bims-aporos 2018-08-26 papers

Issue of 2018‒08‒26
four papers selected by
Gavin McStay
Staffordshire University

Food Chem Toxicol. 2018 Aug 16. pii: S0278-6915(18)30582-9. [Epub ahead of print]121 15-23

Mitigation of cell apoptosis induced by ochratoxin A (OTA) is possibly through organic cation transport 2 (OCT2) knockout.

Xiaozhe Qi, Liye Zhu, Bo Yang, Haoshu Luo, Wentao Xu, Xiaoyun He, Kunlun Huang.

Ochratoxin A (OTA) is a secondary metabolite of fungi such as Aspergillus ochraceus, A. niger and A. carbonarius, Penicillium verrucosum, and various other Penicillium, Petromyces, and Neopetromyces species. Various foods can be contaminated with OTA, potentially causing several toxic effects such as nephrotoxicity, hepatotoxicity and neurotoxicity. Typically, OTA is excreted by organic anion transporters (OATs). There is no research indicating organic cation transporters (OCTs) are involved in OTA nephrotoxicity. In our study, NRK-52E cells and rats were treated with OTA. OTA changed the expression of OCT1, OCT2 and OCT3 in NRK-52E cells and rat kidneys. TEA alleviated OTA-induced cell death, apoptosis, and DNA damage, and increased ROS. The OCT2 knockout cell line was constructed by the CRISPR/Cas 9 system. OCT2 knockout did not change the gene expression of OCT1, OAT1 and OAT3. OCT2 knockout alleviated the increase of Caspase 3 and CDK1 induced by OTA, leading to a reduction of apoptosis. In addition, OCT2 overexpression increased cell toxicity and expression of Caspase 3. In short, our findings indicate that OCT2 knockout possibly mitigate OTA-induced apoptosis by preventing the increase of Caspase 3 and CDK1.

Keywords: Cell apoptosis; Knockout; OCT2; Ochratoxin A; Overexpression

DOI: https://doi.org/10.1016/j.fct.2018.08.026

J Inorg Biochem. 2018 Aug 03. pii: S0162-0134(18)30239-3. [Epub ahead of print]188 76-87

Vanadyl complexes discriminate between neuroblastoma cells and primary neurons by inducing cell-specific apoptotic pathways.

Yue Zhang, Lichao Wang, Kewu Zeng, Kui Wang, Xiaoda Yang.

Vanadium compounds have arisen as potential therapeutic agent for the treatment of cancers over the past decades. A few studies suggested that vanadyl complexes may discriminate between the cancerous and the normal cells. Here, we reported the investigation on the pro-apoptotic effect and the underlying mechanism of bis(acetylacetonato) oxovanadium(IV) ([VO(acac)2]) on SH-SY5Y neuroblastoma cells in comparison with that of mouse primary cortex neurons. The experimental results revealed that [VO(acac)2] showed about 10-fold higher cytotoxicity (IC50 ~16 μM) on the neuroblastoma cells than on normal neurons (IC50 ~250 μM). Further analysis indicated that the vanadyl complex suppressed the growth of neuroblastoma cells via different pathways depending on its concentration. It induced a special cyclin D-mediated and p53-independent cell apoptosis at <50 μM but cell cycle arrests at >50 μM. In contrast, [VO(acac)2] promoted cell viability of primary neurons in the concentration range of 0-150 μM; while [VO(acac)2] at hundreds of μM would cause neuronal death possibly via the reactive oxygen species (ROS)-mediated signal pathways. The extraordinary discrimination between neuroblastoma cells and primary neurons suggests potential application of vanadyl complexes for therapeutic treatment of neuroblastoma. In addition, the p53-independent apoptotic pathways induced by vanadyl complexes may provide new insights for future discovery of new anticancer drugs overcoming the chemo-resistance due to p53 mutation.

Keywords: Apoptosis; Cyclin D; Neuroblastoma; Vanadium; [VO(acac)(2)]

DOI: https://doi.org/10.1016/j.jinorgbio.2018.08.005

Biomaterials. 2018 Aug 11. pii: S0142-9612(18)30558-1. [Epub ahead of print]182 145-156

Hypoxic tumor therapy by hemoglobin-mediated drug delivery and reversal of hypoxia-induced chemoresistance.

Jie Yang, Wei Li, Lihua Luo, Mengshi Jiang, Chunqi Zhu, Bing Qin, Hang Yin, Xiaoling Yuan, Xiaoyi Yin, Junlei Zhang, Zhenyu Luo, Yongzhong Du, Jian You.

Chemotherapy has become a critical treatment for many cancer types. However, its efficacy is hindered by chemoresistance and limited drug accumulation induced by the hypoxic tumor environment. Therefore, there is an urgent need for useful strategies to alleviate tumor hypoxia and enhance chemotherapy response in solid tumors. Herein, we report the development of a multifunctional liposome simultaneously loading an oxygen carrier (hemoglobin, Hb) and an anti-tumor drug (doxorubicin, DOX) to enhance chemotherapeutic effects against hypoxic tumors. The liposomes, DOX-Hb-lipo (DHL), showed efficient loading of oxygen and site-specific oxygen delivery into tumors, inducing the reversal of tumor hypoxia. Furthermore, the O2 interference capacity increased the uptake of the drug into hypoxic cancer cells, inducing a remarkably increased toxicity of the drug against cancer cells. Interestingly, the obtained DHL showed a significantly enhanced internalization into cancer cells and accumulation in tumors compared to DL (DOX loaded liposomes without Hb), while the enhanced effect did not occur in normal cells. The specific delivery of DHL into cancer cells should be attributed to the mediation of Hb on the surface of the liposomes. In addition, DHL considerably increased reactive oxygen species (ROS) production in a hypoxic environment and promoted the ROS-mediated cytotoxicity of DOX. Based on the elevated drug accumulation in the tumor sites, increased internalization into cancer cells and enhanced oxygen levels in tumor regions, DHL reversed hypoxia-induced chemoresistance and exhibited stronger antitumor effects. Thus, DHL might be a promising alternative strategy for cancer treatment.

Keywords: Chemoresistance; Doxorubicin; Drug accumulation; Hemoglobin; Hypoxia

DOI: https://doi.org/10.1016/j.biomaterials.2018.08.004

J Theor Biol. 2018 Aug 16. pii: S0022-5193(18)30393-X. [Epub ahead of print]

Why antioxidant therapies have failed in clinical trials.

Adrian Davies, Alan Holt.

In spite of considerable research, and many clinical trials involving thousands of patients, there is a conspicuous lack of antioxidant therapies available. In this paper we present results for the interaction and neutralization of a free radical species. We adopt two modeling techniques, one based upon Gillespieâ;;s Stochastic Simulation Algorithm and one based upon a discrete Markov chain. An advantage of these models is that they incorporate the number of molecules present per unit volume, and with the Markov chain model, the relative dimensions of these molecules. By means of these models we question the basis of antioxidant therapies based on trapping or scavenging of reactive species. We demonstrate the extraordinary capacity of the enzymatic antioxidant defenses relative to non-enzymatic defenses. We conclude that, if the concentration of an non-enzymatic antioxidant is too low there is little chance of collision and interaction with a free radical species. Furthermore, if the rate of reaction between the free radical and the non-enzymatic antioxidant is below a necessary threshold then the effect of an antioxidant will be dwarfed by the free radical defense systems naturally present. As such we suggest that failure of most antioxidant therapies in clinical trials is to be expected.

Keywords: Antioxidant; Free Radical; Gillespie; Markov Model; ROS

DOI: https://doi.org/10.1016/j.jtbi.2018.08.014