显了对新型治疗策略的需求。一种有前景的方法涉及研究具有增强抗癌特性的新分子实体。在本研究中，我们研究了一种新型杂合治疗候选药物GEM144的作用机制，它整合了DNA聚合酶α（POLA1）抑制剂和组蛋白去乙酰化酶11（HDAC11）抑制剂两个部分，两者均被报道在CRC中发挥关键作用。
方法：使用人CRC细胞系HCT116和HT29，以及“正常样”人结肠细胞CCD-841-CoN，进行增殖试验以分析GEM144在体外对细胞存活的影响。此外，使用CRC异种移植小鼠模型来证明GEM144在体内对肿瘤生长的影响。最后，SDS-聚丙烯酰胺凝胶电泳能够识别GEM144所靶向的分子通路。
结果：我们的结果显示，GEM144在体外降低CRC细胞活力，同时不损伤“正常样”结肠细胞。这种生长抑制似乎部分依赖于凋亡诱导，当细胞用GEM144处理时，在治疗后24小时起、浓度低至1 μM的条件下，通过促凋亡蛋白Bax表达增加而被检测到。此外，GEM144抑制EMT，如E-钙黏蛋白（一种维持细胞间黏附和上皮完整性的关键上皮标志物）表达上调所证实。这伴随着用GEM144处理的HCT116异种移植小鼠模型中肿瘤负荷的减少。
结论：总的来说，这些发现为GEM144抗癌活性背后的分子机制提供了新的见解，并支持其作为CRC治疗有前景的候选药物的潜力。
查看英文原文 English abstract
Background and objectives: Colorectal cancer (CRC) initiation and progression are governed by complex molecular networks that regulate cell survival and the epithelial-to-mesenchymal transition (EMT). This malignancy remains one of the leading causes of cancer-related mortality worldwide, underscoring the need for novel therapeutic strategies. One promising approach involves the investigation of new molecular entities with enhanced anticancer properties. In this study, we investigated the mechanism of action of a novel hybrid therapeutic candidate, GEM144, which integrates a DNA polymerase-alpha (POLA1) inhibitor and a histone deacetylase 11 (HDAC11) inhibitor moieties, both reported to play crucial roles in CRC.
Methods: Using human CRC cell lines HCT116 and HT29, and “normal-like” human colon cells CCD-841-CoN, proliferation assays were performed to analyze the effect of GEM144 on cell survival in vitro . In addition, CRC xenograft mouse models were used to demonstrate the effect of GEM144 on tumor growth in vivo . Finally, SDS-polyacrylamide gel electrophoresis allowed the identification of molecular pathways that are targeted by GEM144.
Results: Our results revealed that GEM144 decreased CRC cell viability in vitro , sparing “normal-like” colon cells. This growth inhibition seemed to be partly relying on apoptosis induction, detected by an increase in the expression of the pro-apoptotic protein Bax when cells were treated with GEM144, at concentrations as low as 1 μM starting 24 hours post-treatment. In addition, GEM144 suppressed the EMT, as evidenced by the upregulation of E-cadherin expression, a key epithelial marker that maintains cell-cell adhesion and epithelial integrity. This was accompanied by a tumor burden reduction in HCT116 xenograft mouse models treated with GEM144.
Conclusion: Collectively, these findings provide new insights into the molecular mechanisms underlying the anticancer activity of GEM144 and support its potential as a promising therapeutic candidate for CRC treatment.
利益披露 Disclosure
R. Abdel-Samad, None..
A. Lazaro, None..
M. Mack, None..
B. Hayar, None..
C. Pisano, None..
N. Darwiche, None.