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Oncotarget Jun 2016Cancer is a disease caused by the abnormal proliferation and differentiation of cells governed by tumorigenic factors. Chemotherapy is one of the major cancer treatment... (Review)
Review
Cancer is a disease caused by the abnormal proliferation and differentiation of cells governed by tumorigenic factors. Chemotherapy is one of the major cancer treatment strategies, and it functions by targeting the physiological capabilities of cancer cells, including sustained proliferation and angiogenesis, the evasion of programmed cell death, tissue invasion and metastasis. Remarkably, natural products have garnered increased attention in the chemotherapy drug discovery field because they are biologically friendly and have high therapeutic effects. Tetrandrine, isolated from the root of Stephania tetrandra S Moore, is a traditional Chinese clinical agent for silicosis, autoimmune disorders, inflammatory pulmonary diseases, cardiovascular diseases and hypertension. Recently, the novel anti-tumor effects of tetrandrine have been widely investigated. More impressive is that tetrandrine affects multiple biological activities of cancer cells, including the inhibition of proliferation, angiogenesis, migration, and invasion; the induction of apoptosis and autophagy; the reversal of multidrug resistance (MDR); and the enhancement of radiation sensitization. This review focuses on introducing the latest information about the anti-tumor effects of tetrandrine on various cancers and its underlying mechanism. Moreover, we discuss the nanoparticle delivery system being developed for tetrandrine and the anti-tumor effects of other bisbenzylisoquinoline alkaloid derivatives on cancer cells. All current evidence demonstrates that tetrandrine is a promising candidate as a cancer chemotherapeutic.
Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Benzylisoquinolines; Cell Movement; Cell Proliferation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drugs, Chinese Herbal; Humans; Mice; Mice, Nude; Nanoparticles; Neoplasm Invasiveness; Neoplasm Transplantation; Neoplasms; Neovascularization, Pathologic; Plant Extracts; Plant Roots; Stephania
PubMed: 27027348
DOI: 10.18632/oncotarget.8315 -
Biology Open Jun 2019The classical view of cell death has long assumed that, once initiated, the dying process is irreversible. However, recent studies reveal that recovery of dying cells...
The classical view of cell death has long assumed that, once initiated, the dying process is irreversible. However, recent studies reveal that recovery of dying cells can actually occur, even after initiation of a cell suicide process called apoptosis. This discovery raised fundamental key questions about which forms of the cell death process could be reversible and how reversal is mediated. Here, we uncover an unanticipated reversibility of ferroptotic cell death process. Unlike apoptosis reversal, removal of ferroptosis inducers, such as erastin and glutamate, is insufficient to allow ferroptotic dying cells to escape the cell death process. However, by removing the cell death inducer and providing the reduced form of glutathione or the radical-trapping antioxidant ferrostatin-1, ferroptotic dying cells can be rescued and promoted to recover. Interestingly, although ferroptotic inhibitors such as aminooxyacetic acid, deferoxamine, dopamine and vitamin C can prevent initiation of ferroptosis, added alone they are unable to reverse the initiated ferroptosis, suggesting regulatory distinctions between preventing and reversing ferroptosis. Together, these results reveal the first evidence that ferroptosis is reversible and suggest strategies to enhance its reversibility, thereby providing a useful model for studying the physiological, pathological and therapeutic potentials of this cell recovery process.
PubMed: 31186229
DOI: 10.1242/bio.043182 -
Diabetes, Obesity & Metabolism Nov 2008Cardiovascular disease (CVD) exceeds infection and cancer as the leading cause of death. In the USA alone, approximately a million individuals suffer an acute myocardial... (Review)
Review
Cardiovascular disease (CVD) exceeds infection and cancer as the leading cause of death. In the USA alone, approximately a million individuals suffer an acute myocardial infarction (AMI) annually. As the prevalence of CVD risk factors (e.g. hypertension, obesity and type 2 diabetes) rises, CVD is increasing in younger individuals. Fortunately, existing therapies have improved post-AMI mortality, but in turn have increased the prevalence of post-AMI heart failure (HF). Approximately half-a-million new HF cases are diagnosed each year in the USA. In the next 25 years, up to 15% of the population over the age of 65 in the USA is projected to have HF. Therapeutic interventions that prevent/reverse atherosclerosis, prevent post-AMI HF and halt the progressive functional deterioration once HF occurs are all needed. Cell therapy - either via exogenous delivery or by endogenous mobilization of cells - may be able to do so, in part, by improving the body's capacity for repair. To date, primarily bone marrow- or blood-derived cells have been utilized after AMI to prevent left ventricular dysfunction, and skeletal myoblasts have been transplanted into failing myocardium. Preclinical studies are directed at prevention/reversal of atherosclerosis with bone marrow precursors, and ultimately at replacing failing heart with a cell-based bioartificial construct.
