NSC 319726

NSC 319726 is a reactivator of mutant p53 with IC50 value of 8nM [1].

NSC 319726 belongs to the thiosemicarbazone family. In a mouse fibroblast cell line Balb/c 3T3, NSC 319726 shows greater inhibition of cell growth in cells expressing mutant p53 than in WT p53 control. NSC 319726 is also nontoxic to WI38 human fibroblasts (p53 WT). In three different ovarian carcinoma cell lines (TOV112D (p53R175H), OVCAR3 (p53R248W) and SKOV3 (p53-/-)), treatment of NSC 319726 results in an induction of apoptosis in the p53R175 mutant. NSC 319726 restores p53 function through inducing a conformation change of mutant p53 to a “WT-like” structure which can be recognized by the WT specific antibody. The inhibition of cell growth caused by NSC 319726 is also found in the TOV112D (p53R175H) xenografts when the dose of NSC 319726 is 1mg/kg. Furthermore, it is shown that zinc ion chelation and ROS changes are important for the apoptosis induced by NSC319726 [1].

References:
[1] Yu X, Vazquez A, Levine AJ, Carpizo DR. Allele-specific p53 mutant reactivation. Cancer Cell. 2012 May 15;21(5):614-25.

VEGF alleviates ALS-CSF induced cytoplasmic accumulations of TDP-43 and FUS/TLS in NSC-34 cells.[Pubmed:28163215]

J Chem Neuroanat. 2017 Apr;81:48-52.

Cytoplasmic mislocalisation and aggregation of TDP-43 and FUS/TLS proteins in spinal motor neurons contribute to the pathogenesis of the highly fatal disorder amyotrophic lateral sclerosis (ALS). We investigated the neuroprotective effect of VEGF on expression of these proteins in the motor neuronal cell line NSC-34 modelled to reminisce sporadic form of ALS. We studied the expression of TDP-43 and FUS/TLS proteins after exposure to ALS-CSF and following VEGF supplementation by quantitative confocal microscopy and electron microscopy. ALS-CSF caused cytoplasmic overexpression of both the proteins and stress-granule formation in the cells. These alterations were alleviated by VEGF supplementation. The related ultrastructural changes like nuclear membrane dysmorphism and p-bodies associated changes were also reversed. However the protein expression did not completely translocate to the nucleus, as some cells continued to show to cytoplasmic mislocalisation. Thus, the present findings indicate that VEGF alleviates TDP43 and FUS pathology by complimenting its role in controlling apoptosis and reversing choline acetyl transferase expression. Hence, VEGF appears to target multiple pathogenic processes in the neurodegenerative cascade of ALS.

Important modifications by sugammadex, a modified gamma-cyclodextrin, of ion currents in differentiated NSC-34 neuronal cells.[Pubmed:28049438]

BMC Neurosci. 2017 Jan 3;18(1):6.

BACKGROUND: Sugammadex (SGX) is a modified gamma-cyclodextrin used for reversal of steroidal neuromuscular blocking agents during general anesthesia. Despite its application in clinical use, whether SGX treatment exerts any effects on membrane ion currents in neurons remains largely unclear. In this study, effects of SGX treatment on ion currents, particularly on delayed-rectifier K(+) current [I K(DR)], were extensively investigated in differentiated NSC-34 neuronal cells. RESULTS: After cells were exposed to SGX (30 muM), there was a reduction in the amplitude of I K(DR) followed by an apparent slowing in current activation in response to membrane depolarization. The challenge of cells with SGX produced a depolarized shift by 15 mV in the activation curve of I K(DR) accompanied by increased gating charge of this current. However, the inactivation curve of I K(DR) remained unchanged following SGX treatment, as compared with that in untreated cells. According to a minimal reaction scheme, the lengthening of activation time constant of I K(DR) caused by cell treatment with different SGX concentrations was quantitatively estimated with a dissociation constant of 17.5 muM, a value that is clinically achievable. Accumulative slowing in I K(DR) activation elicited by repetitive stimuli was enhanced in SGX-treated cells. SGX treatment did not alter the amplitude of voltage-gated Na(+) currents. In SGX-treated cells, dexamethasone (30 muM), a synthetic glucocorticoid, produced little or no effect on L-type Ca(2+) currents, although it effectively suppressed the amplitude of this current in untreated cells. CONCLUSIONS: The treatment of SGX may influence the amplitude and gating of I K(DR) and its actions could potentially contribute to functional activities of motor neurons if similar results were found in vivo.

