Doxorubicin (DOX), or Adriamycin, an anthracycline antibiotic discovered serendipitously as a chemotherapeutic drug several decades ago, is still one of the most effective drugs for treating various ...adult and pediatric cancers (breast cancer, Hodgkin's disease, lymphoblastic leukemia). However, one of the major side effects of the continuous use of DOX is dose-dependent, long-term, and potentially lethal cardiovascular toxicity (congestive heart failure and cardiomyopathy) in cancer survivors many years after cessation of chemotherapy. In addition, predisposition to cardiotoxicity varied considerably among individuals. The long-held notion that DOX cardiotoxicity is caused by reactive oxygen species formed from the redox-cycling of DOX semiquinone lacks rigorous proof in a chronic animal model, and administration of reactive oxygen species detoxifying agents failed to reverse DOX-induced cardiac problems. In this review, I discuss the pros and cons of the reactive oxygen species pathway as a primary or secondary mechanism of DOX cardiotoxicity, the role of topoisomerases, and the potential use of mitochondrial-biogenesis-enhancing compounds in reversing DOX-induced cardiomyopathy. New approaches for well-designed clinical trials that repurpose FDA-approved drugs and naturally occurring polyphenolic compounds prophylactically to prevent or mitigate cardiovascular complications in both pediatric and adult cancer survivors are needed. Essentially, the focus should be on enhancing mitochondrial biogenesis to prevent or mitigate DOX-induced cardiotoxicity.
Display omitted
•Evidence linking ROS to DOX-induced cardiomyopathy is lacking.•Iron-chelating mechanism of cardioprotection by dexrazoxane is not established.•Mitochondrial biogenesis-inducing drugs may enhance protection against DOX toxicity.
This review of the basics of cancer metabolism focuses on exploiting the metabolic differences between normal and cancer cells. The first part of the review covers the different metabolic pathways ...utilized in normal cells to generate cellular energy, or ATP, and the glycolytic intermediates required to build the cellular machinery. The second part of the review discusses aerobic glycolysis, or the Warburg effect, and the metabolic reprogramming involving glycolysis, tricarboxylic acid cycle, and glutaminolysis in the context of developing targeted inhibitors in cancer cells. Finally, the selective targeting of cancer mitochondrial metabolism using positively charged lipophilic compounds as potential therapeutics and their ability to mitigate the toxic side effects of conventional chemotherapeutics in normal cells are discussed. I hope this graphical review will be useful in helping undergraduate, graduate, and medical students understand how investigating the basics of cancer cell metabolism could provide new insight in developing potentially new anticancer treatment strategies.
This article provides a succinct but limited overview of the protective and deleterious effects of reactive oxygen and nitrogen species in a clinical context. Reactive oxygen species include ...superoxide, hydrogen peroxide, single oxygen and lipid peroxides. Reactive nitrogen species include species derived from nitric oxide. This review gives a brief overview of the reaction chemistry of these species, the role of various enzymes involved in the generation and detoxification of these species in disease mechanisms and drug toxicity and the protective role of dietary antioxidants. I hope that the graphical review will be helpful for teaching both the first year medical and graduate students in the U.S. and abroad the fundamentals of reactive oxygen and nitrogen species in redox biology and clinical medicine.
N-acetylcysteine (NAC) has been used as a direct scavenger of reactive oxygen species (hydrogen peroxide, in particular) and an antioxidant in cancer biology and immuno-oncology. NAC is the ...antioxidant drug most frequently employed in studies using tumor cells, immune cells, and preclinical mouse xenografts. Most studies use redox-active fluorescent probes such as dichlorodihydrofluorescein, hydroethidine, mitochondria-targeted hydroethidine, and proprietary kit-based probes (i.e., CellROX Green and CellROX Red) for intracellular detection of superoxide or hydrogen peroxide. Inhibition of fluorescence by NAC was used as a key experimental observation to support the formation of reactive oxygen species and redox mechanisms proposed for ferroptosis, tumor metastasis, and redox signaling in the tumor microenvironment. Reactive oxygen species such as superoxide and hydrogen peroxide stimulate or abrogate tumor cells and immune cells depending on multiple factors. Understanding the mechanism of antioxidants is crucial for interpretation of the results. Because neither NAC nor the fluorescent probes indicated above react directly with hydrogen peroxide, it is critically important to reinterpret the results to advance our understanding of the mechanism of action of NAC and shed additional mechanistic insight on redox-regulated signaling in tumor biology. To this end, this review is focused on how NAC could affect multiple pathways in cancer cells, including iron signaling, ferroptosis, and the glutathione-dependent antioxidant and redox signaling mechanism, and how NAC could inhibit oxidation of the fluorescent probes through multiple mechanisms.
