A biomimetic nanodrug self-assembled from small molecules for enhanced ferroptosis therapy

2022 ◽  
Author(s):  
Xueming Xu ◽  
Yuan Chen ◽  
Jinyong Gui ◽  
Peilian Liu ◽  
Yong Huang ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Cancer Treatment ◽  
Small Molecules ◽  
Antioxidant Defense ◽  
Redox Balance ◽  
Self Assembled ◽  
Intracellular Redox

The ferroptosis drugs often induce oxidative damage or block antioxidant defense due to the key mechanism of ferroptosis in cancer treatment involved regulating the intracellular redox balance. However, these ferroptosis...

Targeting Redox Overcomes Proteasome Inhibitor Resistance in Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1819-1819
Author(s):  
Nathan G. Dolloff ◽  
Leticia Reyes ◽  
Brittany Smith ◽  
John Fairbanks Langenheim ◽  
Yefim Manevich
Keyword(s):  
Oxidative Stress ◽  
Multiple Myeloma ◽  
Stress Response ◽  
Oxidative Damage ◽  
Small Molecules ◽  
Redox Balance ◽  
Oxidative Stress Response ◽  
Protein Thiols ◽  
Cellular Bioenergetics ◽  
Resistant Cells

Abstract Proteasome inhibitors (PIs) like bortezomib (Btz) and carfilzomib (Crflz) induce an oxidative stress response in Multiple Myeloma (MM) cells. Oxidative stress is a key effector pathway in PI-induced cell death, and altered redox signaling has been implicated in the acquisition of PI resistance. The potential of redox as a therapeutic target/pathway for PI resistant MM has not been realized due to the absence of a precise molecular targeted strategy that exploits redox signaling in a way that attacks PI resistant cells while sparing normal cells. Therefore, we set out in this study to characterize redox adaptations that contribute to PI resistance in MM, and to use drug screening platforms to identify specific redox-targeted small molecules that restore PI sensitivity. Using multiple isogenic pairs of PI sensitive and resistant MM cell lines, we found that resistant cells exist under high basal levels of reactive oxygen species (ROS) and oxidation of protein thiols (i.e., oxidative damage). Resistant cells induce significantly higher relative levels of ROS following PI treatment, but exhibit no further increase in oxidative damage. By comparison, their PI sensitive counterparts have relatively low levels of basal and PI-induced ROS levels, but undergo significantly higher levels of oxidative damage following PI treatment. These findings demonstrate that PI resistance is associated with alterations in redox balance; they further suggest that PI resistant cells have acquired adaptations that allow them to survive under high basal levels of oxidative stress, and that provide protection from PI-induced oxidative damage. We also identified significant changes in cellular bioenergetics that are typical of PI resistant cells. Generally, PI resistant cells appear to be more metabolically efficient, relying on mitochondrial respiration as their primary source of ATP production. Specifically, PI resistant cells have higher basal oxygen consumption rates (OCR), expanded respiratory capacity, increased NAD(P)H levels and pyruvate dehydrogenase (PDH) activity, and nearly absent activation of the AMP kinase energy stress signaling pathway. Thus, the acquisition of PI resistance is associated with significant changes in redox balance as well as in cellular bioenergetics. Given these findings, we next used a cell-based drug screening method to screen for redox-targeted small molecules capable of restoring PI sensitivity to resistant cells. We screened a compound collection of known pro- and anti-oxidant small molecules with wide-ranging mechanisms of action. From this screen we identified compound E61, which demonstrated strong synergy with multiple PIs, including Btz, Crflz, ixazomib, and oprozomib. E61 induced an oxidative stress response characterized by a burst of ROS generation and oxidation of protein thiols, and synergistically enhanced the PI-induced oxidative stress response in resistant cells. The synergistic cytotoxic response to E61 and PI co-treatment was dependent on ROS, and was evident across several models of PI resistance, representing cells of diverse genetic backgrounds. While E61 enhanced PI-induced cell death in resistant MM cells, its effects were protective in normal cell types, including peripheral blood mononuclear cells (PMBCs) and lymphocytes from normal human donors. These findings suggest that compound E61 will have a wide therapeutic index in combination with PI therapy in preclinical mouse models of MM, a hypothesis that we are currently testing. All together, our findings identify specific redox and bioenergetics changes that are acquired by PI resistant MM cells. Furthermore, our work offers a novel redox-targeted small molecule, E61, to be used in combination with PI-based therapeutic regimens in refractory MM. Disclosures No relevant conflicts of interest to declare.

scholarly journals Alternative approaches to target Myc for cancer treatment

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Chen Wang ◽  
Jiawei Zhang ◽  
Jie Yin ◽  
Yichao Gan ◽  
Senlin Xu ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Small Molecules ◽  
Drug Target ◽  
The Past ◽  
Physiological Processes ◽  
Alternative Approaches ◽  
Global Transcriptome ◽  
Factor C ◽  
Signaling Modules ◽  
Druggable Targets

AbstractThe Myc proto-oncogene family consists of three members, C-MYC, MYCN, and MYCL, which encodes the transcription factor c-Myc (hereafter Myc), N-Myc, and L-Myc, respectively. Myc protein orchestrates diverse physiological processes, including cell proliferation, differentiation, survival, and apoptosis. Myc modulates about 15% of the global transcriptome, and its deregulation rewires the cellular signaling modules inside tumor cells, thereby acquiring selective advantages. The deregulation of Myc occurs in >70% of human cancers, and is related to poor prognosis; hence, hyperactivated Myc oncoprotein has been proposed as an ideal drug target for decades. Nevertheless, no specific drug is currently available to directly target Myc, mainly because of its “undruggable” properties: lack of enzymatic pocket for conventional small molecules to bind; inaccessibility for antibody due to the predominant nucleus localization of Myc. Although the topic of targeting Myc has actively been reviewed in the past decades, exciting new progresses in this field keep emerging. In this review, after a comprehensive summarization of valuable sources for potential druggable targets of Myc-driven cancer, we also peer into the promising future of utilizing macropinocytosis to deliver peptides like Omomyc or antibody agents to intracellular compartment for cancer treatment.

