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Chlorine dioxide solution in metastatic uncurable cancer: case series
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Abstract
Immunotherapy has recently yielded tremendous progress in the fight against malignancies. Its precise mechanism of action remains controversial. Activated leukocytes release reactive oxygen species which kill cancer cells. In the body, chlorine dioxide, orally ingested degrades into free radicals such as found in neutrophils.
Chlorine dioxide is a potent oxidant with in vitro anticancer activity. Its precise mechanism of action has not been thoroughly explored, but it is proposed that it acts through the redox imbalance of cancer cells. Six patients were treated for metastatic cancer (breast, kidney, prostate, lymphoma, uterus and melanoma), on a compassionate basis. We report lasting tumor response with a combination of oral, enema and/or intravenous chlorine dioxide, without any side effects. This preliminary work suggest that chlorine dioxide and free radicals might be the mediators for immunotherapies. Chlorine dioxide is both a promising and unexpensive anticancer agent. Rigorous clinical trials are needed to confirm these preliminary results.
Keywords : Chlorine dioxide , cancer, immunotherapy, Warburg effect, reactive oxygen species, intermittent fasting, ketogenic diet.
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Chlorine dioxide is a powerful and cost-effective oxidizing agent that has demonstrated anti-cancer activity both in vitro and in vivo. Its proposed mechanism involves the release of free radicals, which disrupt the delicate oxidative balance within cancer cells. In case report, the patient has voluntarily opted for compassionate chlorine dioxide therapy over continuing conventional chemotherapy and immunotherapy due to side effects and uncertain survival outcomes. The concentration of the chlorine dioxide solution was 1/100 times lower than the LOAEL threshold, ensuring that not compromise the patients' health. This is the first follow-up in patient diagnosed with metastatic prostate cancer, who shown tumor reduction at distant sites from the primary tumor with no side effects. This preliminary observation suggests that chlorine dioxide and its free radicals could be potential mediators of an anticancer response. However, it is imperative to emphasize the importance of conducting rigorous clinical trials to validate these initial findings.
Background
Chlorine dioxide (ClO2) is an effective disinfectant consisting of oxygen, chloride, and potassium. Because of its high oxidative capacity, ClO2 exerts antimicrobial, antiviral, and antifungal effects. However, its anticancer effects remain to be elucidated.
Methodology
The anticancer activity of CIO2 was assessed on DMS114 small-cell lung cancer (SCLC) cells and human umbilical vein endothelial cells (HUVEC) as control by WST-1, Annexin V, cell cycle analysis, and acridine orange staining. We for the first time investigated the possible therapeutic effects of long-term stabilized ClO2 solution (LTSCD).
Results
Our preliminary findings showed that LTSCD significantly inhibited the proliferation of SCLC cells (p < 0.01) with less toxicity in HUVEC cells. Additionally, LTSCD induced apoptotic cell death in SCLC cells through nuclear blebbing and vacuolar formation. However, LTSCD treatment did not induce cell cycle arrest in both cell lines.
Conclusions
LTSCD can be a therapeutic potential for the treatment of SCLC. However, further investigations are required to assess the LTSCD-induced cell death in SCLC both in vitro and in vivo.
Chlorine dioxide has been condemned as a dangerous poison and has been touted as a cure for COVID-19. This narrative review examines the controversy surrounding the use of aqueous chlorine dioxide by investigating evidence-based research articles, government documents, press reports, and the results of the first clinical trial utilizing chlorine dioxide as a treatment for COVID-19. Chlorine dioxide was found to be employed by numerous industries for antimicrobial and other uses. Aqueous chlorine dioxide was found to be safe when ingested in low doses, but when ingested in high doses, it can cause adverse hematologic and renal effects. Additionally, chlorine dioxide was found to be a strong and rapidly acting virucide with activity against a wide range of viruses. Results of the first clinical trial utilizing chlorine dioxide to treat COVID-19 are reviewed and this molecule is found to be a safe and effective treatment. A dispassionate review of the evidence-based research literature finds preliminary evidence supporting the opinion that aqueous chlorine dioxide may be a safe and effective treatment of COVID-19, and likely for other viral illnesses as well. Further studies are needed to confirm these findings and to explore potential uses of chlorine dioxide.
