Overexpression of Reactive Oxygen Species Modulator 1 Predicts Unfavorable Clinical Outcome in EGFR-Mutant Lung Adenocarcinomas Treated With Targeted Therapy

PurposeReactive oxygen species modulator 1 (Romo1) is a novel protein that regulates the production of intracellular reactive oxygen species. Romo1 has been shown to be associated with poor survival in various clinical settings for the treatment of lung cancer. In this study, we evaluated whether tissue Romo1 expression was associated with clinical outcomes in epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma treated with tyrosine kinase inhibitors (TKIs).MethodRomo1 expression in tumor tissues was examined by immunohistochemistry and evaluated by histologic score. Univariate and multivariate analyses were performed to identify the clinicopathologic parameters, including Romo1 expression, which may be associated with progression-free survival (PFS), overall survival (OS), and incidence of secondary T790M mutation.ResultsA total of 96 tumor specimens were analyzed. With the cut-off value of 200, 71 (74.0%) and 25 (26.0%) patients were classified into low and high Romo1 groups, respectively. The median PFS of the high Romo1 group was significantly shorter than that of the low Romo1 group (13.1 vs 19.9 months, p = 0.0165). The median OS of the high Romo1 group was also significantly shorter than that of the low Romo1 group (19.8 vs 37.0 months, p = 0.0006). Multivariate analyses showed that high Romo1 expression was independently associated with both poor PFS (hazard ratio [HR] = 2.48, 95% confidence interval [CI]: 1.35–4.56, p = 0.0034) and poor OS (HR = 3.17, 95% CI: 1.57–6.41, p = 0.0013). In addition, the rate of secondary T790M mutation after TKI failure was significantly lower in the high Romo1 group than the low Romo1 group (16.7% vs. 38.3%, p = 0.0369).ConclusionsRomo1 overexpression was associated with poor response to treatment and short survival in patients treated with EGFR-TKIs, suggesting a distinct subgroup warranting active surveillance and tailored therapeutic approach. In addition, our data highlight that Romo1 could be a potential predictive and prognostic biomarker for this patient population.

Download Full-text

Mechanisms of Mitochondrial Damage in Keratinocytes by Pemphigus Vulgaris Antibodies

Journal of Biological Chemistry ◽

10.1074/jbc.m113.472100 ◽

2013 ◽

Vol 288 (23) ◽

pp. 16916-16925 ◽

Cited By ~ 22

Author(s):

Mina Kalantari-Dehaghi ◽

Yumay Chen ◽

Wu Deng ◽

Alex Chernyavsky ◽

Steve Marchenko ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Mouse Skin ◽

Reactive Oxygen ◽

Pemphigus Vulgaris ◽

Mitochondrial Damage ◽

Response To Treatment ◽

Transfer Model ◽

Clear Understanding ◽

Oxygen Species ◽

Mitochondrial Functions

The development of nonhormonal treatment of pemphigus vulgaris (PV) has been hampered by a lack of clear understanding of the mechanisms leading to keratinocyte (KC) detachment and death in pemphigus. In this study, we sought to identify changes in the vital mitochondrial functions in KCs treated with the sera from PV patients and healthy donors. PV sera significantly increased proton leakage from KCs, suggesting that PV IgGs increase production of reactive oxygen species. Indeed, measurement of intracellular reactive oxygen species production showed a drastic increase of cell staining in response to treatment by PV sera, which was confirmed by FACS analysis. Exposure of KCs to PV sera also caused dramatic changes in the mitochondrial membrane potential detected with the JC-1 dye. These changes can trigger the mitochondria-mediated intrinsic apoptosis. Although sera from different PV patients elicited unique patterns of mitochondrial damage, the mitochondria-protecting drugs nicotinamide (also called niacinamide), minocycline, and cyclosporine A exhibited a uniform protective effect. Their therapeutic activity was validated in the passive transfer model of PV in neonatal BALB/c mice. The highest efficacy of mitochondrial protection of the combination of these drugs found in mitochondrial assay was consistent with the ability of the same drug combination to abolish acantholysis in mouse skin. These findings provide a theoretical background for clinical reports of the efficacy of mitochondria-protecting drugs in PV patients. Pharmacological protection of mitochondria and/or compensation of an altered mitochondrial function may therefore become a novel approach to development of personalized nonhormonal therapies of patients with this potentially lethal autoimmune blistering disease.

