The synthetic purine reversine selectively induces cell death of cancer cells

Piccoli, Marco; Palazzolo, Giacomo; Conforti, Erika; Lamorte, Giuseppe; Papini, Nadia; Creo, Pasquale; Fania, Chiara; Scaringi, Raffaella; Bergante, Sonia; Tringali, Cristina; Roncoroni, Leda; Mazzoleni, Stefania; Doneda, Luisa; Galli, Rossella; Venerando, Bruno; Tettamanti, Guido; Gelfi, Cecilia; Anastasia, Luigi

doi:10.1002/jcb.24197

Cited by 20 publications

(12 citation statements)

References 37 publications

(69 reference statements)

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“…As a strategy for dual inhibition of AURKA and AURKB, reversine [2-(4-morpholinoanilino)-6-cyclohexylaminopurine] was employed. Reversine is a small synthetic purine analogue that induces mitotic catastrophe, cell-cycle arrest, polyploidy, and apoptosis in several cancer models 16–19 . Herein, we described the molecular and cellular effects of the treatment with reversine in the context of JAK2 V617F -positive MPN.…”

Section: Introductionmentioning

confidence: 99%

Reversine exhibits antineoplastic activity in JAK2V617F-positive myeloproliferative neoplasms

Lima

Carlos

Alves-Paiva

et al. 2019

Sci Rep

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JAK2/STAT signaling participates in the Ph-negative myeloproliferative neoplasms (MPN) pathophysiology and has been targeted by ruxolitinib, a JAK1/2 inhibitor. In the present study, the impact of ruxolitinib treatment on cytoskeleton-related genes expression was explored. In SET2 cells, AURKA and AURKB expression/activity were downregulated in a dose- and time-dependent manner by ruxolitinib. Reversine, a multikinase inhibitor selective for aurora kinases, reduced cell viability in a dose- and/or time-dependent manner in JAK2 V617F cells. Reversine significantly increased apoptosis and mitotic catastrophe, and reduced cell proliferation and clonogenic capacity in SET2 and HEL cells. In the molecular scenario, reversine induced DNA damage and apoptosis markers, as well as, reduced AURKA and AURKB expression/activity. In SET2 cells, reversine modulated the expression of 32 out of 84 apoptosis-related genes investigated, including downregulation of antiapoptotic ( BCL2 , BCL2L1 , and BIRC5 ) and upregulation of proapoptotic ( BIK , BINP3 , and BNIP3L ) genes. Synergism experiments indicated that low dose of reversine had a potentiating effect under ruxolitinib treatment at low doses in SET2 cells. In summary, our exploratory study establishes new targets, related to the regulation of the cellular cytoskeleton, for potential pharmacological intervention in MPN. These findings indicate that AURKA and AURKB participate in the JAK2/STAT signaling pathway and contribute to the MPN phenotype.

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Section: Introductionmentioning

confidence: 99%

Reversine exhibits antineoplastic activity in JAK2V617F-positive myeloproliferative neoplasms

Lima

Carlos

Alves-Paiva

et al. 2019

Sci Rep

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“…Interestingly, this protein has emerged as a potential target for cancer therapy and reversine is known to inhibit Mps1 more efficiently than Aurora-B kinase, based on experimental and computational approaches [ 9 ]. As inhibitor of Aurora-A and Aurora-B kinases and Mps1, reversine causes an incorrect mitotic spindle assembly and chromosome separation, cell cycle arrest in G2/M phase, endoreduplication and eventually cell death due to a phenomenon called “mitotic catastrophe” observed in many cancer cell lines [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Moreover, reversine treatment of human follicular thyroid cancer cells leads to the activation of autophagy due to its capability to down-regulate mTOR [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…p53 has been observed to play an important role in modulation of reversine effect. It has been demonstrated that silencing of p53, and the consequent loss of transcriptional activation of its target p21, whose checkpoint function can prevent endoreduplication, renders fibroblasts more sensitive to reversine [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 2,6-Diamino-Substituted Purine Derivatives and Evaluation of Cell Cycle Arrest in Breast and Colorectal Cancer Cells

