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1.
Acta Trop ; 238: 106801, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36563831

ABSTRACT

Leishmaniasis is a parasitic disease found in tropical and subtropical regions around the world, caused by parasites of the genus Leishmania. The disease is a public health concern and presents clinical manifestations that can cause death, disability, and mutilation. The parasite has promastigote (vector) and amastigote (vertebrate host) forms and kinase enzymes are involved in this differentiation process. In the present investigation, we show, for the first time, evidence of a serine/arginine protein kinase in Leshmania braziliensis (LbSRPK). Our results show that amastigotes express more LbSRPK than promastigotes.  Analogues of SRPIN340 (a known inhibitor of SRPK) were evaluated for their leishmanicidal activity and two of them, namely SRVIC22 and SRVIC32 showed important leishmanicidal activity in vitro. SRVIC22 and SRVIC32 were able to reduce the infection rate in macrophages and the number of intracellular amastigotes by 55 and 60%, respectively. Bioinformatics analysis revealed the existence of two different amino acid residues in the active site of LbSRPK compared to their human homologue (Tyr/Leu-and Ser/Tyr), which could explain the absence of leishmanicidal activity of SRPIN340 on infected macrophages. In order to enhance leishmanicidal activity of the analogues, optimizations were proposed in the structures of the ligands, suggesting strong interactions with the catalytic site of LbSRPK. Although the evidence on the action of inhibitors upon LbSRPK is only indirect, our studies not only reveal, for the first time, evidence of a SRPK in Leishmania, but also shed light on a new therapeutic target for drug development.


Subject(s)
Arginine Kinase , Leishmania braziliensis , Leishmania , Humans , Animals , Mice , Protein Kinases , Protein Serine-Threonine Kinases , Arginine , Serine , Mice, Inbred BALB C
2.
Anticancer Drugs ; 31(7): 718-727, 2020 08.
Article in English | MEDLINE | ID: mdl-32568827

ABSTRACT

Conventional treatments for metastatic melanomas are still ineffective and generate numerous side effects, justifying the search for new therapies. The antimetastatic effect of the named N-(2-(4-bromophenylamino)-5-(trifluoromethyl)phenyl)nicotinamide (SRVIC30) compound has been previously demonstrated in murine melanoma. Herein, we aimed to evaluate its effect when topically administrated in a murine subcutaneous melanoma model. For that, mice C57BL/6 were injected subcutaneously with 2 × 10 B16-F10 cells. Topical treatment began when tumors became visible on animal's back. Therefore, tumor volume was measured three times a week until it reaches 12 mm approximately. At this point, 40 mg oil-in-water cream (Lanette) without (control mice; n = 10) or with SRVIC30 compound (SRVIC30 group; n = 10 animals) were spread daily over the tumor external surface using a small brush for 14 days. The treatments increased the percentage of peroxidase antioxidant enzyme and dead cells via caspase-3 activation, with a consequent deposit of collagen fibers in the tumors. In addition, the skin of treated animals showed the presence of inflammatory infiltrate. Finally, SRVIC30 did not show signs of toxicity. Thus, we concluded that the topic administration of SRVIC30 was able to influence crucial anticancer processes such as tumor cells apoptosis and surrounding microenvironment.


Subject(s)
Melanoma, Experimental/drug therapy , Niacinamide/analogs & derivatives , Skin Neoplasms/drug therapy , Administration, Topical , Animals , Caspase 3/metabolism , Cell Death/drug effects , Male , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Niacinamide/adverse effects , Niacinamide/pharmacology , Skin Neoplasms/pathology
3.
Toxicol In Vitro ; 65: 104777, 2020 Jun.
Article in English | MEDLINE | ID: mdl-31962201

ABSTRACT

The serine/arginine protein kinases respond to the EGFR-PI3K-AKT signaling module in the context of pre-mRNA alternative splicing regulation. These enzymes (notably SRPK1 and SRPK2) have been found dysregulated in a variety of cancers, which suggests them as promising drug targets in oncology. SRPK2 has been related to leukemia cells proliferation and found preferentially overexpressed in T-cell acute lymphoblastic leukemia (T-ALL). Previously, synergistic combination between vincristine and SRPK inhibitors has been observed in leukemia cells in vitro. Herein we sought to evaluate the in vitro combinatory effects of inhibiting SRPK and multiple other kinase targets from the EGFR pathway in T-ALL, a hematological malignancy with a still poor prognosis. We found that the combined SRPK and AKT pharmacological inhibition is synergistic in Jurkat, CCRF-CEM, and TALL-1 (all T-ALL) but not in HL60, an acute myelogenous leukemia cell lineage. Combined treatments also impaired SR proteins phosphorylation in accordance with an improved suppression of SRPK activity. Furthermore, the synergism of treatments seemed associated with apoptosis triggering, as revealed by flow cytometry analyses. Taken together, these results suggest the therapeutic potential of the combined SRPK and AKT pharmacological inhibition against T-ALL.


