scholarly journals Targeting Mitochondrial Ion Channels to Fight Cancer

2018 ◽  
Vol 19 (7) ◽  
pp. 2060 ◽  
Author(s):  
Magdalena Bachmann ◽  
Roberto Costa ◽  
Roberta Peruzzo ◽  
Elena Prosdocimi ◽  
Vanessa Checchetto ◽  
...  
Keyword(s):  
Ion Channels ◽  
Tumor Development ◽  
Cancer Development ◽  
Cancer Growth ◽  
Altered Expression ◽  
New Frontier ◽  
Near Future

In recent years, several experimental evidences have underlined a new role of ion channels in cancer development and progression. In particular, mitochondrial ion channels are arising as new oncological targets, since it has been proved that most of them show an altered expression during tumor development and the pharmacological targeting of some of them have been demonstrated to be able to modulate cancer growth and progression, both in vitro as well as in vivo in pre-clinical mouse models. In this scenario, pharmacology of mitochondrial ion channels would be in the near future a new frontier for the treatment of tumors. In this review, we discuss the new advances in the field, by focusing our attention on the improvements in new drug developments to target mitochondrial ion channels.

A Review on Melatonin’s Effects in Cancer: Potential Mechanisms

2018 ◽  
Vol 18 (7) ◽  
pp. 985-992 ◽  
Author(s):  
Aysegul Hanikoglu ◽  
Ertan Kucuksayan ◽  
Rana Cagla Akduman ◽  
Tomris Ozben
Keyword(s):  
Systematic Review ◽  
Antioxidant Activity ◽  
Membrane Receptors ◽  
Cancer Development ◽  
Secretory Product ◽  
Prevention And Treatment ◽  
G Protein Coupled

This systematic review aims to elucidate the role of melatonin (N-acetyl-5-metoxy-tryptamine) (MLT) in the prevention and treatment of cancer. MLT is a pineal gland secretory product, an evolutionarily highly conserved molecule; it is also an antioxidant and an impressive protector of mitochondrial bioenergetic activity. MLT is characterized by an ample range of activities, modulating the physiology and molecular biology of the cell. Its physiological functions relate principally to the interaction of G Protein-Coupled MT1 and MT2 trans-membrane receptors (GPCRs), a family of guanidine triphosphate binding proteins. MLT has been demonstrated to suppress the growth of various tumours both, in vivo and in vitro. In this review, we analyze in depth, the antioxidant activity of melatonin, aiming to illustrate the cancer treatment potential of the molecule, by limiting or reversing the changes occurring during cancer development and growth.

scholarly journals Dual oxidase 1 limits the IFNγ-associated antitumor effect of macrophages

2020 ◽  
Vol 8 (1) ◽  
pp. e000622
Author(s):  
Lydia Meziani ◽  
Marine Gerbé de Thoré ◽  
Pauline Hamon ◽  
Sophie Bockel ◽  
Ruy Andrade Louzada ◽  
...  
Keyword(s):  
Antitumor Effect ◽  
Therapeutic Strategy ◽  
Critical Role ◽  
Tumor Development ◽  
Intratumoral Injection ◽  
Histocompatibility Complex ◽  
Dual Oxidase

BackgroundMacrophages play pivotal roles in tumor progression and the response to anticancer therapies, including radiotherapy (RT). Dual oxidase (DUOX) 1 is a transmembrane enzyme that plays a critical role in oxidant generation.MethodsSince we found DUOX1 expression in macrophages from human lung samples exposed to ionizing radiation, we aimed to assess the involvement of DUOX1 in macrophage activation and the role of these macrophages in tumor development.ResultsUsing Duox1−/− mice, we demonstrated that the lack of DUOX1 in proinflammatory macrophages improved the antitumor effect of these cells. Furthermore, intratumoral injection of Duox1−/− proinflammatory macrophages significantly enhanced the antitumor effect of RT. Mechanistically, DUOX1 deficiency increased the production of proinflammatory cytokines (IFNγ, CXCL9, CCL3 and TNFα) by activated macrophages in vitro and the expression of major histocompatibility complex class II in the membranes of macrophages. We also demonstrated that DUOX1 was involved in the phagocytotic function of macrophages in vitro and in vivo. The antitumor effect of Duox1−/− macrophages was associated with a significant increase in IFNγ production by both lymphoid and myeloid immune cells.ConclusionsOur data indicate that DUOX1 is a new target for macrophage reprogramming and suggest that DUOX1 inhibition in macrophages combined with RT is a new therapeutic strategy for the management of cancers.