Download Full-text

Abstract LB-024: PIM kinase inhibitors selectively kill hypoxic cancer cells by reducing Nrf2 activity and increasing reactive oxygen species

10.1158/1538-7445.am2016-lb-024 ◽

2016 ◽

Author(s):

Alva G. Sainz ◽

Jin H. Song ◽

Andrew S. Kraft ◽

Noel A. Warfel

Keyword(s):

Reactive Oxygen Species ◽

Cancer Cells ◽

Kinase Inhibitors ◽

Reactive Oxygen ◽

Oxygen Species

Download Full-text

The Arabidopsis SIAMESE-RELATED Cyclin-Dependent Kinase Inhibitors SMR5 and SMR7 Regulate the DNA Damage Checkpoint in Response to Reactive Oxygen Species

The Plant Cell ◽

10.1105/tpc.113.118943 ◽

2014 ◽

Vol 26 (1) ◽

pp. 296-309 ◽

Cited By ~ 73

Author(s):

Dalong Yi ◽

Claire Lessa Alvim Kamei ◽

Toon Cools ◽

Sandy Vanderauwera ◽

Naoki Takahashi ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Dna Damage ◽

Kinase Inhibitors ◽

Reactive Oxygen ◽

Dna Damage Checkpoint ◽

Oxygen Species ◽

Cyclin Dependent Kinase

Download Full-text

CPT1A Over-Expression Increases Reactive Oxygen Species in the Mitochondria and Promotes Antioxidant Defenses in Prostate Cancer

Cancers ◽

10.3390/cancers12113431 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3431 ◽

Cited By ~ 1

Author(s):

Molishree Joshi ◽

Jihye Kim ◽

Angelo D’Alessandro ◽

Emily Monk ◽

Kimberley Bruce ◽

...

Keyword(s):

Prostate Cancer ◽

Reactive Oxygen Species ◽

Environmental Changes ◽

Reactive Oxygen ◽

Progression Free Survival ◽

Antioxidant Defenses ◽

Oxygen Species ◽

Altered Expression ◽

Lipid Catabolism ◽

Mitochondrial Ros

Cancers reprogram their metabolism to adapt to environmental changes. In this study, we examined the consequences of altered expression of the mitochondrial enzyme carnitine palmitoyl transferase I (CPT1A) in prostate cancer (PCa) cell models. Using transcriptomic and metabolomic analyses, we compared LNCaP-C4-2 cell lines with depleted (knockdown (KD)) or increased (overexpression (OE)) CPT1A expression. Mitochondrial reactive oxygen species (ROS) were also measured. Transcriptomic analysis identified ER stress, serine biosynthesis and lipid catabolism as significantly upregulated pathways in the OE versus KD cells. On the other hand, androgen response was significantly downregulated in OE cells. These changes associated with increased acyl-carnitines, serine synthesis and glutathione precursors in OE cells. Unexpectedly, OE cells showed increased mitochondrial ROS but when challenged with fatty acids and no androgens, the Superoxide dismutase 2 (SOD2) enzyme increased in the OE cells, suggesting better antioxidant defenses with excess CPT1A expression. Public databases also showed decreased androgen response correlation with increased serine-related metabolism in advanced PCa. Lastly, worse progression free survival was observed with increased lipid catabolism and decreased androgen response. Excess CPT1A is associated with a ROS-mediated stress phenotype that can support PCa disease progression. This study provides a rationale for targeting lipid catabolic pathways for therapy in hormonal cancers.

