bims-aporos 2018-07-01 papers

Issue of 2018–07–01
six papers selected by
Gavin McStay, Staffordshire University

Semin Cancer Biol. 2018 Jun 20. pii: S1044-579X(18)30047-6. [Epub ahead of print]

Reactive oxygen species in cancer stem cells of head and neck squamous cancer.

Xu Qian, Xiaobo Nie, Wenhao Yao, Konrad Klinghammer, Holger Sudhoff, Andreas M Kaufmann, Andreas E Albers.

One of the greatest challenges in systemic treatment of head and neck squamous cell carcinoma (HNSCC) is a small tumor cell population, namely, cancer stem-like cells (CSC). CSC can regenerate and maintain a heterogenic tumor by their self-renewal capacity. Their potential ability to be more resistant to and survival after chemo- and radiation therapy was also identified. Further studies have shown that reactive oxygen species (ROS) contribute to this CSC-associated resistance. In this review, we focus on the current knowledge of HNSCC-CSC, with regard to ROS as a possible and novel therapeutic approach in targeting CSC.

Keywords: Cancer stem cell; Disulfiram; Head and neck cancer; Nanotherapeutics; Reactive oxygen species

DOI: https://doi.org/10.1016/j.semcancer.2018.06.001

Free Radic Biol Med. 2018 Jun 20. pii: S0891-5849(18)31100-6. [Epub ahead of print]

Targeting redox vulnerability of cancer cells by prooxidative intervention of a glutathione-activated Cu(II) pro-ionophore: hitting three birds with one stone.

Xia-Zhen Bao, Fang Dai, Xin-Rong Li, Bo Zhou.

Altered redox homeostasis including higher levels of copper, the reduced glutathione (GSH) and reactive oxygen species (ROS) in cancer cells than in normal cells illustrates their redox vulnerability, and has opened a window for developing prooxidative anticancer agents (PAAs) to hit this status. However, how to design PAAs with high selectivity in killing cancer cells over normal cells remains a challenge. Herein we designed a 3-hydroxyflavone-inspired copper pro-ionophore (PHF) as a potent PAA based on the GSH-mediated conversion of 2,4-dinitrobenzenesulfonates to enols. Mechanistic investigation reveals that it is capable of exploiting increased levels of GSH in cancer cells to in situ release an active ionophore, 3-hydroxyflavone, inducing redox imbalance (copper accumulation, GSH depletion and ROS generation) and achieving highly selective killing of cancer cells upon specific transport of small amounts of Cu(II). To the best of our knowledge, it is the first example of Cu(II) pro-ionophore type of PAA which hits (changes) the three birds (abnormal copper, GSH and ROS levels in cancer cells) with one stone (PHF) in terms of its ability to induce preferentially redox imbalance of cancer cells by copper accumulation, GSH depletion and ROS generation.

Keywords: Copper; Glutathione; Ionophore; Reactive Oxygen Species; Redox imbalance

DOI: https://doi.org/10.1016/j.freeradbiomed.2018.06.021

Diabetes Res Clin Pract. 2018 Jun 21. pii: S0168-8227(17)31824-7. [Epub ahead of print]

LncRNA MALAT1 promotes the apoptosis and oxidative stress of human lens epithelial cells via p38MAPK pathway in diabetic cataract.

Weifeng Gong, Guangyue Zhu, Jie Li, Xin Yang.

BACKGROUND: LncRNAs are involved in various biological processes and disorders. We aimed to investigate the role of lncRNA MALAT1 deregulation in the pathogenic mechanism of diabetic cataract (DC).
METHODS: The expression of MALAT1 in the tissues and cells was detected by qRT-PCR. The levels of SP1, p38 and apoptosis-related protein were assessed by Western blot assay. Chromatin immunoprecipitation assay and Dual luciferase assay were performed to evaluate the relationship between SP1 and MALAT1. The viability and apoptosis of human lens epithelial cells (HLECs) were analyzed by MTT assay and flow cytometry. The levels of malonyldialdehyde (MDA), superoxide dismutase (SOD) and phospholipid hydroperoxide glutathione peroxidase (GSH-Px) were used to examine the level of oxidative stress.
RESULTS: MALAT1 not only was aberrantly expressed in DC anterior lenscapsule tissues and high glucose (HG)-treated HLECs, but also were up-regulated by HG to promote the apoptosis and oxidative stress of HLECs. HG induced the up-regulation of MALAT1 via SP1 binding MALAT1 promoter regions in HLECs. Moreover, p38 was up-regulated in HG-treated HLECs, and knockdown of p38 reversed the effect of MALAT1 over-expression on HLECs.
CONCLUSION: HG induced the up-regulation of MALAT1 in HLECs via SP1 binding SP1 binding MALAT1, which promoted the the apoptosis and oxidative stress of HLECs through the activation of p38MAPK signaling pathway.

Keywords: MALAT1; SP1; diabetic cataract; p38

DOI: https://doi.org/10.1016/j.diabres.2018.06.020

Chem Biol Interact. 2018 Jun 20. pii: S0009-2797(18)30058-9. [Epub ahead of print]

Mitochondrial damage and apoptosis: Key features in BDE-153-induced hepatotoxicity.