et al. 2018

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Reversine is a potent antitumor 2,6-diamino-substituted purine acting as an Aurora kinases inhibitor and interfering with cancer cell cycle progression. In this study we describe three reversine-related molecules, designed by docking calculation, that present structural modifications in the diamino units at positions 2 and 6. We investigated the conformations of the most stable prototropic tautomers of one of these molecules, the N6-cyclohexyl-N6-methyl-N2-phenyl-7H-purine-2,6-diamine (3), by Density Functional Theory (DFT) calculation in the gas phase, water and chloroform, the last solvent considered to give insights into the detection of broad signals in NMR analysis. In all cases the HN(9) tautomer resulted more stable than the HN(7) form, but the most stable conformations changed in different solvents. Molecules 1–3 were evaluated on MCF-7 breast and HCT116 colorectal cancer cell lines showing that, while being less cytotoxic than reversine, they still caused cell cycle arrest in G2/M phase and polyploidy. Unlike reversine, which produced a pronounced cell cycle arrest in G2/M phase in all the cell lines used, similar concentrations of 1–3 were effective only in cells where p53 was deleted or down-regulated. Therefore, our findings support a potential selective role of these structurally simplified, reversine-related molecules in p53-defective cancer cells.

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“…The interference raised by Rev with the mitotic spindle organization is described to block cells mainly in the G 2 /M (Chen et al, ) and G1/S transitions (Piccoli et al, ). We also confirmed this assumption for OA chondrocytes by quantitative RT‐PCR experiments, assessing the Ki67 and cyclin D1 mRNA levels.…”

Section: Resultsmentioning

confidence: 99%

Exposure to reversine affects the chondrocyte morphology and phenotypein vitro

Gasparini¹,

Villa²,

Molfetta

et al. 2017

J Tissue Eng Regen Med

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Articular chondrocytes derived from osteoarthritic tissues (OA HAC) show a severely reduced chondrogenic commitment. This impairment undermines their use for tissue-engineered cartilage repair, which relies on cell proliferation and growth to meet therapeutic needs, but also on efficient cell plasticity to recover the chondrogenic phenotype. Reversine (Rev), a 2,6-disubstituted purine inhibitor of spindle-assembly checkpoints, was described to convert differentiated mesenchymal cells to their undifferentiated precursors. We hypothesized that Rev exposure could divert OA HAC to more plastic cells, re-boosting their subsequent commitment. HAC were enzymatically released from OA cartilage specimens, expanded for 2 weeks and treated with 5 μm Rev in dimethylsulphoxide (DMSO) or with DMSO alone for 6 days. Cell growth was assessed using the AlamarBlue assay. Cytoskeletal structure, endoproliferation and caspase-3-immunopositivity were assayed by epifluorescence microscopy. The OA HAC chondrogenic performance was evaluated by quantitative reverse transcription-polymerase chain reaction (RT-PCR) for glyceraldehyde-3-phosphate dehydrogenase, Sox9, Aggrecan (Agg), type II collagen (Col2), Ki67, cyclinD1, transforming growth factor-β1 (TGF-β1), -2 and -3, interleukin-1β (IL-1β) and -6 , SMAD3 and -7, and vascular endothelial growth factor. Rev-treated OA HAC recovered polygonal morphology and reduced Ki67 expression and proliferation. Cell-cycle impairment accounted for altered cytoskeletal organization, endoproliferation and apoptosis, whereas a compensatory mechanism sustained the increased cyclinD1 transcript levels. Sox9, Agg and TGFs were overexpressed, but not Col2. IL transcripts were massively downregulated. These events were dose-related and transient. Overall, in spite of a higher Rev-induced transcriptional activity for extracellular matrix components and in spite of a Rev-treated cell phenotype closer to that of the three-dimensional native articular chondrocyte, Rev effects seem unleashed from a full regained chondrogenic potential.

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The synthetic purine reversine selectively induces cell death of cancer cells

Cited by 20 publications

References 37 publications

Reversine exhibits antineoplastic activity in JAK2V617F-positive myeloproliferative neoplasms

Reversine exhibits antineoplastic activity in JAK2V617F-positive myeloproliferative neoplasms

Synthesis of 2,6-Diamino-Substituted Purine Derivatives and Evaluation of Cell Cycle Arrest in Breast and Colorectal Cancer Cells

Exposure to reversine affects the chondrocyte morphology and phenotypein vitro

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