The coronavirus disease 2019 (COVID19) has generated widespread healthcare concerns and has overburdened healthcare institutions. As the number of COVID19 patients recovers, so does the frequency of reports of COVID19-like symptoms following discharge. A telephone survey with standardized questions was undertaken in which participants were asked if they had had any of 25 possible sequelae after being diagnosed with COVID19 and treated with a Chlorine Dioxide Solution (CDS). One hundred sixty-one people completed the survey. We discovered that rising age is a risk factor (OR = 1.035, p = 0.028, 95% CI = 1.004-1.069), and the odds of having any symptoms in moderate patients is 0.077 compared to mild patients (P = 0.003). It was predicted that 64.6 percent of patients treated with CDS for SARS-CoV-2 infection experienced an average of 3.41 long-term effects. There were no variations in the number of sequelae reported by sex, age, COVID19 severity, or therapy method. The five most prevalent manifestations of the 25 distinct long-term symptoms observed in this study were fatigue, hair loss, dyspnea, concentration problem, and sleep difficulties. In addition, individuals treated with multiple drugs (COVID19 conventional treatment plus a CDS) had 2.7 fewer cases of sequelae, and patients treated exclusively with CDS had 6.14 fewer incidences of long-term effects. People who get a CDS are 19% less likely to experience long-term health effects than patients who receive standard COVID19 therapy. According to the findings of this study, patients who receive a CDS have a reduced probability of developing sequelae. Furthermore, the incidence of long-term effects is lower in individuals treated exclusively with a CDS. The recent findings involving Chlorine Dioxide support the development of clinical studies to evaluate its efficacy in preventing the development of COVID19 long-term effects.
Chronic caloric restriction (CR) has powerful anticarcinogenic actions in both preclinical and clinical studies but may be difficult to sustain. As an alternative to CR, there has been growing interest in intermittent fasting (IF) in both the scientific and lay community as a result of promising study results, mainly in experimental animal models. According to a survey by the International Food Information Council Foundation, IF has become the most popular diet in the last year, and patients with cancer are seeking advice from oncologists about its beneficial effects for cancer prevention and treatment. However, as discussed in this review, results from IF studies in rodents are controversial and suggest potential detrimental effects in certain oncologic conditions. The effects of IF on human cancer incidence and prognosis remain unknown because of a lack of high‐quality randomized clinical trials. Preliminary studies suggest that prolonged fasting in some patients who have cancer is safe and potentially capable of decreasing chemotherapy‐related toxicity and tumor growth. However, because additional trials are needed to elucidate the risks and benefits of fasting for patients with cancer, the authors would not currently recommend patients undergoing active cancer treatment partake in IF outside the context of a clinical trial. IF may be considered in adults seeking cancer‐prevention benefits through means of weight management, but whether IF itself affects cancer‐related metabolic and molecular pathways remains unanswered.
To date, there is no effective prophylactic agent to prevent COVID-19. However, the development of symptoms similar to covid19 could be prevented with an aqueous solution of chlorine dioxide (ClO2). This retrospective study evaluated the effectiveness of an aqueous solution of ClO2 (CDS) as a prophylactic agent in 1,163 family members living with positive/suspected COVID19 patients. Prophylactic treatment consisted of 0.0003% chlorine dioxide solution (CDS) orally for at least fourteen days. Family members in whom no reports of the development of covid19-like symptoms were found in the medical history were considered successful cases. The efficacy of CDS in preventing covid19-like symptoms was 90.4% (1,051 of 1,163 relatives did not report any symptoms). The comorbidities, sex and severity of the illness of the sick patient did not contribute to the development of symptoms similar to covid19 (P = 0.092, P = 0.351 and P = 0.574, respectively). However, older relatives were more likely to develop covid19-like symptoms (ORa = 4.22, P = 0.002). There was no evidence of alterations in blood parameters or in the QTc interval in relatives who consumed CDS. The recent findings regarding Chlorine Dioxide justify designing clinical trials to assess its efficacy for preventing SARS-CoV-2 infection.