scholarly journals Yanghe Huayan decoction inhibits the capability of trans-endothelium and angiogenesis of HER2+ breast cancer via pAkt signaling

2019 ◽  
Vol 39 (2) ◽  
Author(s):  
Xiao-Fei Liu ◽  
Jing-Wei Li ◽  
Hong-Zhi Chen ◽  
Zi-Yuan Sun ◽  
Guang-Xi Shi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Chinese Medicine ◽  
Precancerous Lesion ◽  
Tumor Development ◽  
Akt Activation ◽  
Her2 Breast Cancer ◽  
Prevention And Treatment

Abstract Background: Yanghe Huayan Decoction (YHD), a traditional Chinese medicine, is one of the most common complementary medicine currently used in the treatment of breast cancer (BC). It has been recently linked to suppress precancerous lesion and tumor development. The current study sought to explore the role of YHD on trans-endothelium and angiogenesis of BC. Methods: HER2+ BC cells were treated with YHD, Trastuzumab, or the combination in vitro and in vivo to compare the effects of them on trans-endothelium and angiogenesis features. The present study also investigated the potential molecular mechanism of YHD in inhibiting angiogenesis of BC. Results: YHD significantly suppressed the invasion and angiogenesis of BC cells via elevated pAkt signaling. Administration of YHD in vivo also strikingly repressed angiogenesis in tumor grafts. Conclusion: YHD could partially inhibit and reverse tumorigenesis of BC. It also could inhibit Akt activation and angiogenesis in vitro and in vivo. Its effect was superior to trastuzumab. Thus it was suitable for prevention and treatment of BC.

scholarly journals Linc00426 accelerates lung adenocarcinoma progression by regulating miR-455-5p as a molecular sponge

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Hongli Li ◽  
Qingjie Mu ◽  
Guoxin Zhang ◽  
Zhixin Shen ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Tumor Development ◽  
Biological Significance ◽  
Mesenchymal Transition

AbstractIncreasing lines of evidence indicate the role of long non-coding RNAs (LncRNAs) in gene regulation and tumor development. Hence, it is important to elucidate the mechanisms of LncRNAs underlying the proliferation, metastasis, and invasion of lung adenocarcinoma (LUAD). We employed microarrays to screen LncRNAs in LUAD tissues with and without lymph node metastasis and revealed their effects on LUAD. Among them, Linc00426 was selected for further exploration in its expression, the biological significance, and the underlying molecular mechanisms. Linc00426 exhibits ectopic expression in LUAD tissues and cells. The ectopic expression has been clinically linked to tumor size, lymphatic metastasis, and tumor differentiation of patients with LUAD. The deregulation of Linc00426 contributes to a notable impairment in proliferation, invasion, metastasis, and epithelial–mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, the deregulation of Linc00426 could reduce cytoskeleton rearrangement and matrix metalloproteinase expression. Meanwhile, decreasing the level of Linc00426 or increasing miR-455-5p could down-regulate the level of UBE2V1. Thus, Linc00426 may act as a competing endogenous RNA (ceRNA) to abate miR-455-5p-dependent UBE2V1 reduction. We conclude that Linc00426 accelerates LUAD progression by acting as a molecular sponge to regulate miR-455-5p, and may be a potential novel tumor marker for LUAD.

scholarly journals Interleukin 6 is essential for in vivo development of B lineage neoplasms.