Display omitted
•NAC-mediated antioxidant mechanism does not directly scavenge ROS.•Inhibitory effects of NAC on fluorescent dyes should be reinterpreted.•Tumor enhancing and antitumor immune mechanism of NAC is intriguing.
Parkinson's disease (PD) and cancer share common mutations in mitochondrial proteins: Parkin and PINK1. The overlapping of genes involved in PD and cancer implies that the two diseases might share a ...common pathogenic mechanism. There are other compelling rationales for a mechanistic link between these diseases. Mitochondria and autophagy/mitophagy are emerging as therapeutic targets in PD and cancer: Ongoing research in our laboratories has shown that, when administered early, mitochondria-targeted agents afford neuroprotection in preclinical mice models of PD. Also, we discovered that mitochondria-targeted drugs inhibit tumor cell proliferation. We propose that mitochondrial targeting stimulates conservation of cellular energy critical for neuronal cell survival, whereas the energy conservation mechanism inhibits proliferation of cancer cells by depriving the energy necessary for cancer cell growth. We propose a promising drug repurposing strategy involving mitochondria-targeted drugs synthesized from naturally occurring molecules and FDA-approved drugs that are relatively nontoxic in both PD and cancer. These compounds have been shown to induce various cellular signaling pathways for autophagy/mitophagy, anti-inflammatory, and immunomodulatory effects that are implicated as therapeutic mechanisms in PD and cancer.
Display omitted
•Targeting mitochondria in cancer and PD could be a useful drug repurposing strategy.•Modification of natural compounds with TPP+ targets mitochondria.•Mitochondria-targeted agents induce multiple cell signaling mechanisms.
This review focuses on the hypothetical mechanisms for enhanced vulnerability of African Americans to SARS-CoV-2 infection, COVID-19 severity, and increased deaths. A disproportionately higher number ...of African Americans are afflicted with autoimmune and inflammatory diseases (e.g., diabetes, hypertension, obesity), and SARS-CoV-2 has helped expose these health disparities. Several factors including socioeconomic status, inferior health care, and work circumstances contribute to these disparities. Identifying potential inflammatory biomarkers and decreasing basal levels in high-risk individuals with comorbidities through preventive measures is critical. Immune cells, particularly neutrophils, protect us against pathogens (bacteria, fungi, and viruses) through increased generation of free radicals or oxidants and neutrophil extracellular traps (NETs) that ensnare pathogens, killing them extracellularly. However, continued generation of NETs coupled with the lack of prompt removal pose danger to host cells. NET levels are increased during pro-inflammatory diseases. COVID-19 patients exhibit elevated NET levels, depending upon disease severity. Conceivably, high-risk individuals with elevated basal NET levels would exhibit hyper-inflammation when infected with SARS-CoV-2, amplifying disease severity and deaths. Drugs inhibiting oxidant formation and vitamin supplements decreased NET formation in mice models of inflammation. Thus, it is conceivable that preventive treatments lowering NET levels and inflammation in high-risk individuals could mitigate SARS-CoV-2-induced complications and decrease mortality.
Display omitted
•COVID-19 severity is magnified in people with underlying medical conditions.•African Americans are disproportionately affected by COVID-19.•Decreasing inflammatory & immune-system-related markers might mitigate COVID-19 severity.
Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs ...specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the cell and mitochondrial membrane potentials, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this Review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes, and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.
