Synergistic inhibition of tumor cell proliferation by metformin and mito-metformin in the presence of iron chelators.

Synergistic inhibition of tumor cell proliferation by metformin and mito-metformin in the presence of iron chelators. Oncotarget. 2019 May 28;10(37):3518-3532 Authors: Cheng G, Zielonka J, Hardy M, Ouari O, Chitambar CR, Dwinell MB, Kalyanaraman B Abstract We demonstrate that combined treatment with metformin (Met) or its mitochondria-targeted analog, mito-metformin (Mito-Met), and various iron chelators synergistically inhibits proliferation of pancreatic and triple-negative breast cancer cells. Previously, we reported that Met (at millimolar levels) and Mito-Met (at micromolar levels) inhibited pancreatic cancer cell proliferation. Inhibition of mitochondrial complex I and mitochondrial oxidative phosphorylation (OXPHOS) through stimulation of mitochondrial redox signaling was proposed as a key mechanism for decreased cancer cell proliferation. Because of its poor bioavailability, the use of Met as a "stand-alone" antitumor drug has been questioned. Iron chelators such as deferasirox (DFX) and dexrazoxane (DXR) exhibit antiproliferative effects in cancer cells. The potency of Met and Mito-Met was synergistically enhanced in the presence of iron chelators, DFX, N,N'-bis(2-hydroxyphenyl)ethylendiamine-N,N'-diacetic acid (HBED), and deferoxamine (DFO). Met, DXR (also ICRF-187), and DFO are FDA-approved drugs for treating diabetes, decreasing the incidence and severity of cardiotoxicity following chemotherapy, and mitigating iron toxicity, respect...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research

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Abstract There is conflicting evidence regarding the association between metformin use and cancer risk in diabetic patients. During 2002-2012, we followed a cohort of 315,890 incident diabetic individuals aged 21-87 years insured in the largest health maintenance organization in Israel. We used a discrete form of the weighted cumulative metformin exposure to evaluate its association with cancer incidence. This was implemented in a time-dependent covariate Cox model, adjusting for treatments with other glucose lowering medications, as well as age, sex, ethnic background, socioeconomic status, smoking (for bladder a...
Source: Am J Epidemiol - Category: Epidemiology Authors: Tags: Am J Epidemiol Source Type: research
Conclusions Two, Not Mutually Exclusive, Hypotheses We have reviewed and organized the literature with the intent of showing the existing parallels between excessive fat accumulation and the aging process. We have categorized these reports following what have been proposed to be the nine hallmarks of aging (21) (Figure 1). Based on the evidence, two distinct hypotheses can be proposed. One is that the cellular responses provoked by an excess of nutrients cause obesity, and that obesity is responsible for accelerating the pace of aging. Supporting this hypothesis are the observations that knocking out the fat-specific ins...
Source: Frontiers in Endocrinology - Category: Endocrinology Source Type: research
Discussion MDSCs violently emerge in pathological conditions in an attempt to limit potentially harmful immune and inflammatory responses. Mechanisms supporting their expansion and survival are deeply investigated in cancer, in the perspective to reactivate specific antitumor responses and prevent their contribution to disease evolution. These findings will likely contribute to improve the targeting of MDSCs in anticancer immunotherapies, either alone or in combination with immune checkpoint inhibitors. New evidence indicates that the expansion of myeloid cell differentiation in pathology is subject to fine-tuning, as its...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Gulcin Tezcan1, Ekaterina V. Martynova1, Zarema E. Gilazieva1, Alan McIntyre2, Albert A. Rizvanov1 and Svetlana F. Khaiboullina1,3* 1Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia 2Centre for Cancer Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, United Kingdom 3Department of Microbiology and Immunology, University of Nevada, Reno, Reno, NV, United States Inflammation has a crucial role in protection against various pathogens. The inflammasome is an intracellular multiprotein signaling complex that is linked to pathogen sensing and...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
Conclusion and Perspectives The IL-6/JAK/STAT signaling cascade plays a dominant role in skeletal muscle pathophysiology. IL-6 autocrine, paracrine, and endocrine functions assign to its downstream effectors pivotal importance in skeletal muscle-wasting-associated diseases and other multiple system diseases where muscle acts in communication with other organs. Targeting the components of the JAK/STAT pathway recently emerged as a strategic approach for the treatment of inflammatory diseases and human cancer. This review highlights the opposite outcomes on muscle biology caused by the amount of local and systemic release ...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
Conclusions This review describes how leukocyte-heparanase can be a double-edged sword in tumor progression; it can enhance tumor immune surveillance and tumor cell clearance, but also promote tumor survival and growth. We also discuss the potential of using heparanase in leukocyte therapies against tumors, and the effects of heparanase inhibitors on tumor progression and immunity. We are just beginning to understand the influence of heparanase on a pro/anti-tumor immune response, and there are still many questions to answer. How do the pro/anti-tumorigenic effects of heparanase differ across different cancer types? Does...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusion The elucidation of the function of circRNAs is an emerging field of science with a tremendous potential after previously being dismissed as RNA artifacts. They are ubiquitously expressed and thousands of members have already been identified. This fact only expands their potential to possibly enhance our knowledge to understand the difference between health and disease. Owing to their structure stability and their presence in exosomes circRNAs may also exert their function in an autocrine, paracrine and possible endocrine fashion. In addition, the fact that circRNAs are widely distributed in the cellular compart...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
Hui Tang1, Tao Zeng1* and Luonan Chen1,2,3,4* 1Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China 2CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China 3School of Life Science and Technology, ShanghaiTech University, Shanghai, China 4Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, China Quantifying or labeling th...
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
Conclusion The periconceptional environment and lifestyle factors modify sperm epigenome. This alteration might be maintained in the zygote and throughout development, thereby leading to the inheritance of newly acquired pathologies. The role of sperm miRNA, not only as innovative markers of fertility issues but also as vectors involved in the inheritance of paternal diseases, appears to be crucial. Overweight and obesity seem to alter sperm miRNA profile, thereby leading to transmission of different miRNA profiles in zygote, with consequences on embryo development. In long term, metabolic disorders have been described in...
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
Conclusions and Perspectives In this review, we have discussed important milestones from the early description of “Serum-sickness” as being due to antibodies directed against Neu5Gc epitopes all the way to the present-day therapeutic implications of these antibodies in cancer therapy. Some of these milestones have been represented in a concise timeline (Figure 6). While the “Xenosialitis” hypothesis is well-supported in the human-like mouse models, it has yet to be conclusively proven in humans. It remains to be seen if “Xenosialitis” plays a role in other uniquely-human diseases. FI...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
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