1995 ◽  
Vol 182 (1) ◽  
pp. 243-248 ◽  
Author(s):  
D M Hilbert ◽  
M Kopf ◽  
B A Mock ◽  
G Köhler ◽  
S Rudikoff
Keyword(s):  
Plasma Cell ◽  
Plasma Cells ◽  
Tumor Development ◽  
Selective Pressures ◽  
B Lineage ◽  
Deficient Mice ◽  
Human B Cell

Interleukin (IL) 6 has been suggested to be the major cytokine responsible for proliferation of neoplastic plasma cells in both human myeloma and mouse plasmacytoma. Much of the evidence supporting this suggestion is derived from in vitro studies in which the survival or proliferation of some plasma cell tumors has been found to be IL-6 dependent. However, it remains unclear whether this dependency is the consequence of in vivo or in vitro selective pressures that preferentially expand IL-6-responsive tumor cells, or whether it reflects a critical in vivo role for IL-6 in plasma cell neoplasia. To address this question, we have attempted to induce plasma cell tumors in normal mice and in IL-6-deficient mice generated by introduction of a germline-encoded null mutation in the IL-6 gene. The results demonstrate that mice homozygous (+/+) or heterozygous (+/-) for the wild-type IL-6 allele yield the expected incidences of plasma cell tumors. In contrast, mice homozygous for the IL-6-null allele (-/-) are completely resistant to plasma cell tumor development. These studies define the essential role of IL-6 in the development of B lineage tumors in vivo and provide experimental support for continued efforts to modulate this cytokine in the treatment of appropriate human B cell malignancies.

scholarly journals Targeted knock-in mice expressing the oxidase-fixed form of xanthine oxidoreductase favor tumor growth

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Teruo Kusano ◽  
Driss Ehirchiou ◽  
Tomohiro Matsumura ◽  
Veronique Chobaz ◽  
Sonia Nasi ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Immune Surveillance ◽  
Tumor Development ◽  
Cancer Growth ◽  
Xanthine Oxidoreductase ◽  
Oxygen Species ◽  
Wild Type ◽  
Macrophage Depletion

Abstract Xanthine oxidoreductase has been implicated in cancer. Nonetheless, the role played by its two convertible forms, xanthine dehydrogenase (XDH) and oxidase (XO) during tumorigenesis is not understood. Here we produce XDH-stable and XO-locked knock-in (ki) mice to address this question. After tumor transfer, XO ki mice show strongly increased tumor growth compared to wild type (WT) and XDH ki mice. Hematopoietic XO expression is responsible for this effect. After macrophage depletion, tumor growth is reduced. Adoptive transfer of XO-ki macrophages in WT mice increases tumor growth. In vitro, XO ki macrophages produce higher levels of reactive oxygen species (ROS) responsible for the increased Tregs observed in the tumors. Blocking ROS in vivo slows down tumor growth. Collectively, these results indicate that the balance of XO/XDH plays an important role in immune surveillance of tumor development. Strategies that inhibit the XO form specifically may be valuable in controlling cancer growth.

scholarly journals Locus Coeruleus Modulates Neuroinflammation in Parkinsonism and Dementia

2020 ◽  
Vol 21 (22) ◽  
pp. 8630
Author(s):  
Filippo Sean Giorgi ◽  
Francesca Biagioni ◽  
Alessandro Galgani ◽  
Nicola Pavese ◽  
Gloria Lazzeri ◽  
...  
Keyword(s):  
Experimental Data ◽  
Locus Coeruleus ◽  
Clinical Symptoms ◽  
Experimental Studies ◽  
Anatomy And Physiology ◽  
The Central Nervous System ◽  
Near Future

Locus Coeruleus (LC) is the main noradrenergic nucleus of the central nervous system, and its neurons widely innervate the whole brain. LC is severely degenerated both in Alzheimer’s disease (AD) and in Parkinson’s disease (PD), years before the onset of clinical symptoms, through mechanisms that differ among the two disorders. Several experimental studies have shown that noradrenaline modulates neuroinflammation, mainly by acting on microglia/astrocytes function. In the present review, after a brief introduction on the anatomy and physiology of LC, we provide an overview of experimental data supporting a pathogenetic role of LC degeneration in AD and PD. Then, we describe in detail experimental data, obtained in vitro and in vivo in animal models, which support a potential role of neuroinflammation in such a link, and the specific molecules (i.e., released cytokines, glial receptors, including pattern recognition receptors and others) whose expression is altered by LC degeneration and might play a key role in AD/PD pathogenesis. New imaging and biochemical tools have recently been developed in humans to estimate in vivo the integrity of LC, the degree of neuroinflammation, and pathology AD/PD biomarkers; it is auspicable that these will allow in the near future to test the existence of a link between LC-neuroinflammation and neurodegeneration directly in patients.

