Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells

Cardama, Georgina Alexandra; González, Nazareno; Ciarlantini, Matias S; Donadío, Lucía Gandolfi; Comin, Maria Julieta; Alonso, Daniel F.; Menna, Pablo Lorenzano; Gomez, Daniel E.

doi:10.2147/ott.s67998

Cited by 29 publications

(35 citation statements)

References 39 publications

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“…IA-116 demonstrated higher antiproliferative potency than its parental compound in metastatic breast cancer cells, and decreased metastasis to the lung by 60% in an in vivo model of experimental metastasis (Cardama et al, 2014a). Also, IA-116 reduced cell proliferation and invasion in other cancer types, such as leukemia and glioma (Bouquier et al, 2009;Cardama et al, 2014b). In another study, treatment with 1A-116 reverted therapy resistance to tamoxifen in breast cancer cells (Gonzalez et al, 2017), demonstrating the therapeutic potential of Rac inhibitors in overcoming therapy resistance.…”

Section: Targeting Vav1/2/3mentioning

confidence: 97%

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Maldonado

Medina

Velázquez

et al. 2020

Front. Cell Dev. Biol.

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The Rho family GTPases Rho, Rac, and Cdc42 have emerged as key players in cancer metastasis, due to their essential roles in regulating cell division and actin cytoskeletal rearrangements; and thus, cell growth, migration/invasion, polarity, and adhesion. This review will focus on the close homologs Rac and Cdc42, which have been established as drivers of metastasis and therapy resistance in multiple cancer types. Rac and Cdc42 are often dysregulated in cancer due to hyperactivation by guanine nucleotide exchange factors (GEFs), belonging to both the diffuse B-cell lymphoma (Dbl) and dedicator of cytokinesis (DOCK) families. Rac/Cdc42 GEFs are activated by a myriad of oncogenic cell surface receptors, such as growth factor receptors, G-protein coupled receptors, cytokine receptors, and integrins; consequently, a number of Rac/Cdc42 GEFs have been implicated in metastatic cancer. Hence, inhibiting GEF-mediated Rac/Cdc42 activation represents a promising strategy for targeted metastatic cancer therapy. Herein, we focus on the role of oncogenic Rac/Cdc42 GEFs and discuss the recent advancements in the development of Rac and Cdc42 GEF-interacting inhibitors as targeted therapy for metastatic cancer, as well as their potential for overcoming cancer therapy resistance.

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Section: Targeting Vav1/2/3mentioning

confidence: 97%

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Maldonado

Medina

Velázquez

et al. 2020

Front. Cell Dev. Biol.

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“…In fact, it is highly conserved in other members of the Rho GTPase family of proteins, such as Rac2/3 and RhoA/B/C/D/G (Haeusler et al, 2003). 1A-116 Rac1 inhibitor showed antitumoral activity in vitro on a wide variety of cancer types such as breast cancer (Cardama et al, 2014a;Gonzalez et al, 2017), glioblastoma (Cardama et al, 2014b) and acute myeloid leukemia (Cabrera et al, 2017). In this regard, we have already reported that 1A-116 has a profound effect on proliferation, migration, invasion, metastasis, apoptosis, and cell cycle arrest.…”

Section: Introductionmentioning

confidence: 99%

Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity

González

Cardama

Chinestrad

et al. 2020

Front. Cell Dev. Biol.

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In the last years, the development of new drugs in oncology has evolved notably. In particular, drug development has shifted from empirical screening of active cytotoxic compounds to molecularly targeted drugs blocking specific biologic pathways that drive cancer progression and metastasis. Using a rational design approach, our group has developed 1A-116 as a promising Rac1 inhibitor, with antitumoral and antimetastatic effects in several types of cancer. Rac1 is over activated in a wide range of tumor types and and it is one of the most studied proteins of the Rho GTPase family. Its role in actin cytoskeleton reorganization has effects on endocytosis, vesicular trafficking, cell cycle progression and cellular migration. In this context, the regulatory activity of Rac1 affects several key processes in the course of the cancer including invasion and metastasis. The purpose of this preclinical study was to focus on the mode of action of 1A-116, conducting an interdisciplinary approach with in silico bioinformatics tools and in vitro assays. Here, we demonstrate that the tryptophan 56 residue is necessary for the inhibitory effects of 1A-116 since this compound interferes with protein-protein interactions (PPI) of Rac1GTPase involving several GEF activators. 1A-116 is also able to inhibit the oncogenic Rac1 P29S mutant protein, one of the oncogenic drivers found in sun-exposed melanoma. It also inhibits numerous Rac1-regulated cellular processes such as membrane ruffling and lamellipodia formation. These results deepen our knowledge of 1A-116 inhibition of Rac1 and its biological impact on cancer progression. They also represent a good example of how in silico analyses represent a valuable approach for drug development.

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“…The importance of cytoskeleton-associated proteins and pathways involved in glioma has also been reported in numerous previous studies ( 27 , 28 ). In addition, increasing evidence revealed that lncRNAs are associated with the occurrence and development of glioma by regulating the structure of reorganization of cytoskeleton-associated proteins and signaling pathways ( 29 , 30 ). Additionally, the association between metastasis or cytoskeleton and the prognosis of glioma has also been reported ( 31 , 32 ).…”

Section: Discussionmentioning

confidence: 99%

Risk assessment model constructed by differentially expressed lncRNAs for the prognosis of glioma

Zhou

Liu

et al. 2018

Oncol Rep

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A risk assessment model was constructed using differentially expressed long non-coding (lnc)RNAs for the prognosis of glioma. Transcriptome sequencing of the lncRNAs and mRNAs from glioma samples were obtained from the TCGA database. The samples were divided into bad and good prognosis groups based on survival time, then differently expressed lncRNAs between these two groups were screened using DEseq and edgeR packages. Multivariate Cox regression analysis was performed to establish a risk assessment system according to the weighted regression coefficient of lncRNA expression. Survival analysis and receiver operating characteristic curve were conducted for the risk assessment model. Furthermore, the co-expression network of the screened lncRNAs was constructed, followed by the functional enrichment analysis for associated genes. A total of 117 lncRNAs were screened using edgeR and DEseq packages. Among all differently expressed lncRNAs, five lncRNAs (RP3-503A6, LINC00940, RP11-453M23, AC009411 and CDRT7) were identified to establish the risk assessment model. The risk assessment model demonstrated a good prognostic function with high area under the curve values in the training, validation and entire sets. The risk score was certified as an independent prognostic factor for gliomas. Multiple genes were screened to be co-expressed with these five lncRNAs. Functional enrichment analysis demonstrated that they were involved in cytoskeleton, adhesion and Janus kinase/signal transducer and activator of transcription signaling pathway-associated processes. The present study established a risk assessment model integrating five significantly different expressed lncRNAs, which may help to assess the prognosis of patients with glioma with increased accuracy.

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Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells

Cited by 29 publications

References 39 publications

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity

Risk assessment model constructed by differentially expressed lncRNAs for the prognosis of glioma

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