Adult NSC diversity and plasticity: the role of the niche.[Pubmed:27978480]

Curr Opin Neurobiol. 2017 Feb;42:68-74.

Adult somatic stem cells are generally defined as cells with the ability to differentiate into multiple different lineages and to self-renew during long periods of time. These features were long presumed to be represented in one single tissue-specific stem cell. Recent development of single-cell technologies reveals the existence of diversity in fate and activation state of somatic stem cells within the blood, skin and intestinal compartments [1] but also in the adult brain. Here we review how recent advances have expanded our view of neural stem cells (NSCs) as a diverse pool of cells and how the specialized microenvironment in which they reside acts to maintain this diversity. In addition, we discuss the plasticity of the system in the injured brain.

c-Jun Amino-Terminal Kinase is Involved in Valproic Acid-Mediated Neuronal Differentiation of Mouse Embryonic NSCs and Neurite Outgrowth of NSC-Derived Neurons.[Pubmed:28321599]

Neurochem Res. 2017 Apr;42(4):1254-1266.

Valproic acid (VPA), an anticonvulsant and mood-stabilizing drug, can induce neuronal differentiation, promote neurite extension and exert a neuroprotective effect in central nervous system (CNS) injuries; however, comparatively little is known regarding its action on mouse embryonic neural stem cells (NSCs) and the underlying molecular mechanism. Recent studies suggested that c-Jun N-terminal kinase (JNK) is required for neurite outgrowth and neuronal differentiation during neuronal development. In the present study, we cultured mouse embryonic NSCs and treated the cells with 1 mM VPA for up to 7 days. The results indicate that VPA promotes the neuronal differentiation of mouse embryonic NSCs and neurite outgrowth of NSC-derived neurons; moreover, VPA induces the phosphorylation of c-Jun by JNK. In contrast, the specific JNK inhibitor SP600125 decreased the VPA-stimulated increase in neuronal differentiation of mouse embryonic NSCs and neurite outgrowth of NSC-derived neurons. Taken together, these results suggest that VPA promotes neuronal differentiation of mouse embryonic NSCs and neurite outgrowth of NSC-derived neurons. Moreover, JNK activation is involved in the effects of VPA stimulation.

Allele-specific p53 mutant reactivation.[Pubmed:22624712]

Cancer Cell. 2012 May 15;21(5):614-25.

Rescuing the function of mutant p53 protein is an attractive cancer therapeutic strategy. Using the National Cancer Institute's anticancer drug screen data, we identified two compounds from the thiosemicarbazone family that manifest increased growth inhibitory activity in mutant p53 cells, particularly for the p53(R175) mutant. Mechanistic studies reveal that NSC319726 restores WT structure and function to the p53(R175) mutant. This compound kills p53(R172H) knockin mice with extensive apoptosis and inhibits xenograft tumor growth in a 175-allele-specific mutant p53-dependent manner. This activity depends upon the zinc ion chelating properties of the compound as well as redox changes. These data identify NSC319726 as a p53(R175) mutant reactivator and as a lead compound for p53-targeted drug development.

NSC319726 (ZMC1) is a mutant p53R175 reactivator; inhibits growth of fibroblasts expressing the p53R175 mutation (IC50 = 8 nM); shows no inhibition for p53 wild-type cells.

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