Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender-dependent murine anemia and nephrotoxicity by regulating SIRT3-mediated SOD deacetylation

KPT-9274 is a phase 1 first-in-class dual PAK4/NAMPT inhibitor for solid tumor and non-Hodgkin’s lymphoma. It demonstrates pre-clinical efficacy toward a broad spectrum of acute myeloid leukemia (AML) subtypes by inhibiting NAMPT-dependent NAD+ production. NAMPT is the rate-limiting enzyme in the salvage metabolic pathway leading to NAD+ generation. Tumor cells which are deficient in de novo pathway enzyme NAPRT1 are addicted to NAMPT. In clinical trials, treatment with NAMPT inhibitors resulted in dose-limiting toxicities. In order to dissect the mechanism of toxicity, mice were treated with KPT-9274 and resulting toxicities were characterized histopathologically and biochemically. KPT-9274 treatment caused gender-dependent stomach and kidney injuries and anemia. Female mice treated with KPT-9274 had EPO deficiency and associated impaired erythropoiesis. KPT-9274 treatment suppressed SIRT3 expression and concomitantly upregulated acetyl-manganese superoxide dismutase (MnSOD) in IMCD3 cells, providing a mechanistic basis for observed kidney toxicity. Importantly, niacin supplementation mitigated KPT-9274-caused kidney injury and EPO deficiency without affecting its efficacy. Altogether, our study delineated the mechanism of KPT-9274-mediated toxicity and sheds light onto developing strategies to improve the tolerability of this important anti-AML inhibitor.

A chemical screen for modulators of mRNA translation identifies a distinct mechanism of toxicity for sphingosine kinase inhibitors

We here conducted an image-based chemical screen to evaluate how medically approved drugs, as well as drugs that are currently under development, influence overall translation levels. None of the compounds up-regulated translation, which could be due to the screen being performed in cancer cells grown in full media where translation is already present at very high levels. Regarding translation down-regulators, and consistent with current knowledge, inhibitors of the mechanistic target of rapamycin (mTOR) signaling pathway were the most represented class. In addition, we identified that inhibitors of sphingosine kinases (SPHKs) also reduce mRNA translation levels independently of mTOR. Mechanistically, this is explained by an effect of the compounds on the membranes of the endoplasmic reticulum (ER), which activates the integrated stress response (ISR) and contributes to the toxicity of SPHK inhibitors. Surprisingly, the toxicity and activation of the ISR triggered by 2 independent SPHK inhibitors, SKI-II and ABC294640, the latter in clinical trials, are also observed in cells lacking SPHK1 and SPHK2. In summary, our study provides a useful resource on the effects of medically used drugs on translation, identified compounds capable of reducing translation independently of mTOR and has revealed that the cytotoxic properties of SPHK inhibitors being developed as anticancer agents are independent of SPHKs.

Signaling Pathways Regulated by Silica Nanoparticles

Silica nanoparticles are a class of molecules commonly used in drug or gene delivery systems that either facilitate the delivery of therapeutics to specific drug targets or enable the efficient delivery of constructed gene products into biological systems. Some in vivo or in vitro studies have demonstrated the toxic effects of silica nanoparticles. Despite the availability of risk management tools in response to the growing use of synthetic silica in commercial products, the molecular mechanism of toxicity induced by silica nanoparticles is not well characterized. The purpose of this study was to elucidate the effects of silica nanoparticle exposure in three types of cells including human aortic endothelial cells, mouse-derived macrophages, and A549 non-small cell lung cancer cells using toxicogenomic analysis. The results indicated that among all three cell types, the TNF and MAPK signaling pathways were the common pathways upregulated by silica nanoparticles. These findings may provide insight into the effects of silica nanoparticle exposure in the human body and the possible mechanism of toxicity.

Global Proteomics to Study Silica Nanoparticle-Induced Cytotoxicity and Its Mechanisms in HepG2 Cells

Silica nanoparticles (SiO2 NPs) are commonly used in medical and pharmaceutical fields. Research into the cytotoxicity and overall proteomic changes occurring during initial exposure to SiO2 NPs is limited. We investigated the mechanism of toxicity in human liver cells according to exposure time [0, 4, 10, and 16 h (h)] to SiO2 NPs through proteomic analysis using mass spectrometry. SiO2 NP-induced cytotoxicity through various pathways in HepG2 cells. Interestingly, when cells were exposed to SiO2 NPs for 4 h, the morphology of the cells remained intact, while the expression of proteins involved in mRNA splicing, cell cycle, and mitochondrial function was significantly downregulated. These results show that the toxicity of the nanoparticles affects protein expression even if there is no change in cell morphology at the beginning of exposure to SiO2 NPs. The levels of reactive oxygen species changed significantly after 10 h of exposure to SiO2 NPs, and the expression of proteins associated with oxidative phosphorylation, as well as the immune system, was upregulated. Eventually, these changes in protein expression induced HepG2 cell death. This study provides insights into cytotoxicity evaluation at early stages of exposure to SiO2 NPs through in vitro experiments.

EFFICIENT CHROMATOGRAPHIC APPROACH FOR THE ANALYSIS OF INSECTICIDES AND ECO-TOXICOLOGICAL ASPECTS

In today's rapid growing industries and technology, the frequent use of various insecticide in agriculture sector can be commonly encountered. Insecticides such as carbamate, organochlorine and pyrethroids helps protecting the crop from various insects, which ultimately leads to the better yield of agricultural products. But the main concern that comes out in such frequent practice is the adverse effects to the adjacent ecosystems. Especially, the very commonly used carbofuran, DDT, Cypermethrin and its adverse effects can be put forwarded as a potential example in this article. Apart from this, the scope of this article covers the mechanism of toxicity by insecticides to nontargeted organisms in the ecosystem, the recent developments in the analytical techniques considering HPLC and GC, the method of extraction and quantication of active component in sample. A comparison between GC and HPLC is done and the preferred instrumentation is concluded while considering the analysis of Insecticide. Scope of this review also covers the symptoms and treatment of insecticide poisoning.