Tumors of the abdominal cavity, such as colorectal, pancreatic and ovarian cancer, frequently metastasize into the peritoneum. Large numbers of metastatic nodules hinder curative surgical resection, necessitating lavage with hyperthermic intraperitoneal chemotherapy (HIPEC). However, HIPEC not only causes severe side effects but also has limited therapeutic efficacy in various instances. At the same time, the age of immunotherapies such as biological agents, checkpoint‑ inhibitors or immune‑cell therapies, increasingly emphasizes the critical role of anticancer immunity in targeting malignancies. The present study investigated the ability of three types of long‑lived reactive species (oxidants) to inactivate cancer cells and potentially complement current HIPEC regimens, as well as to increase tumor cell expression of danger signals that stimulate innate immunity. The human abdominal cancer cell lines HT‑29, Panc‑01 and SK‑OV‑3 were exposed to different concentrations of hydrogen peroxide (H2O2), hypochlorous acid (HOCl) and peroxynitrite (ONOO‑). Metabolic activity was measured, as well as determination of cell death and danger signal expression levels via flow cytometry and detection of intracellular oxidation via high‑content microscopy. Oxidation of tumor decreased intracellular levels of the antioxidant glutathione and induced oxidation in mitochondria, accompanied by a decrease in metabolic activity and an increase in regulated cell death. At similar concentrations, HOCl showed the most potent effects. Non‑malignant HaCaT keratinocytes were less affected, suggesting the approach to be selective to some extent. Pro‑immunogenic danger molecules were investigated by assessing the expression levels of calreticulin (CRT), and heat‑shock protein (HSP)70 and HSP90. CRT expression was greatest following HOCl and ONOO‑ treatment, whereas HOCl and H2O2 resulted in the greatest increase in HSP70 and HSP90 expression levels. These results suggested that HOCl may be a promising agent to complement current HIPEC regimens targeting peritoneal carcinomatosis.
Several changes of magnesium (Mg) metabolism have been reported with aging, including diminished Mg intake, impaired intestinal Mg absorption and renal Mg wasting. Mild Mg deficits are generally asymptomatic and clinical signs are usually non-specific or absent. Asthenia, sleep disorders, hyperemotionality, and cognitive disorders are common in the elderly with mild Mg deficit, and may be often confused with age-related symptoms. Chronic Mg deficits increase the production of free radicals which have been implicated in the development of several chronic age-related disorders. Numerous human diseases have been associated with Mg deficits, including cardiovascular diseases, hypertension and stroke, cardio-metabolic syndrome and type 2 diabetes mellitus, airways constrictive syndromes and asthma, depression, stress-related conditions and psychiatric disorders, Alzheimer’s disease (AD) and other dementia syndromes, muscular diseases (muscle pain, chronic fatigue, and fibromyalgia), bone fragility, and cancer. Dietary Mg and/or Mg consumed in drinking water (generally more bioavailable than Mg contained in food) or in alternative Mg supplements should be taken into consideration in the correction of Mg deficits. Maintaining an optimal Mg balance all through life may help in the prevention of oxidative stress and chronic conditions associated with aging. This needs to be demonstrated by future studies.
There is a rapidly growing body of literature supporting the notion that differential oxidative metabolism in cancer versus normal cells represents a metabolic frailty that can be exploited to open a therapeutic window into cancer therapy. These cancer cell-specific metabolic frailties may be amenable to manipulation with non-toxic small molecule redox active compounds traditionally thought to be antioxidants. In this review we describe the potential mechanisms and clinical applicability in cancer therapy of four small molecule redox active agents: melatonin, vitamin E, selenium, and vitamin C. Each has shown the potential to have pro-oxidant effects in cancer cells while retaining antioxidant activity in normal cells. This dichotomy can be exploited to improve responses to radiation and chemotherapy by opening a therapeutic window based on a testable biochemical rationale amenable to confirmation with biomarker studies during clinical trials. Thus, the unique pro-oxidant/antioxidant properties of melatonin, vitamin E, selenium, and vitamin C have the potential to act as effective adjuvants to traditional cancer therapies, thereby improving cancer patient outcomes.