scholarly journals In vivo NCL targeting affects breast cancer aggressiveness through miRNA regulation

2013 ◽  
Vol 210 (5) ◽  
pp. 951-968 ◽  
Author(s):  
Flavia Pichiorri ◽  
Dario Palmieri ◽  
Luciana De Luca ◽  
Jessica Consiglio ◽  
Jia You ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Target Genes ◽  
Human Cancer ◽  
Mirna Regulation ◽  
Altered Expression ◽  
Specific Subset ◽  
Cancer Aggressiveness

Numerous studies have described the altered expression and the causal role of microRNAs (miRNAs) in human cancer. However, to date, efforts to modulate miRNA levels for therapeutic purposes have been challenging to implement. Here we find that nucleolin (NCL), a major nucleolar protein, posttranscriptionally regulates the expression of a specific subset of miRNAs, including miR-21, miR-221, miR-222, and miR-103, that are causally involved in breast cancer initiation, progression, and drug resistance. We also show that NCL is commonly overexpressed in human breast tumors and that its expression correlates with that of NCL-dependent miRNAs. Finally, inhibition of NCL using guanosine-rich aptamers reduces the levels of NCL-dependent miRNAs and their target genes, thus reducing breast cancer cell aggressiveness both in vitro and in vivo. These findings illuminate a path to novel therapeutic approaches based on NCL-targeting aptamers for the modulation of miRNA expression in the treatment of breast cancer.

249 Targeting IFNβ-regulated secretory profiles to overcome acquired anti-PD-L1 resistance

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A270-A270
Author(s):  
Yuhao Shi ◽  
Melissa Dolan ◽  
Michalis Mastri ◽  
Kevin Eng ◽  
John Ebos
Keyword(s):  
Treatment Failure ◽  
Acquired Resistance ◽  
Secreted Proteins ◽  
Tumor Growth Inhibition ◽  
Type I ◽  
Altered Expression ◽  
The Impact

BackgroundTherapeutic targeting of programmed cell death protein ligand 1 (PD-L1) has led to durable benefits for many cancer patients; however, the development of acquired resistance is common. Dysregulated type II interferon (IFN) signaling on tumor cells can contribute to resistance via altered expression of IFN stimulated genes (ISGs), which include cytokines and growth factors capable of immune-suppression and tumor promotion. However, the role of type I IFNs, including IFNα and IFNβ, in acquired resistance remain understudied. Here we examined the impact of chronic PD-L1 blockade to evaluate the role of IFN-related secretory changes in preclinical models of resistance.MethodsUsing a mouse breast EMT6 orthotopic tumor model, we selected PD-L1 drug resistant (PDR) cells from tumors initially responsive to PD-L1 blockade, but that later relapsed. Using transcriptomic and proteomic approaches, we evaluated secreted proteins associated with IFN signaling. To test for direct connections between PD-L1 and IFN signaling in secretory profile modulation, genetic and therapeutic disruption of PD-L1/IFNAR1 were conducted in vitro.ResultsWe identified a unique gene signature for secreted proteins following acquired resistance to PD-L1 blockade that associated with IFN signaling. This secretory signature was validated using publicly available datasets derived from preclinical tumors and clinical biopsies after anti-PD-L1 treatment failure. Interestingly, genetic and antibody inhibition of PD-L1 in vitro enhanced PDR secretory signatures following IFNβ stimulation suggesting PD-L1 tumor-intrinsic functions may regulate IFN responses following acquired resistance. To test whether secretory profiles impact tumor growth, inhibition of specific ISGs (IL-6) or ISG regulators (IFNAR1) were examined and found to inhibit PDR tumors in vivo, compared to parental controls.ConclusionsTogether, these findings identify a secretory profile associated with acquired resistance to PD-L1 blockade that may be modulated, at least in part, by IFNβ. Selective targeting of secreted ISGs may provide a benefit for patients after anti-PD-L1 treatment failure.

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