bims-aporos 2018-11-04 papers

Issue of 2018–11–04
three papers selected by
Gavin McStay, Staffordshire University

Curr Mol Med. 2018 Oct 24.

Excessive oxidative stress in the synergistic effects of shikonin on the hyperthermia-induced apoptosis.

J-L Piao, Y-J Jin, M-L Li, S A Zakki, L Sun, Q -W Feng, D Zhou, T Kondo, Z-G Cui, H Inadera.

BACKGROUND: Hyperthermia (HT) has been used widely for cancer therapy, and the development of modern devices has made it more efficient. Shikonin (SHK) is a natural naphthoquinone derivative from a Chinese herb. Although the anti-cancer properties of SHK are evident, the underlying molecular mechanisms are not fully understood.
OBJECTIVE: In this study, the effects of combining low doses of SHK with mild HT were investigated in the U937 cell line.
METHODS: The cells were subjected to HT at 44°C for 10 min with or without SHK pretreatment, and parameters reflecting apoptosis, ROS generation and intracellular calcium elevation were evaluated by using DNA fragmentation, flow cytometry, and western blot analyses.
RESULTS: SHK 0.5 µM significantly enhanced HT-induced apoptosis as indicated by DNA fragmentation and caspase-3 activation with increased generation of ROS and elevation of intracellular calcium. The combined treatment also synergistically activated pro-apoptotic proteins and inactivated anti-apoptotic proteins. Furthermore, the phosphorylation of JNK and PKC- δ and the dephosphorylation of ERK and AKT were the upstream effects that may have compounded the induction of apoptosis. The modulatory effects of HT and SHK were abrogated with employment of NAC and JNK-I-8 by inactivating the MAPK pathway and cleavage of caspase-3. Intracellular calcium was also elevated and responsible for induction of cell death evident by the DNA fragmentation with or without employment of BAPTA-AM.
CONCLUSION: SHK enhances HT-induced apoptosis via a mitochondrial caspase-dependent pathway. The underlying mechanisms involve are increased intracellular ROS generation, elevation of intracellular calcium and JNK activation.

DOI: https://doi.org/10.2174/1566524018666181024161704

Stem Cell Res Ther. 2018 Oct 25. 9(1): 289

Inhibition of autophagy promoted high glucose/ROS-mediated apoptosis in ADSCs.

Qiang Li, Yating Yin, Yuqing Zheng, Feifei Chen, Peisheng Jin.

BACKGROUND: Increased apoptosis in adipose tissue-derived stem cells (ADSCs) limits their application in treating diabetes complications. Autophagy is a molecular process that allows cells to degrade and recover damaged macromolecules, and closely interacts with apoptosis. The aim of the present study was to investigate the potential role of autophagy in ADSC apoptosis induced by high glucose.
METHODS: Human ADSCs were cultured in normal or high-glucose medium for 6 h, 12 h, or 24 h. The effects of high glucose on ADSC autophagy, reactive oxygen species (ROS) production, and apoptosis were evaluated. The impact of autophagy on ROS production and apoptosis was explored by treatment with rapamycin or 3-methyladenine (3-MA). The c-jun kinase (JNK) signaling pathway was investigated by pharmacological disruption of SP600125.
RESULTS: ADSCs subjected to high glucose stress showed an obvious induction of autophagy and apoptosis and a significant increase in intracellular ROS levels. The JNK signaling pathway was confirmed to be involved in high glucose-induced autophagy. Pre-treatment with SP600125 or N-acetylcysteine reversed the effects of high glucose on the JNK signaling pathway and autophagy-related proteins. Pretreatment of ADSCs with 3-MA under high glucose stress induced a further increase in ROS levels compared to those of high glucose-treated cells. Furthermore, ADSCs pretreated with 3-MA under high glucose stress showed a marked increase in apoptosis compared with that of the cells treated with high glucose. Conversely, pre-treatment with rapamycin inhibited the apoptosis of ADSCs.
CONCLUSIONS: Taken together, our data suggest that autophagy may play a protective role in high glucose-induced apoptosis in ADSCs. ROS/JNK signaling is essential in upregulating high glucose-induced autophagy. This study provides new insights into the molecular mechanism of autophagy involved in high glucose-induced apoptosis in ADSCs.

Keywords: Adipose tissue-derived stem cells; Apoptosis; Autophagy; High glucose

DOI: https://doi.org/10.1186/s13287-018-1029-4

Redox Biol. 2018 Oct 12. pii: S2213-2317(18)30551-2. [Epub ahead of print]20 182-194

A novel platinum complex containing a piplartine derivative exhibits enhanced cytotoxicity, causes oxidative stress and triggers apoptotic cell death by ERK/p38 pathway in human acute promyelocytic leukemia HL-60 cells.

Maiara de S Oliveira, Marília I F Barbosa, Thiago Belarmino de Souza, Diogo R M Moreira, Felipe Terra Martins, Wilmer Villarreal, Rafael P Machado, Antônio Carlos Doriguetto, Milena B P Soares, Daniel P Bezerra.

Piplartine (piperlongumine) is a plant-derived compound found in some Piper species that became a novel potential antineoplastic agent. In the present study, we synthesized a novel platinum complex containing a piplartine derivative cis-[PtCl(PIP-OH)(PPh3)2]PF6 (where, PIP-OH = piplartine demethylated derivative; and PPh3 = triphenylphosphine) with enhanced cytotoxicity in different cancer cells, and investigated its apoptotic action in human promyelocytic leukemia HL-60 cells. The structure of PIP-OH ligand was characterized by X-ray crystallographic analysis and the resulting platinum complex was characterized by infrared, molar conductance measurements, elemental analysis and NMR experiments. We found that the complex is more potent than piplartine in a panel of cancer cell lines. Apoptotic cell morphology, increased internucleosomal DNA fragmentation, without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization and caspase-3 activation were observed in complex-treated HL-60 cells. Treatment with the complex also caused a marked increase in the production of reactive oxygen species (ROS), and the pretreatment with N-acetyl-L-cysteine, an antioxidant, reduced the complex-induced apoptosis, indicating activation of ROS-mediated apoptosis pathway. Important, pretreatment with a p38 MAPK inhibitor (PD 169316) and MEK inhibitor (U-0126), known to inhibit ERK1/2 activation, also prevented the complex-induced apoptosis. The complex did not induce DNA intercalation in cell-free DNA assays. In conclusion, the complex exhibits more potent cytotoxicity than piplartine in a panel of different cancer cells and triggers ROS/ERK/p38-mediated apoptosis in HL-60 cells.

Keywords: Apoptosis; ERK; Leukemia; Piperlongumine; Piplartine; Platinum complex; ROS; p38

DOI: https://doi.org/10.1016/j.redox.2018.10.006