Systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia
Abstract Chronic lymphocytic leukemia (CLL) is a B lymphoid malignancy highly dependent on the microenvironment. Despite new targeted therapies such as ibrutinib and venetoclax, disease progression and relapse remain an issue. CLL cell interactions with the supportive tissue microenvironment play a...
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Nature Portfolio
2020
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oai:doaj.org-article:eaa533646552409fbba838dfbdc5b89d2021-12-02T13:58:23ZSystems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia10.1038/s41598-020-78315-02045-2322https://doaj.org/article/eaa533646552409fbba838dfbdc5b89d2020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78315-0https://doaj.org/toc/2045-2322Abstract Chronic lymphocytic leukemia (CLL) is a B lymphoid malignancy highly dependent on the microenvironment. Despite new targeted therapies such as ibrutinib and venetoclax, disease progression and relapse remain an issue. CLL cell interactions with the supportive tissue microenvironment play a critical role in disease pathogenesis. We used a platform for drug discovery based on systems biology and artificial intelligence, to identify drugs targeting key proteins described to have a role in the microenvironment. The selected compounds were screened in CLL cell lines in the presence of stromal cells to mimic the microenvironment and validated the best candidates in primary CLL cells. Our results showed that the commercial drug simvastatin was the most effective and selective out of the tested compounds. Simvastatin decreased CLL cell survival and proliferation as well as cell adhesion. Importantly, this drug enhanced the antitumor effect of venetoclax and ibrutinib. We proposed that systems biology approaches combined with pharmacological screening could help to find new drugs for CLL treatment and to predict new combinations with current therapies. Our results highlight the possibility of repurposing widely used drugs such as statins to target the microenvironment and to improve the efficacy of ibrutinib or venetoclax in CLL cells.Neus GimenezRupal TripathiAriadna GiróLaia RosichMònica López-GuerraIrene López-OrejaHeribert Playa-AlbinyanaFabian ArenasJosé Manuel MasPatricia Pérez-GalánJulio DelgadoElias CampoJudith FarrésDolors ColomerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-16 (2020) |
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Medicine R Science Q Neus Gimenez Rupal Tripathi Ariadna Giró Laia Rosich Mònica López-Guerra Irene López-Oreja Heribert Playa-Albinyana Fabian Arenas José Manuel Mas Patricia Pérez-Galán Julio Delgado Elias Campo Judith Farrés Dolors Colomer Systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia |
| description |
Abstract Chronic lymphocytic leukemia (CLL) is a B lymphoid malignancy highly dependent on the microenvironment. Despite new targeted therapies such as ibrutinib and venetoclax, disease progression and relapse remain an issue. CLL cell interactions with the supportive tissue microenvironment play a critical role in disease pathogenesis. We used a platform for drug discovery based on systems biology and artificial intelligence, to identify drugs targeting key proteins described to have a role in the microenvironment. The selected compounds were screened in CLL cell lines in the presence of stromal cells to mimic the microenvironment and validated the best candidates in primary CLL cells. Our results showed that the commercial drug simvastatin was the most effective and selective out of the tested compounds. Simvastatin decreased CLL cell survival and proliferation as well as cell adhesion. Importantly, this drug enhanced the antitumor effect of venetoclax and ibrutinib. We proposed that systems biology approaches combined with pharmacological screening could help to find new drugs for CLL treatment and to predict new combinations with current therapies. Our results highlight the possibility of repurposing widely used drugs such as statins to target the microenvironment and to improve the efficacy of ibrutinib or venetoclax in CLL cells. |
| format |
article |
| author |
Neus Gimenez Rupal Tripathi Ariadna Giró Laia Rosich Mònica López-Guerra Irene López-Oreja Heribert Playa-Albinyana Fabian Arenas José Manuel Mas Patricia Pérez-Galán Julio Delgado Elias Campo Judith Farrés Dolors Colomer |
| author_facet |
Neus Gimenez Rupal Tripathi Ariadna Giró Laia Rosich Mònica López-Guerra Irene López-Oreja Heribert Playa-Albinyana Fabian Arenas José Manuel Mas Patricia Pérez-Galán Julio Delgado Elias Campo Judith Farrés Dolors Colomer |
| author_sort |
Neus Gimenez |
| title |
Systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia |
| title_short |
Systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia |
| title_full |
Systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia |
| title_fullStr |
Systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia |
| title_full_unstemmed |
Systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia |
| title_sort |
systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia |
| publisher |
Nature Portfolio |
| publishDate |
2020 |
| url |
https://doaj.org/article/eaa533646552409fbba838dfbdc5b89d |
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