Topics: Adult; Age Factors; Aged; Cell Transplantation; Coronary Artery Disease; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Neovascularization, Physiologic; United States; Ventricular Function, Left; Ventricular Remodeling
PubMed: 18834428
DOI: 10.1111/j.1463-1326.2008.00937.x -
International Journal of Molecular... Oct 2022Over 50 years of cancer research has resulted in the generation of massive amounts of information, but relatively little progress has been made in the treatment of... (Review)
Review
What Are the Reasons for Continuing Failures in Cancer Therapy? Are Misleading/Inappropriate Preclinical Assays to Be Blamed? Might Some Modern Therapies Cause More Harm than Benefit?
Over 50 years of cancer research has resulted in the generation of massive amounts of information, but relatively little progress has been made in the treatment of patients with solid tumors, except for extending their survival for a few months at best. Here, we will briefly discuss some of the reasons for this failure, focusing on the limitations and sometimes misunderstanding of the clinical relevance of preclinical assays that are widely used to identify novel anticancer drugs and treatment strategies (e.g., "synthetic lethality"). These include colony formation, apoptosis (e.g., caspase-3 activation), immunoblotting, and high-content multiwell plate cell-based assays, as well as tumor growth studies in animal models. A major limitation is that such assays are rarely designed to recapitulate the tumor repopulating properties associated with therapy-induced cancer cell dormancy (durable proliferation arrest) reflecting, for example, premature senescence, polyploidy and/or multinucleation. Furthermore, pro-survival properties of apoptotic cancer cells through phoenix rising, failed apoptosis, and/or anastasis (return from the brink of death), as well as cancer immunoediting and the impact of therapeutic agents on interactions between cancer and immune cells are often overlooked in preclinical studies. A brief review of the history of cancer research makes one wonder if modern strategies for treating patients with solid tumors may sometimes cause more harm than benefit.
Topics: Animals; Antineoplastic Agents; Apoptosis; Neoplasms
PubMed: 36362004
DOI: 10.3390/ijms232113217 -
Journal of Translational Medicine Nov 2013In recent years an increasing number of publications have emphasized the growing importance of hydrogen ion dynamics in modern cancer research, from etiopathogenesis and... (Review)
Review
Cariporide and other new and powerful NHE1 inhibitors as potentially selective anticancer drugs--an integral molecular/biochemical/metabolic/clinical approach after one hundred years of cancer research.
In recent years an increasing number of publications have emphasized the growing importance of hydrogen ion dynamics in modern cancer research, from etiopathogenesis and treatment. A proton [H+]-related mechanism underlying the initiation and progression of the neoplastic process has been recently described by different research groups as a new paradigm in which all cancer cells and tissues, regardless of their origin and genetic background, have a pivotal energetic and homeostatic disturbance of their metabolism that is completely different from all normal tissues: an aberrant regulation of hydrogen ion dynamics leading to a reversal of the pH gradient in cancer cells and tissues (↑pHi/↓pHe, or "proton reversal"). Tumor cells survive their hostile microenvironment due to membrane-bound proton pumps and transporters, and their main defensive strategy is to never allow internal acidification because that could lead to their death through apoptosis. In this context, one of the primary and best studied regulators of both pHi and pHe in tumors is the Na+/H+ exchanger isoform 1 (NHE1). An elevated NHE1 activity can be correlated with both an increase in cell pH and a decrease in the extracellular pH of tumors, and such proton reversal is associated with the origin, local growth, activation and further progression of the metastatic process. Consequently, NHE1 pharmaceutical inhibition by new and potent NHE1 inhibitors represents a potential and highly selective target in anticancer therapy. Cariporide, being one of the better studied specific and powerful NHE1 inhibitors, has proven to be well tolerated by humans in the cardiological context, however some side-effects, mainly related to drug accumulation and cerebrovascular complications were reported. Thus, cariporide could become a new, slightly toxic and effective anticancer agent in different human malignancies.
