Structure–Activity Relationships of Withanolides
as Antiproliferative Agents for Multiple Myeloma: Comparison of Activity
in 2D Models and a 3D Coculture Model
posted on 2021-08-17, 13:40authored byMicaela
F. Freitas Misakyan, E. M. Kithsiri Wijeratne, Mark E. Issa, Ya-ming Xu, Aymeric Monteillier, A. A. Leslie Gunatilaka, Muriel Cuendet
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.