Subject(s)
Antineoplastic Agents/pharmacology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Chlorocebus aethiops , Drug Synergism , ErbB Receptors/metabolism , Humans , Mice , NIH 3T3 Cells , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Vero Cells
4.
Toxicol Appl Pharmacol ; 356: 214-223, 2018 10 01.
Article in English | MEDLINE | ID: mdl-30138656

ABSTRACT

The Serine/arginine-rich protein kinases (SRPK) are involved in pre-mRNA splicing control through the phosphorylation of the SR protein family of splicing factors. Over the last years, several studies have shown the relevance of SRPK for human cancers and their potential as promising drug targets. In this context, we have previously selected three trifluoromethyl arylamides (named here as SRVIC24, SRVIC30 and SRVIC36) with improved in vitro antileukemia effect and ability of impairing the cellular activity of SRPK. Given the increasing amount of reports on the implication of these kinases in metastatic cancers, in this study, we have evaluated the antimetastatic effect of these compounds and the known SRPK inhibitor (SRPIN340) on a murine model of metastatic melanoma. The compounds were able to impact the melanoma cell metastatic behavior by decreasing migration, invasion, adhesion, and colony formation in in vitro assays. Also, they presented antimetastatic in vivo activity, without apparent signs of systemic toxicity after treatments, as revealed by the histology of organs and analysis of key serum biochemical markers. Moreover, the effect of the treatments on SRPK1 nuclear translocation and SR protein phosphorylation was observed. Finally, molecular docking studies were carried out to gain structural information on the SRPK-compound complexes. Together, these data suggest that SRPK pharmacological inhibition should be considered as an interesting therapeutic strategy against metastatic cancers.


Subject(s)
Antineoplastic Agents/pharmacology , Melanoma, Experimental/drug therapy , Neoplasm Metastasis/prevention & control , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Cell Adhesion/drug effects , Cell Movement/drug effects , Drug Screening Assays, Antitumor , Female , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Neoplasm Invasiveness , Niacinamide/analogs & derivatives , Niacinamide/pharmacology , Niacinamide/therapeutic use , Piperidines/pharmacology , Piperidines/therapeutic use , Tumor Stem Cell Assay
5.
Eur J Med Chem ; 134: 97-109, 2017 Jul 07.
Article in English | MEDLINE | ID: mdl-28407594

ABSTRACT

The serine/arginine-rich protein kinases (SRPKs) have frequently been found with altered activity in a number of cancers, suggesting they could serve as potential therapeutic targets in oncology. Here we describe the synthesis of a series of twenty-two trifluoromethyl arylamides based on the known SRPKs inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) and the evaluation of their antileukemia effects. Some derivatives presented superior cytotoxic effects against myeloid and lymphoid leukemia cell lines compared to SRPIN340. In particular, compounds 24, 30, and 36 presented IC50 values ranging between 6.0 and 35.7 µM. In addition, these three compounds were able to trigger apoptosis and autophagy, and to exhibit synergistic effects with the chemotherapeutic agent vincristine. Furthermore, compound 30 was more efficient than SRPIN340 in impairing the intracellular phosphorylation status of SR proteins as well as the expression of MAP2K1, MAP2K2, VEGF, and RON oncogenic isoforms. Therefore, novel compounds with increased intracellular effects against SRPK activity were obtained, contributing to medicinal chemistry efforts towards the development of new anticancer agents.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Leukemia/drug therapy , Niacinamide/analogs & derivatives , Piperidines/chemistry , Piperidines/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents, Phytogenic/pharmacology , Cell Death/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Leukemia/metabolism , Niacinamide/chemical synthesis , Niacinamide/chemistry , Niacinamide/pharmacology , Piperidines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Vincristine/pharmacology
6.
PLoS One ; 10(8): e0134882, 2015.
Article in English | MEDLINE | ID: mdl-26244849

ABSTRACT

Dysregulation of pre-mRNA splicing machinery activity has been related to the biogenesis of several diseases. The serine/arginine-rich protein kinase family (SRPKs) plays a critical role in regulating pre-mRNA splicing events through the extensive phosphorylation of splicing factors from the family of serine/arginine-rich proteins (SR proteins). Previous investigations have described the overexpression of SRPK1 and SRPK2 in leukemia and other cancer types, suggesting that they would be useful targets for developing novel antitumor strategies. Herein, we evaluated the effect of selective pharmacological SRPK inhibition by N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) on the viability of lymphoid and myeloid leukemia cell lines. Along with significant cytotoxic activity, the effect of treatments in regulating the phosphorylation of the SR protein family and in altering the expression of MAP2K1, MAP2K2, VEGF and FAS genes were also assessed. Furthermore, we found that pharmacological inhibition of SRPKs can trigger early and late events of apoptosis. Finally, intrinsic tryptophan fluorescence emission, molecular docking and molecular dynamics were analyzed to gain structural information on the SRPK/SRPIN340 complex. These data suggest that SRPK pharmacological inhibition should be considered as an alternative therapeutic strategy for fighting leukemias. Moreover, the obtained SRPK-ligand interaction data provide useful structural information to guide further medicinal chemistry efforts towards the development of novel drug candidates.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Niacinamide/analogs & derivatives , Piperidines/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Binding Sites , Blotting, Western , Cell Survival/drug effects , Cells, Cultured , Gene Expression Regulation, Leukemic , HL-60 Cells , HeLa Cells , Humans , Jurkat Cells , K562 Cells , Leukemia/genetics , Leukemia/metabolism , Leukemia/pathology , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Niacinamide/chemistry , Niacinamide/metabolism , Niacinamide/pharmacology , Piperidines/chemistry , Piperidines/metabolism , Protein Binding , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Tertiary , Reverse Transcriptase Polymerase Chain Reaction , Spectrometry, Fluorescence
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