Lilian Cristina Pereira, Luiz Felipe Cabral Miranda, Mariana Furio Franco-Bernardes, Maria Julia Tasso, Filipe Valente Duarte, Ana Teresa Inácio Varela, Anabela Pinto Rolo, Carlos Manuel Marques Palmeira, Daniel Junqueira Dorta.

Brominated flame retardants are used in consumer goods to increase product resistance to fire and/or high temperatures. Polybrominated diphenyl ethers (PBDEs) are the most commonly employed class of brominated flame retardants because they are inexpensive and can effectively prevent flame from spreading. PBDEs are persistent, can bioaccumulate, are transported over long distances, and display toxicity. However, their toxic mechanisms of action have not been well established. Because mitochondria are recognized as the main energy-producing cell organelle and play a vital role in cellular function maintenance, here we apply mitochondria as an experimental model to evaluate the toxic effects of the PBDE congener BDE-153 (Hexa-BDE) at concentrations ranging from 0.1 to 25 μM. We also assess BDE-153 cytotoxicity to HepG2 cells in order to elucidate its mechanisms of toxicity. Exposure to BDE-153 affects isolated mitochondria: this congener can interact with the mitochondrial membrane, to dissipate the membrane potential and to induce significant ATP depletion. Furthermore, BDE-153 can diminish MTT reduction and cell proliferation and can interfere in cell cycle, as evaluated in cell cultures. These cytotoxic effects are related to mitochondrial dysfunction due to mitochondrial membrane potential dissipation and reactive oxygen species accumulation. These effects result in apoptotic cell death, as demonstrated by phosphatidylserine maintenance on the cell membrane external surface, nuclear condensation and fragmentation, and presence of pro-apoptotic factors such as cytochrome c and Apoptosis-inducing Factor (AIF) plus caspase 3 activation in the cytosol. Together, our results show PBDEs can induce cytotoxicity, reinforcing the idea that these compounds pose a risk to the exposed population.

DOI: https://doi.org/10.1016/j.cbi.2018.06.021

Pharmacol Rep. 2018 Mar 21. pii: S1734-1140(17)30807-1. [Epub ahead of print]70(4): 766-768

An important pathway of apoptotic effect of nickel early released from orthodontic appliances-Preliminary data.

Piotr Buczko, Dariusz Pawlak, Irena Kasacka.

BACKGROUND: Limited data demonstrate the effect of nickel released from orthodontic appliances. The mechanism of this action is not clear. The present study aimed to investigate the role of kynurenines, oxidative stress and caspase pathway in the mechanism of nickel action.
METHODS: We studied the concentration of nickel, 3-hydroxykynurenine, total oxidative status in saliva and caspase-3 in epithelial cells in 10 subjects before and one week after orthodontic treatment.
RESULTS: Orthodontic appliances significantly enhanced the concentration of nickel, 3-hydroxykynurenine, total oxidative status and augmented the expression of caspase-3 seven days after treatment in the oral cavity in respect to pre-treatment values.
CONCLUSION: Our data suggest that nickel released from orthodontic appliances activate tryptophan metabolism in oral cavity via the kynurenine pathway. The metal directly or through kynurenines enhancement activates oxidative stress and then via the caspase pathway induce apoptosis of buccal epithelial cells.

Keywords: 3-Hydroxykynurenine; Caspasae-3; Nickel; Orthodontic appliances; Oxidative stress

DOI: https://doi.org/10.1016/j.pharep.2018.02.019

Hum Pathol. 2018 Jun 20. pii: S0046-8177(18)30216-8. [Epub ahead of print]

Evaluation and prognostic significance of manganese superoxide dismutase in clear cell renal cell carcinoma.

Zuohui Zhao, Jiaju Lu, Hongyi Qu, Zunsong Wang, Qiang Liu, Xiaoqing Yang, Shuai Liu, Juntao Ge, Yue Xu, Na Li, Yijiao Yuan.

The antioxidant enzyme manganese superoxide dismutase (MnSOD) is upregulated in renal cell carcinoma (RCC) and has been implicated in multiple stages of RCC tumorigenesis and progression. However, the prognostic significance of MnSOD in RCC has not been fully elucidated. This study aimed to investigate the expression profile of MnSOD in clear cell RCC (ccRCC) tissues and evaluate the clinical significance of this enzyme in ccRCC patients. MnSOD mRNA was assessed in 42 ccRCC and 33 normal kidney tissues by the Oncomine database, and its protein was detected in 145 ccRCC and 3 normal tissues by immunohistochemistry staining (IHC). The Oncomine database confirmed higher MnSOD mRNA expression in ccRCC than in normal tissues, and IHC analysis revealed that MnSOD protein expression was inversely associated with pathologic grade, clinical stage, tumor size, M status, and cancer-specific survival. In addition, univariate survival analysis demonstrated that high-grade, late-stage, large tumors, stage M1, and low MnSOD expression were associated with a poorer prognosis for cancer-specific survival, and further multivariate analysis revealed that tumor grade, stage, M1 stage, and MnSOD were identified as independent prognostic factors for cancer-specific survival in patients with ccRCC. Collectively, these findings imply that MnSOD is a promising prognostic marker in ccRCC and implies that oxidative stress might be involved in the tumorigenesis and progression of ccRCC.

Keywords: Cancer-Specific Survival; MnSOD; Prognosis; Reactive Oxygen Species; Renal Cell Carcinoma

DOI: https://doi.org/10.1016/j.humpath.2017.12.032