Interlude of cGMP and cGMP/Protein Kinase G Type 1 in Pancreatic Adenocarcinoma Cells

Karakhanova, Svetlana; Golovastova, Marina O.; Philippov, Pavel P.; Werner, Jens; Bazhin, Alexandr V.

doi:10.1097/mpa.0000000000000104

Cited by 25 publications

(17 citation statements)

References 26 publications

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“…Panc02 cells were treated 48 h with different concentrations of SkQ1. After that viability and proliferation assays were performed as described elsewhere …”

Section: Methodsmentioning

confidence: 99%

The novel mitochondria‐targeted antioxidant SkQ1 modulates angiogenesis and inflammatory micromilieu in a murine orthotopic model of pancreatic cancer

Bazhin

Yang

D’Haese

et al. 2016

Intl Journal of Cancer

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Our understanding in the last few years about reactive oxygen species (ROS) has changed from being harmful substances to crucial intra-and extracellular messengers as well as important regulators controlling a wide spectrum of signaling pathways, including those in cancer immunology. Therefore, these multiple essential roles of ROS and especially of mitochondria-derived ROS in malignant transformation and cancer progression make them a promising target for anticancer therapy. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. A link between ROS, antioxidants and the PDAC development and progression has been recently established. Therefore, usage of specific highly efficient antioxidants could bring an option for treatment and/or prevention of PDAC. 10-(6'-plastoquinonyl) decyltriphenylphosphonium (SkQ1) is a new antioxidant with the highest mitochondrion membrane penetrating ability and potent antioxidant capability. In this work, we investigated an impact of SkQ1 on tumor angiogenesis, immune micromilieu, and oncological parameters in the orthotopic Panc02 murine model of PDAC. We showed that in this model SkQ1 treatment leads to the elevation of pro-angiogenic factors and to building of mainly an anti-inflammatory cytokine milieu. On the cellular level we showed an increase in a percentage of memory T cells and a decrease in frequency on natural killer T (NKT) cells. At the same time, SkQ1 was ineffective in the improvement of oncological parameters of PDAC-bearing mice. New studies are needed to clarify the absence of therapeutic and/or prophylactic benefits of the antioxidant.Reactive oxygen species (ROS) are a group of highly reactive oxygen-containing chemicals. ROS can interact with many intracellular macromolecules, such as nucleic acids, lipids, and proteins. Normally, the intracellular ROS level is under tight control by various antioxidants. A delicately controlled ROS homeostasis is critical for maintaining normal cell functions. Any disruption in the oxidation-antioxidation balance will lead to oxidative stress which is associated with a wide spectrum of human disorders such as chronic inflammation, age-related diseases and cancer (for review see Ref. 1).Angiogenesis is essential for nutrient and oxygen supply, and metabolic waste removal in cancer. Vascular endothelial growth factor (VEGF) is one of the most important proangiogenic factors. 2 VEGF can stimulate ROS production, most probably by NADPH oxidase enzyme complex, in endothelial cells. 3 Besides, ROS are able to regulate various redox-sensitive transcription factors and genes that are involved in angiogenesis. 3 ROS are also involved in various aspects of the immune system, such as host defence, immune cells interaction, immune cell signalling, immune response and immune regulation (for review see Ref. 1). Therefore, the multiple essential roles of ROS and especially of mitochondria-derived ROS in malignant transformation and cancer progression make them a promising target for anticancer therapy.A variety...

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“…Panc02 cells were treated 48 h with different concentrations of SkQ1. After that viability and proliferation assays were performed as described elsewhere …”

Section: Methodsmentioning

confidence: 99%

The novel mitochondria‐targeted antioxidant SkQ1 modulates angiogenesis and inflammatory micromilieu in a murine orthotopic model of pancreatic cancer

Bazhin

Yang

D’Haese

et al. 2016

Intl Journal of Cancer

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“…Cell viability after gem treatment was measured with a EZ4U Kit (Biomedica, Austria) in the whole medium as described elsewhere [23]. Briefly, for the EZ4U assay 20,000 cells per well were seeded in 96-well plates.…”

Section: Cell Viability Assaysmentioning

confidence: 99%

In vitro immunomodulatory properties of gemcitabine alone and in combination with interferon-alpha

et al. 2015

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“…It has been demonstrated that the basal activity of PKG is essential for preventing spontaneous apoptosis of cancer cells (Fraser et al 2006). Recently, our group has found out that the PKG inhibitor DT3 can reduce the viability and proliferation as well as migration of human PDAC cells in vitro (Karakhanova et al 2014a), pointing to the therapeutic potential of PKG inhibition for PDAC. DT3 is a specific membrane-permeant peptide-based inhibitor of PKG.…”

Section: Introductionmentioning

confidence: 98%

Anti-tumor properties of the cGMP/protein kinase G inhibitor DT3 in pancreatic adenocarcinoma

Soltek

Karakhanova

Golovastova

et al. 2015

Naunyn-Schmiedeberg's Arch Pharmacol

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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. Therefore, new therapeutic options are urgently needed to improve the survival of PDAC patients. Protein kinase G (PKG) conducts the interlude of cGMP signaling which is important for healthy as well as for cancer cells. DT3 is a specific inhibitor of PKG, and it has been shown to possess an anti-tumor cytotoxic activity in vitro. The main aim of this work was to investigate anti-tumor effects of DT3 upon PDAC in vivo.Expression of PKG was assessed with real-time PCR analysis in the normal and tumor pancreatic cells. In vitro cell viability, proliferation, apoptosis, necrosis, migration, and invasion of the murine PDAC cell line Panc02 were assessed after DT3 treatment. In vivo anti-tumor effects of DT3 were investigated in the murine Panc02 orthotopic model of PDAC. Western blot analysis was used to determine the phosphorylation state of the proteins of interest.Functional PKGI is preferentially expressed in PDAC cells. DT3 was capable to reduce viability, proliferation, and migration of murine PDAC cells in vitro. At the same time, DT3 treatment did not change the viability of normal epithelial cells of murine liver. In vivo, DT3 treatment reduced the tumor volume and metastases in PDAC-bearing mice, but it was ineffective to prolong the survival of the tumor-bearing animals. In addition, DT3 treatment decreased phosphorylation of GSK-3, P38, and CREB in murine PDAC.Inhibition of PKG could be a potential therapeutic strategy for PDAC treatment which should be carefully validated in future pre-clinical studies.

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Interlude of cGMP and cGMP/Protein Kinase G Type 1 in Pancreatic Adenocarcinoma Cells

Abstract: The cGMP and PKG signaling may be a target for developing new therapeutic approaches for PDAC.

Cited by 25 publications

References 26 publications

The novel mitochondria‐targeted antioxidant SkQ1 modulates angiogenesis and inflammatory micromilieu in a murine orthotopic model of pancreatic cancer

The novel mitochondria‐targeted antioxidant SkQ1 modulates angiogenesis and inflammatory micromilieu in a murine orthotopic model of pancreatic cancer

In vitro immunomodulatory properties of gemcitabine alone and in combination with interferon-alpha

Anti-tumor properties of the cGMP/protein kinase G inhibitor DT3 in pancreatic adenocarcinoma

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