Cancer cells are characterized by higher levels of reactive oxygen species (ROS) compared to normal cells as a result of an imbalance between oxidants and antioxidants. However, cancer cells maintain their redox balance due to their high antioxidant capacity. Recently, a high level of oxidative stress is considered a novel target for anticancer therapy. This can be induced by increasing exogenous ROS and/or inhibiting the endogenous protective antioxidant system. Additionally, the immune system has been shown to be a significant ally in the fight against cancer. Since ROS levels are important to modulate the antitumor immune response, it is essential to consider the effects of oxidative stress-inducing treatments on this response. In this review, we provide an overview of the mechanistic cellular responses of cancer cells towards exogenous and endogenous ROS-inducing treatments, as well as the indirect and direct antitumoral immune effects, which can be both immunostimulatory and/or immunosuppressive. For future perspectives, there is a clear need for comprehensive investigations of different oxidative stress-inducing treatment strategies and their specific immunomodulating effects, since the effects cannot be generalized over different treatment modalities. It is essential to elucidate all these underlying immune effects to make oxidative stress-inducing treatments effective anticancer therapy.
Objectives
Periodontal ligament stem cells (PDLSCs) have an underlined significance as their high proliferative capacity and multipotent differentiation provide an important therapeutic potential. The integrity of these cells is frequently disturbed by the routinely used irrigative compounds applied as periodontal or endodontic disinfectants (e.g., hydrogen peroxide (H2O2) and chlorhexidine (CHX)). Our objectives were (i) to monitor the cytotoxic effect of a novel dental irrigative compound, chlorine dioxide (ClO2), compared to two traditional agents (H2O2, CHX) on PDLSCs and (ii) to test whether the aging factor of PDLSC cultures determines cellular responsiveness to the chemicals tested.
Methods
Impedimetry (concentration-response study), WST-1 assays (WST = water soluble tetrazolium salt), and morphology analysis were performed to measure changes in cell viability induced by the 3 disinfectants; immunocytochemistry of stem cell markers (STRO-1, CD90, and CD105) measured the induced mesenchymal characteristics.
Results
Cell viability experiments demonstrated that the application of ClO2 does not lead to a significant decrease in viability of PLDSCs in concentrations used to kill microbes. On the contrary, traditional irrigants, H2O2, and CHX are highly toxic on PDLSCs. Aging of PLDSC cultures (passages 3 vs. 7) has characteristic effects on their responsiveness to these agents as the increased expression of mesenchymal stem cell markers turns to decreased.
Conclusions and clinical relevance
While the active ingredients of mouthwash (H2O2, CHX) applied in endodontic or periodontitis management have a serious toxic effect on PDLSCs, the novel hyperpure ClO2 is less toxic providing an environment favoring dental structure regenerations during disinfectant interventions.
Motivation:
Viruses have caused many epidemics throughout human history. The novel coronavirus [10] is just the latest example. A new viral outbreak can be unpredictable, and development of specific defense tools and countermeasures against the new virus remains time-consuming even in today's era of modern medical science and technology. In the lack of effective and specific medication or vaccination, it would be desirable to have a nonspecific protocol or substance to render the virus inactive, a substance/protocol, which could be applied whenever a new viral outbreak occurs. This is especially important in cases when the emerging new virus is as infectious as SARS-CoV-2 [4].
Aims and structure of the present communication:
In this editorial, we propose to consider the possibility of developing and implementing antiviral protocols by applying high purity aqueous chlorine dioxide (ClO2) solutions. The aim of this proposal is to initiate research that could lead to the introduction of practical and effective antiviral protocols. To this end, we first discuss some important properties of the ClO2 molecule, which make it an advantageous antiviral agent, then some earlier results of ClO2 gas application against viruses will be reviewed. Finally, we hypothesize on methods to control the spread of viral infections using aqueous ClO2 solutions.
Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. It is now well accepted that moderate levels of ROS are required for several cellular functions, including gene expression. The production of ROS is elevated in tumor cells as a consequence of increased metabolic rate, gene mutation and relative hypoxia, and excess ROS are quenched by increased antioxidant enzymatic and nonenzymatic pathways in the same cells. Moderate increases of ROS contribute to several pathologic conditions, among which are tumor promotion and progression, as they are involved in different signaling pathways and induce DNA mutation. However, ROS are also able to trigger programmed cell death (PCD). Our review will emphasize the molecular mechanisms useful for the development of therapeutic strategies that are based on modulating ROS levels to treat cancer. Specifically, we will report on the growing data that highlight the role of ROS generated by different metabolic pathways as Trojan horses to eliminate cancer cells.
Although the oral route is the most convenient route for drug administration, there are a number of circumstances where this is not possible from either a clinical or pharmaceutical perspective. In these cases, the rectal route may represent a practical alternative and can be used to administer drugs for both local and systemic actions. The environment in the rectum is considered relatively constant and stable and has low enzymatic activity in comparison to other sections of the gastrointestinal tract. In addition, drugs can partially bypass the liver following systemic absorption, which reduces the hepatic first-pass effect. Therefore, rectal drug delivery can provide significant local and systemic levels for various drugs, despite the relatively small surface area of the rectal mucosa. Further development and optimization of rectal drug formulations have led to improvements in drug bioavailability, formulation retention, and drug release kinetics. However, despite the pharmaceutical advances in rectal drug delivery, very few of them have translated to the clinical phase. This review will address the physiological and pharmaceutical considerations influencing rectal drug delivery as well as the conventional and novel drug delivery approaches. The translational challenges and development aspects of novel formulations will also be discussed.
Purpose
This meta-analysis aimed to extensively investigate the association between various measures of vitamin D status and non-Hodgkin lymphoma (NHL) and its subtypes.
Methods
We searched MEDLINE (PubMed), Embase, and the Cochrane Library in February 2018. Two authors independently reviewed and selected articles based on predetermined criteria.
Results
A total of 30 studies with 56,458 NHL cases were finally selected, with 24, 9, and 3 studies on sunlight/ultraviolet radiation (UVR) exposure, dietary intake, and serum/plasma 25-hydroxyvitamin D levels, respectively. Significant protective effects of overall sunlight/UVR exposure on NHL and subtypes were observed, with summary relative risks (RRs) ranging from 0.67–0.80 (RR for NHL = 0.80; 95% confidence interval [CI]: 0.71–0.90) among subjects with high exposure compared to those with low exposure. The results were consistent with various classifications of sunlight/UVR exposure. In contrast, when exposure measures of dietary vitamin D intake (RR for NHL = 1.03; 95% CI: 0.90–1.19) and serum/plasma 25-hydroxyvitamin D levels (RR for NHL = 0.97; 95% CI: 0.82–1.15) were used, risk estimates were inconsistent or non-significant for NHL and the subtypes.
Conclusion
While risk estimates varied by different measures of vitamin D status, a protective effect of sunlight/UVR exposure on NHL incidence was verified, across most of the tested subtypes as well as exposure categories.
Over the past century, the notion that vitamin C can be used to treat cancer has generated much controversy. However, new knowledge regarding the pharmacokinetic properties of vitamin C and recent high-profile preclinical studies have revived interest in the utilization of high-dose vitamin C for cancer treatment. Studies have shown that pharmacological vitamin C targets many of the mechanisms that cancer cells utilize for their survival and growth. In this Opinion article, we discuss how vitamin C can target three vulnerabilities many cancer cells share: redox imbalance, epigenetic reprogramming and oxygen-sensing regulation. Although the mechanisms and predictive biomarkers that we discuss need to be validated in well-controlled clinical trials, these new discoveries regarding the anticancer properties of vitamin C are promising to help identify patient populations that may benefit the most from high-dose vitamin C therapy, developing effective combination strategies and improving the overall design of future vitamin C clinical trials for various types of cancer.