Lung cancer often has a poor prognosis, with brain metastases a major reason for mortality. We modified lonidamine (LND), an antiglycolytic drug with limited efficacy, to mitochondria-targeted ...mito-lonidamine (Mito-LND) which is 100-fold more potent. Mito-LND, a tumor-selective inhibitor of oxidative phosphorylation, inhibits mitochondrial bioenergetics in lung cancer cells and mitigates lung cancer cell viability, growth, progression, and metastasis of lung cancer xenografts in mice. Mito-LND blocks lung tumor development and brain metastasis by inhibiting mitochondrial bioenergetics, stimulating the formation of reactive oxygen species, oxidizing mitochondrial peroxiredoxin, inactivating AKT/mTOR/p70S6K signaling, and inducing autophagic cell death in lung cancer cells. Mito-LND causes no toxicity in mice even when administered for eight weeks at 50 times the effective cancer inhibitory dose. Collectively, these findings show that mitochondrial targeting of LND is a promising therapeutic approach for investigating the role of autophagy in mitigating lung cancer development and brain metastasis.
Glycolytic and mitochondrial oxidative metabolism, which are two major energy sources in tumors, are potential targets in cancer treatment. Metabolic reprogramming from glycolysis to mitochondrial ...oxidative metabolism and vice versa is an adaptive strategy with which tumor cells obtain energy to survive and thrive under the compromised conditions of glycolysis and mitochondrial respiration. Developing highly potent, nontoxic, and tumor-selective oxidative phosphorylation (OXPHOS) inhibitors may help advance therapeutic targeting of mitochondrial drugs in cancer. The FDA-approved antimalarial drug atovaquone (ATO), a mitochondrial complex III inhibitor, was repurposed in cancer treatment. Here, we developed a new class of PEGylated mitochondria-targeted ATO (Mito-(PEG)n-ATO). Depending on the PEGylation chain length (n), Mito-PEG-ATO analogs inhibit both mitochondrial complex I- and complex III-induced oxygen consumption in human pancreatic (MiaPaCa-2) and brain (U87MG) cancer cells. Mito-PEG
-ATO is one of the most potent antiproliferative mitochondria-targeted compounds (IC
= 38 nM) in MiaPaCa-2 cells, and is more effective than other inhibitors of OXPHOS in MiaPaCa-2 and U87MG cells. Furthermore, we show that the combined use of the most potent OXPHOS-targeted inhibitors (Mito-PEG
-ATO) and inhibitors of monocarboxylate transporters (MCT-1 and MCT-4), Krebs cycle redox metabolism, or glutaminolysis will synergistically abrogate tumor cell proliferation. Potential clinical benefits of these combinatorial therapies are discussed.
In this review, some of the recent developments in probes and assay techniques specific for superoxide (O2–) and hydrogen peroxide (H2O2) are discussed. Over the last decade, significant progress has ...been made in O2– and H2O2 detection due to syntheses of new redox probes, better understanding of their chemistry, and development of specific and sensitive assays. For superoxide detection, hydroethidine (HE) is the most suitable probe, as the product, 2-hydroxyethidium, is specific for O2–. In addition, HE-derived dimeric products are specific for one-electron oxidants. As red-fluorescent ethidium is always formed from HE intracellularly, chromatographic techniques are required for detecting 2-hydroxyethidium. HE analogs, Mito-SOX and hydropropidine, exhibit the same reaction chemistry with O2– and one-electron oxidants. Thus, mitochondrial superoxide can be unequivocally detected using HPLC-based methods and not by fluorescence microscopy. Aromatic boronate-based probes react quantitatively with H2O2, forming a phenolic product. However, peroxynitrite and hypochlorite react more rapidly with boronates, forming the same product. Using ROS-specific probes and HPLC assays, it is possible to screen chemical libraries to discover specific inhibitors of NADPH oxidases. We hope that rigorous detection of O2– and H2O2 in different cellular compartments will improve our understanding of their role in redox signaling.
Display omitted
•Hydroethidine can detect O2– formed upon inhibition of mitochondrial complex I.•Mitochondria-targeted boronates can be used to detect mitochondria-derived H2O2.•HPLC-based assays enable rigorous analysis of cellular production of O2– and H2O2.•Rigorous O2–/H2O2 detection will help elucidate the mechanisms of redox signaling.
PDF