Download Full-text

Reactive oxygen species in BCR-ABL1-expressing cells – relevance to chronic myeloid leukemia

Acta Biochimica Polonica ◽

10.18388/abp.2016_1396 ◽

2016 ◽

Vol 64 (1) ◽

Cited By ~ 3

Author(s):

Joanna Antoszewska-Smith ◽

Elzbieta Pawlowska ◽

Janusz Błasiak

Keyword(s):

Reactive Oxygen Species ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Continuous Production ◽

Chromosomal Translocation ◽

Reactive Oxygen ◽

Oxygen Species ◽

Tki Resistance ◽

Stem And Progenitor Cells

Chronic myeloid leukemia (CML) results from the t(9;22) reciprocal chromosomal translocation producing the BCR-ABL1 gene, conferring growth and proliferation advantages in the CML cells. CML progresses from chronic, often syndrome-free, to blast phase, fatal if not treated. Although the involvement of BCR-ABL1 in some signaling pathways is considered as the cause of CML, the mechanisms resulting in its progression are not completely known. However, BCR-ABL1 stimulates the production of reactive oxygen species (ROS), which levels increase with CML progression and induce BCR-ABL1 self-mutagenesis. Introducing imatinib and other tyrosine kinase inhibitors (TKIs) to CML therapy radically improved its outcome, but TKIs-resistance became an emerging problem. TKI-resistance can be associated with even higher ROS production than in TKI-sensitive cells. Therefore, ROS-induced self-mutagenesis of BCR-ABL1 can be crucial for CML progression and TKI resistance and in this way should be taken into account in therapeutic strategies. As a continuous production of ROS by BCR-ABL1 would lead to its self-destruction and death of CML cells, there must be mechanisms controlling this phenomenon. These can be dependent on DNA repair, which is modulated by BCR-ABL1 and can be different in CML stem and progenitor cells. Altogether, the mechanisms of the involvement of BCR-ABL1 in ROS signaling can be involved in CML progression and TKI-resistance and warrant further study.

Download Full-text

PIM Kinase Inhibitors Kill Hypoxic Tumor Cells by Reducing Nrf2 Signaling and Increasing Reactive Oxygen Species

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-15-1018 ◽

2016 ◽

Vol 15 (7) ◽

pp. 1637-1647 ◽

Cited By ~ 21

Author(s):

Noel A. Warfel ◽

Alva G. Sainz ◽

Jin H. Song ◽

Andrew S. Kraft

Keyword(s):

Reactive Oxygen Species ◽

Tumor Cells ◽

Kinase Inhibitors ◽

Reactive Oxygen ◽

Oxygen Species ◽

Hypoxic Tumor

Download Full-text

Human Fibroblasts Release Reactive Oxygen Species in Response to Treatment with Synovial Fluids from Patients Suffering from Arthritis

Free Radical Research Communications ◽

10.3109/10715769009087988 ◽

1990 ◽

Vol 8 (3) ◽

pp. 149-160 ◽

Cited By ~ 36

Author(s):

Beate Meier ◽

Heinfried H. Radeke ◽

Susanne Selle ◽

H.-H. Raspe ◽

Helmut Sies ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Human Fibroblasts ◽

Reactive Oxygen ◽

Response To Treatment ◽

Oxygen Species ◽

Synovial Fluids

Download Full-text

Reactive Oxygen Species-Mediated Mechanisms of Action of Targeted Cancer Therapy

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/1485283 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 50

Author(s):

Hanna-Riikka Teppo ◽

Ylermi Soini ◽

Peeter Karihtala

Keyword(s):

Reactive Oxygen Species ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Reactive Oxygen ◽

Current Evidence ◽

Cancer Therapies ◽

Oxygen Species ◽

Mediated Effects ◽

Targeted Cancer Therapies

Targeted cancer therapies, involving tyrosine kinase inhibitors and monoclonal antibodies, for example, have recently led to substantial prolongation of survival in many metastatic cancers. Compared with traditional chemotherapy and radiotherapy, where reactive oxygen species (ROS) have been directly linked to the mediation of cytotoxic effects and adverse events, the field of oxidative stress regulation is still emerging in targeted cancer therapies. Here, we provide a comprehensive review regarding the current evidence of ROS-mediated effects of antibodies and tyrosine kinase inhibitors, use of which has been indicated in the treatment of solid malignancies and lymphomas. It can be concluded that there is rapidly emerging evidence of ROS-mediated effects of some of these compounds, which is also relevant in the context of drug resistance and how to overcome it.

Download Full-text