Rimonabant Kills Colon Cancer Stem Cells without Inducing Toxicity in Normal Colon Organoids.
Rimonabant Kills Colon Cancer Stem Cells without Inducing Toxicity in Normal Colon Organoids.
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DOI：
10.3389/fphar.2017.00949
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发表时间：
2017
影响因子：
5.6
通讯作者：
Gazzerro P
中科院分区：
文献类型：
--
作者：
Fiore D;Ramesh P;Proto MC;Piscopo C;Franceschelli S;Anzelmo S;Medema JP;Bifulco M;Gazzerro P
结直肠癌（CRC）与其他肿瘤类型一样，是一种高度异质性的疾病。在肿瘤块内，肿瘤内异质性也可归因于癌症干细胞（CSC）亚群，其特征在于高化学抗性和保留致瘤潜力的独特能力，因此与肿瘤复发相关。CSC的高动态可塑性使得成功的治疗策略的开发更加复杂，以完全根除肿瘤燃料。利莫那班最初作为大麻素受体1的拮抗剂/反向激动剂合成，能够通过抑制p300-组蛋白乙酰转移酶活性在CRC模型中在体外和体内抑制Wnt信号传导。由于Wnt/β-连环蛋白途径是CSC动力学的主要参与者，因此这一发现候选利莫那班作为CRC中癌症干性的潜在调节剂。在这项工作中，使用建立的原代结肠CSC的3D培养物，通过监测Wnt活性考虑肿瘤异质性，我们证明了利莫那班能够减少肿瘤分化细胞和结肠CSC增殖，并控制它们在长期培养物中的存活。有趣的是，在野生型人类器官的离体模型中，保留原始组织的结构和异质性，利莫那班对健康结肠上皮细胞没有毒性，表明其对癌细胞的潜在选择性。总的来说，这项工作的结果为利莫那班的抗肿瘤疗效提供了新的见解，强烈表明它可能是CRC治疗的新型先导化合物。
Colorectal cancer (CRC), like other tumor types, is a highly heterogeneous disease. Within the tumor bulk, intra-tumoral heterogeneity is also ascribable to Cancer Stem Cells (CSCs) subpopulation, characterized by high chemoresistance and the unique ability to retain tumorigenic potential, thus associated to tumor recurrence. High dynamic plasticity of CSCs, makes the development of winning therapeutic strategies even more complex to completely eradicate tumor fuel. Rimonabant, originally synthesized as antagonist/inverse agonist of Cannabinoid Receptor 1, is able to inactivate Wnt signaling, both in vitro and in vivo, in CRC models, through inhibition of p300-histone acetyltransferase activity. Since Wnt/β-Catenin pathway is the main player underlying CSCs dynamic, this finding candidates Rimonabant as potential modulator of cancer stemness, in CRC. In this work, using established 3D cultures of primary colon CSCs, taking into account the tumor heterogeneity through monitoring of Wnt activity, we demonstrated that Rimonabant was able to reduces both tumor differentiated cells and colon CSCs proliferation and to control their survival in long term cultures. Interestingly, in ex vivo model of wild type human organoids, retaining both architecture and heterogeneity of original tissue, Rimonabant showed no toxicity against cells from healthy colon epithelium, suggesting its potential selectivity toward cancer cells. Overall, results from this work provided new insights on anti-tumor efficacy of Rimonabant, strongly suggesting that it could be a novel lead compound for CRC treatment.
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影响因子：
64.8
作者：
Koo, Bon-Kyoung;Spit, Maureen;Clevers, Hans
通讯作者：
Clevers, Hans
影响因子：
1.7
作者：
Bordonaro M;Lazarova DL
通讯作者：
Lazarova DL
影响因子：
4.8
作者：
Aguado, Tania;Carracedo, Arkaitz;Galve-Roperh, Ismael
通讯作者：
Galve-Roperh, Ismael
影响因子：
--
作者：
Ciaglia E;Torelli G;Pisanti S;Picardi P;D'Alessandro A;Laezza C;Malfitano AM;Fiore D;Pagano Zottola AC;Proto MC;Catapano G;Gazzerro P;Bifulco M
通讯作者：
Bifulco M
影响因子：
5.3
作者：
Carmon, Kendra S.;Lin, Qiushi;Liu, Qingyun
通讯作者：
Liu, Qingyun