Key Points• Cytosolic HSP90-bound Lyn mediates resistance to apoptosis by strengthening PP2A/SET interaction in CLL cells.• FTY720-analogues antagonizing the PP2A/SET interaction and Lyn inhibitors may provide a therapeutic approach of CLL.Aberrant protein kinase activities, and the consequent dramatic increase of Ser/Thr and -Tyr phosphorylation, promote the deregulation of the survival pathways in chronic lymphocytic leukemia (CLL), which is crucial to the pathogenesis and progression of the disease. In this study, we show that the tumor suppressor protein phosphatase 2A (PP2A), one of the major Ser/Thr phosphatases, is in an inhibited form because of the synergistic contribution of 2 events, the interaction with its physiologic inhibitor SET and the phosphorylation of Y307 of the catalytic subunit of PP2A. The latter event is mediated by Lyn, a Src family kinase previously found to be overexpressed, delocalized, and constitutively active in CLL cells. This Lyn/PP2A axis accounts for the persistent high level of phosphorylation of the phosphatase's targets and represents a key connection linking phosphotyrosine-and phosphoserine/threonine-mediated oncogenic signals.The data herein presented show that the disruption of the SET/PP2A complex by a novel FTY720-analog (MP07-66) devoid of immunosuppressive effects leads to the reactivation of PP2A, which in turn triggers apoptosis of CLL cells. When used in combination with SFK inhibitors, the action of MP07-66 is synergistically amplified, providing a new option in the therapeutic strategy for CLL patients. (Blood. 2015;125(24):3747-3755) IntroductionChronic lymphocytic leukemia (CLL), the most common leukemia in the Western world, is characterized by the proliferation of CD5 1 / CD19 1 /CD231 B lymphocytes in lymphoid tissues and bone marrow, which progressively accumulate as mature quiescent cells in the peripheral blood. 1,2 A key role in proliferation and survival of CLL cells is played by microenvironmental factors, which in turn trigger multiple signals mediated by cell surface receptors including CD40, toll-like receptor and B-cell receptor (BCR). [3][4][5] The efforts toward a therapeutic intervention, besides the standard chemo-immunotherapy, have recently focused on hyperactive kinases downstream of the BCR, 6,7 with the development of therapeutically promising inhibitors of these enzymes. [8][9][10] Lyn, for instance, a tyrosine kinase belonging to the Src family kinases (SFKs), has been shown to play a crucial role in the onset and progression of CLL. In CLL cells, Lyn is overexpressed and distributed into 2 pools, one associated beneath the cell surface and the other bound to an aberrant cytosolic complex, which exhibits the constitutive activation responsible for the phosphorylation of a myriad of protein targets in the cytosol and for the resistance of CLL cells to apoptosis. 11-13Because Lyn-targeting drugs, such as dasatinib, 14,15 have yielded disappointing results in managing CLL, [16][17][18][19] we have recently focused on the substrates of...

Copper mixed oxide NPs supported on a hematite surface were achieved using a facile hydrothermal method in a single step. The catalytic potential of the Cu@Fe2O3 NPs was explored for the synthesis of aminoindolizines and pyrrolo[1,2-a]quinolines.

Lyn, a member of the Src family of kinases, is a key factor in the dysregulation of survival and apoptotic pathways of malignant B cells in chronic lymphocytic leukemia. One of the effects of Lyn’s action is spatial and functional segregation of the tyrosine phosphatase SHP-1 into two pools, one beneath the plasma membrane in an active state promoting pro-survival signals, the other in the cytosol in an inhibited conformation and unable to counter the elevated level of cytosolic tyrosine phosphorylation. We herein show that SHP-1 activity can be elicited directly by nintedanib, an agent also known as a triple angiokinase inhibitor, circumventing the phospho-S591-dependent inhibition of the phosphatase, leading to the dephosphorylation of pro-apoptotic players such as procaspase-8 and serine/threonine phosphatase 2A, eventually triggering apoptosis. Furthermore, the activation of PP2A by using MP07-66, a novel FTY720 analog, stimulated SHP-1 activity via dephosphorylation of phospho-S591, which unveiled the existence of a positive feedback signaling loop involving the two phosphatases. In addition to providing further insights into the molecular basis of this disease, our findings indicate that the PP2A/SHP-1 axis may emerge as an attractive, novel target for the development of alternative strategies in the treatment of chronic lymphocytic leukemia.

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Malignant gliomas are aggressive and life-threatening tumours that still show a poor prognosis: the current therapeutic approach based on surgical resection and chemotherapy combined with radiotherapy does not provide a satisfactory chance of long-term survival to patients. Natural bioactive compounds represent a precious source of molecules with antiproliferative activity, potentially effective also against glioma cells. Among these, Juglone is a known allelopathic compound extracted from the eastern black walnut (Juglans nigra) whose antimitotic effect has been extensively described in mammalian cells. We investigated the antiproliferative effect of a synthetic derivative of this natural compound, 2-(2,4-dihydroxyphenyl)-8-hydroxy-1,4-naphthoquinone (DiNAF), in rat glioma cells. We compared this molecule and its effect with the natural reference compound and with newly synthesised derivatives to build a preliminar structure-activity relationship. Biological assays and NMR-based redox experiments confirmed that DiNAF is a promising lead and supported the hypothesis of a redox mechanism underlying its cytotoxic activity.

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We here report the synthesis and evaluation of constrained derivatives of a bisantrene isomer known to bind DNA when structured in G-quadruplex. Enhanced high-resolution mass spectrometry was used to evaluate the binding efficiency and stoichiometry of the compounds towards G-quadruplex DNA using a duplex sequence for comparison. Fluorimetric DNA binding studies supported and confirmed these preliminary observations. One of the newly synthesized compounds showed a high tendency and specificity to bind the structured G-quadruplex DNA.