Structure–Activity Relationships of Withanolides as Antiproliferative Agents for Multiple Myeloma: Comparison of Activity in 2D Models and a 3D Coculture Model,Journal of Natural Products

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Structure–Activity Relationships of Withanolides as Antiproliferative Agents for Multiple Myeloma: Comparison of Activity in 2D Models and a 3D Coculture Model
Journal of Natural Products ( IF 3.3 ) Pub Date : 2021-08-17 , DOI: 10.1021/acs.jnatprod.1c00446
Micaela F Freitas Misakyan _{1,

2,

3} , E M Kithsiri Wijeratne ₄ , Mark E Issa _{1,

2,

3} , Ya-Ming Xu ₄ , Aymeric Monteillier _{1,

2,

3} , A A Leslie Gunatilaka ₄ , Muriel Cuendet _{1,

2,

3}

Affiliation

Multiple myeloma (MM) is a hematological cancer in which relapse and resistance are highly frequent. Therefore, alternatives to conventional treatments are necessary. Withaferin A, a withanolide isolated from Withania somnifera, has previously shown promising activity against various MM models. In the present study, structure–activity relationships (SARs) were evaluated using 56 withanolides. The antiproliferative activity was assessed in three MM cell lines and in a 3D MM coculture model to understand the in vitro activity of compounds in models of various complexity. While the results obtained in 2D allowed a quick and simple evaluation of cytotoxicity used for a first selection, the use of the 3D MM coculture model allowed filtering compounds that perform better in a more complex setup. This study shows the importance of the last model as a bridge between 2D and in vivo studies to select the most active compounds and ultimately lead to a reduction of animal use for more sustained in vivo studies. NF-κB inhibition was determined to evaluate if this could be one of the targeted pathways. The most active compounds, withanolide D (2) and 38, should be further evaluated in vivo.

中文翻译：

作为多发性骨髓瘤抗增殖剂的睡莲内酯的结构-活性关系：2D 模型和 3D 共培养模型中的活性比较

多发性骨髓瘤 (MM) 是一种血液系统癌症，复发和耐药性非常高。因此，需要替代常规治疗。Withaferin A，一种从Withania somnifera 中分离的 withanolide，之前已经显示出针对各种 MM 模型的有希望的活动。在本研究中，使用 56 种 withanolides 评估了构效关系 (SAR)。在三种 MM 细胞系和 3D MM 共培养模型中评估了抗增殖活性，以了解化合物在各种复杂模型中的体外活性。虽然在 2D 中获得的结果允许对用于第一次选择的细胞毒性进行快速和简单的评估，但使用 3D MM 共培养模型允许过滤在更复杂的设置中表现更好的化合物。该研究显示了最后一个模型作为 2D 和体内研究之间的桥梁的重要性，以选择最活跃的化合物，并最终导致减少动物使用以进行更持续的体内研究。确定 NF-κB 抑制以评估这是否可能是靶向途径之一。最活跃的化合物，withanolide D (2 ) 和38，应在体内进一步评估。

更新日期：2021-08-27

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