Glyap1 regulates pneumocandin B0 synthesis by controlling the intracellular redox balance in Glarea lozoyensis

2021 ◽  
Author(s):  
Yan Dong ◽  
Lei Zhang ◽  
Weiting Zhang ◽  
Jianan Cao ◽  
Yiping Wei ◽  
...  
Keyword(s):  
Redox Balance ◽  
Intracellular Redox

scholarly journals Exposure to Ti4Al4V Titanium Alloy Leads to Redox Abnormalities, Oxidative Stress, and Oxidative Damage in Patients Treated for Mandible Fractures

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Jan Borys ◽  
Mateusz Maciejczyk ◽  
Bożena Antonowicz ◽  
Adam Krętowski ◽  
Danuta Waszkiel ◽  
...  
Keyword(s):  
Titanium Alloy ◽  
Oxidative Damage ◽  
Activity Concentration ◽  
Maxillofacial Surgery ◽  
Redox Balance ◽  
Passive Layer ◽  
Oxidative Modification ◽  
Mandibular Fractures ◽  
Mandible Fractures ◽  
Increased Activity

Due to the high biotolerance, favourable mechanical properties, and osseointegration ability, titanium is the basic biomaterial used in maxillofacial surgery. The passive layer of titanium dioxide on the surface of the implant effectively provides anticorrosive properties, but it can be damaged, resulting in the release of titanium ions to the surrounding tissues. The aim of our work was to evaluate the influence of Ti6Al4V titanium alloy on redox balance and oxidative damage in the periosteum surrounding the titanium miniplates and screws as well as in plasma and erythrocytes of patients with mandibular fractures. The study included 31 previously implanted patients (aged 21–29) treated for mandibular fractures and 31 healthy controls. We have demonstrated increased activity/concentration of antioxidants both in the mandibular periosteum and plasma/erythrocytes of patients with titanium mandibular fixations. However, increased concentrations of the products of oxidative protein and lipid modifications were only observed in the periosteum of the study group patients. The correlation between the products of oxidative modification of the mandible and antioxidants in plasma/erythrocytes suggests a relationship between the increase of oxidative damage at the implantation site and central redox disorders in patients with titanium miniplates and screws.

Disrupted intracellular redox balance of the diplomonad fish parasite Spironucleus vortens by 5-nitroimidazoles and garlic-derived compounds

2012 ◽  
Vol 190 (1-2) ◽  
pp. 62-73 ◽  
Author(s):  
C.F. Williams ◽  
D. Lloyd ◽  
D. Kolarich ◽  
K. Alagesan ◽  
M. Duchêne ◽  
...  
Keyword(s):  
Redox Balance ◽  
Fish Parasite ◽  
Intracellular Redox

Chemogenetic Approaches to Probe Redox Pathways: Implications for Cardiovascular Pharmacology and Toxicology

2021 ◽  
Vol 62 (1) ◽  
Author(s):  
Benjamin Steinhorn ◽  
Emrah Eroglu ◽  
Thomas Michel
Keyword(s):  
Dynamic Control ◽  
Cardiovascular Pharmacology ◽  
Redox Balance ◽  
Signaling Molecules ◽  
Annual Review ◽  
Publication Date ◽  
Acid Oxidase ◽  
Amino Acid Oxidase ◽  
Pharmacology And Toxicology ◽  
Intracellular Redox

Chemogenetics refers to experimental systems that dynamically regulate the activity of a recombinant protein by providing or withholding the protein's specific biochemical stimulus. Chemogenetic tools permit precise dynamic control of specific signaling molecules to delineate the roles of those molecules in physiology and disease. Yeast d-amino acid oxidase (DAAO) enables chemogenetic manipulation of intracellular redox balance by generating hydrogen peroxide only in the presence of d-amino acids. Advances in biosensors have allowed the precise quantitation of these signaling molecules. The combination of chemogenetic approaches with biosensor methodologies has opened up new lines of investigation, allowing the analysis of intracellular redox pathways that modulate physiological and pathological cell responses. We anticipate that newly developed transgenic chemogenetic models will permit dynamic modulation of cellular redox balance in diverse cells and tissues and will facilitate the identification and validation of novel therapeutic targets involved in both physiological redox pathways and pathological oxidative stress. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Herbal Remedies for Improving Cancer Treatment Through Modulation of Redox Balance

2021 ◽  
pp. 1-17
Author(s):  
Sukhchain Kaur ◽  
Harkomal Verma ◽  
Sharanjot Kaur ◽  
Subham Singh ◽  
Anil K. Mantha ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Redox Balance ◽  
Herbal Remedies
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