Topics: Antineoplastic Agents; Cation Transport Proteins; Guanidines; Humans; Hydrogen-Ion Concentration; Neoplasms; Sodium-Hydrogen Exchanger 1; Sodium-Hydrogen Exchangers; Sulfones
PubMed: 24195657
DOI: 10.1186/1479-5876-11-282 -
Journal of Medical Primatology Oct 2022One strategy to eliminate latently infected cells that persist in people with HIV on antiretroviral therapy is to activate virus transcription and virus production to... (Review)
Review
One strategy to eliminate latently infected cells that persist in people with HIV on antiretroviral therapy is to activate virus transcription and virus production to induce virus or immune-mediated cell death. This is called latency reversal. Despite clear activity of multiple latency reversal agents in vitro, clinical trials of latency-reversing agents have not shown significant reduction in latently infected cells. We review new insights into the biology of HIV latency and discuss novel approaches to enhance the efficacy of latency reversal agents.
Topics: Animals; CD4-Positive T-Lymphocytes; HIV Infections; HIV-1; Humans; Virus Latency
PubMed: 36029233
DOI: 10.1111/jmp.12613 -
Mechanisms of altered redox regulation in neurodegenerative diseases--focus on S--glutathionylation.Antioxidants & Redox Signaling Mar 2012Neurodegenerative diseases are characterized by progressive loss of neurons. A common feature is oxidative stress, which arises when reactive oxygen species (ROS) and/or... (Review)
Review
SIGNIFICANCE
Neurodegenerative diseases are characterized by progressive loss of neurons. A common feature is oxidative stress, which arises when reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) exceed amounts required for normal redox signaling. An imbalance in ROS/RNS alters functionality of cysteines and perturbs thiol-disulfide homeostasis. Many cysteine modifications may occur, but reversible protein mixed disulfides with glutathione (GSH) likely represents the common steady-state derivative due to cellular abundance of GSH and ready conversion of cysteine-sulfenic acid and S-nitrosocysteine precursors to S-glutathionylcysteine disulfides. Thus, S-glutathionylation acts in redox signal transduction and serves as a protective mechanism against irreversible cysteine oxidation. Reversal of protein-S-glutathionylation is catalyzed specifically by glutaredoxin which thereby plays a critical role in cellular regulation. This review highlights the role of oxidative modification of proteins, notably S-glutathionylation, and alterations in thiol homeostatic enzyme activities in neurodegenerative diseases, providing insights for therapeutic intervention.
RECENT ADVANCES
Recent studies show that dysregulation of redox signaling and sulfhydryl homeostasis likely contributes to onset/progression of neurodegeneration. Oxidative stress alters the thiol-disulfide status of key proteins that regulate the balance between cell survival and cell death.
CRITICAL ISSUES
Much of the current information about redox modification of key enzymes and signaling intermediates has been gleaned from studies focused on oxidative stress situations other than the neurodegenerative diseases.
FUTURE DIRECTIONS
The findings in other contexts are expected to apply to understanding neurodegenerative mechanisms. Identification of selectively glutathionylated proteins in a quantitative fashion will provide new insights about neuropathological consequences of this oxidative protein modification.
Topics: Animals; Glutathione; Humans; Neurodegenerative Diseases; Oxidation-Reduction
PubMed: 22066468
DOI: 10.1089/ars.2011.4119 -
International Journal of Nanomedicine 2017Breast cancer is the most common malignant disease in women worldwide, but the current drug therapy is far from optimal as indicated by the high death rate of breast... (Review)
Review
Breast cancer is the most common malignant disease in women worldwide, but the current drug therapy is far from optimal as indicated by the high death rate of breast cancer patients. Nanomedicine is a promising alternative for breast cancer treatment. Nanomedicine products such as Doxil and Abraxane have already been extensively used for breast cancer adjuvant therapy with favorable clinical outcomes. However, these products were originally designed for generic anticancer purpose and not specifically for breast cancer treatment. With better understanding of the molecular biology of breast cancer, a number of novel promising nanotherapeutic strategies and devices have been developed in recent years. In this review, we will first give an overview of the current breast cancer treatment and the updated status of nanomedicine use in clinical setting, then discuss the latest important trends in designing breast cancer nanomedicine, including passive and active cancer cell targeting, breast cancer stem cell targeting, tumor microenvironment-based nanotherapy and combination nanotherapy of drug-resistant breast cancer. Researchers may get insight from these strategies to design and develop nanomedicine that is more tailored for breast cancer to achieve further improvements in cancer specificity, antitumorigenic effect, antimetastasis effect and drug resistance reversal effect.
Topics: Albumin-Bound Paclitaxel; Antineoplastic Agents; Breast Neoplasms; Doxorubicin; Drug Delivery Systems; Female; Humans; Molecular Targeted Therapy; Nanomedicine; Neoplastic Stem Cells; Polyethylene Glycols; Receptor, ErbB-2; Tumor Microenvironment
PubMed: 28860754
DOI: 10.2147/IJN.S123437 -
Computational and Structural... 2015Excitotoxicity involves the excessive release of glutamate from presynaptic nerve terminals and from reversal of astrocytic glutamate uptake, when there is excessive... (Review)
Review
Excitotoxicity involves the excessive release of glutamate from presynaptic nerve terminals and from reversal of astrocytic glutamate uptake, when there is excessive neuronal depolarization. N-methyl-d-aspartate (NMDA) receptors, a subtype of glutamate receptor, are activated in postsynaptic neurons, opening their receptor-operated cation channels to allow Ca(2 +) influx. The Ca(2 +) influx activates two enzymes, calpain I and neuronal nitric oxide synthase (nNOS). Calpain I activation produces mitochondrial release of cytochrome c (cyt c), truncated apoptosis-inducing factor (tAIF) and endonuclease G (endoG), the lysosomal release of cathepsins B and D and DNase II, and inactivation of the plasma membrane Na(+)-Ca(2 +) exchanger, which add to the buildup of intracellular Ca(2 +). tAIF is involved in large-scale DNA cleavage and cyt c may be involved in chromatin condensation; endoG produces internucleosomal DNA cleavage. The nuclear actions of the other proteins have not been determined. nNOS forms nitric oxide (NO), which reacts with superoxide (O2 (-)) to form peroxynitrite (ONOO(-)). These free radicals damage cellular membranes, intracellular proteins and DNA. DNA damage activates poly(ADP-ribose) polymerase-1 (PARP-1), which produces poly(ADP-ribose) (PAR) polymers that exit nuclei and translocate to mitochondrial membranes, also releasing AIF. Poly(ADP-ribose) glycohydrolase hydrolyzes PAR polymers into ADP-ribose molecules, which translocate to plasma membranes, activating melastatin-like transient receptor potential 2 (TRPM-2) channels, which open, allowing Ca(2 +) influx into neurons. NADPH oxidase (NOX1) transfers electrons across cellular membranes, producing O2 (-). The result of these processes is neuronal necrosis, which is a programmed cell death that is the basis of all acute neuronal injury in the adult brain.
PubMed: 25893083
DOI: 10.1016/j.csbj.2015.03.004 -
Cureus Oct 2019The heart is one of the most industrious organs in the human body. It starts beating in the first few weeks of embryonic life and keeps pumping blood till death. This... (Review)
Review
The heart is one of the most industrious organs in the human body. It starts beating in the first few weeks of embryonic life and keeps pumping blood till death. This organ can host a range of diseases as well. Some can hamper the vasculature, while others can affect its electrical activity, the heart valves, etc. All these conditions can lead to end-stage failure where it can no longer meet the requirements of the body's milieu. This imbalance between supply and demand leads to an array of symptoms. Medical management can reduce these clinical effects and possibly prolong the life expectancy in such patients. However, prescription medications can also have their own adverse effects. This necessitates that each line of treatment should be assessed on a risk vs benefit basis. The conventional approach has been to try and slow down the progression of heart failure (HF). However, the inception of stem cells in the management of HF has the potential for reversal of this pathology. Keeping this in view, many studies and trials are under process. To turn the clock back on the HF, before complications set in or get out of control, is the main focus of the time. This article attempts to evaluate various studies about stem cell therapy (SCT) and highlight the important aspects of this novel modality in changing patients' lives.
PubMed: 31803548
DOI: 10.7759/cureus.5959