Abstract Most chemotherapeutics elevate intracellular levels of reactive oxygen species (ROS), and many can alter redox-homeostasis of cancer cells. It is widely accepted that the anticancer effect of these chemotherapeutics is due to the induction of oxidative stress and ROS-mediated cell injury in cancer. However, various new therapeutic approaches targeting intracellular ROS levels have yielded mixed results. Since it is impossible to quantitatively detect dynamic ROS levels in tumors during and after chemotherapy in clinical settings, it is of increasing interest to apply mathematical modeling techniques to predict ROS levels for understanding complex tumor biology during chemotherapy. This review outlines the current understanding of the role of ROS in cancer cells during carcinogenesis and during chemotherapy, provides a critical analysis of the methods used for quantitative ROS detection and discusses the application of mathematical modeling in predicting treatment responses. Finally, we provide insights on and perspectives for future development of effective therapeutic ROS-inducing anticancer agents or antioxidants for cancer treatment.
Background:
Our previous work has shown peroxiredoxin-1 (PRDX1), one of major antioxidant enzymes, to be a biomarker in human breast cancer. Hereby, we further investigate the role of PRDX1, compared to its close homolog PRDX2, in mammary malignant cells.
Methods:
CRISPR/Cas9- or RNAi-based methods were used for genetic targeting PRDX1/2. Cell growth was assessed by crystal violet, EdU incorporation or colony formation assays. In vivo growth was assessed by a xenotransplantation model. Adenanthin was used to inhibit the thioredoxin-dependent antioxidant defense system. The prooxidant agents used were hydrogen peroxide, glucose oxidase and sodium L-ascorbate. A PY1 probe or HyPer-3 biosensor were used to detect hydrogen peroxide content in samples.
Results:
PRDX1 downregulation significantly impaired the growth rate of MCF-7 and ZR-75-1 breast cancer cells. Likewise, xenotransplanted PRDX1-deficient MCF-7 cells presented a retarded tumour growth. Furthermore, genetic targeting of PRDX1 or adenanthin, but not PRDX2, potently sensitised all six cancer cell lines studied, but not the non-cancerous cells, to glucose oxidase and ascorbate.
Conclusions:
Our study pinpoints the dominant role for PRDX1 in management of exogeneous oxidative stress by breast cancer cells and substantiates further exploration of PRDX1 as a target in this disease, especially when combined with prooxidant agents.
Cisplatin, a small platinum-containing molecule, is a widely used, highly effective anticancer drug. However, severe side effects have been found in cancer patients treated with cisplatin, including nephrotoxicity, neurotoxicity, and ototoxicity. These cisplatin-induced side effects can have a major impact on patient quality of life, including social development problems in pediatric patients that develop hearing loss. Previous studies have suggested that the major cause of cisplatin-induced ototoxicity is abnormal accumulation of reactive oxygen species (ROS) and oxidative stress. Alpha-lipoic acid (ALA), one of the most effective antioxidants, is known to be involved in the cellular antioxidant system and may have a protective effect on cisplatin-induced ototoxicity. However, the therapeutic effect of ALA on damaged hearing function and its detailed mechanism of action are not fully understood. This study focused on determining whether ALA has a potential as a protective and/or therapeutic agent for cisplatin-induced ototoxicity. Histological and physiological analyses were performed using cisplatin-treated mouse cochlea and HEI-OC1 culture cells in pre- and post-treatment with ALA in vitro and in vivo. We found that ALA contributes to protecting mitochondrial function by preventing ROS accumulation and inhibiting apoptotic cell death. Importantly, post-treatment with ALA consistently showed an almost equal restorative effect to pretreatment, in vitro and in vivo, supporting the possible use of ALA as a therapeutic agent for cisplatin-induced ototoxicity. This study is the first report on a strong therapeutic potential of ALA to rescue ototoxic hearing loss caused by cisplatin, and our data provide key evidence that ALA may act as a reducing agent for glutathione disulfide to increase glutathione levels on behalf of glutathione reductase. This result was consistent in both cultured cells and the mouse model, which improves the clinical value of ALA for therapy of cisplatin-induced ototoxicity.
In this study, a chlorine dioxide solution (UC-1) composed of chlorine dioxide was produced using an electrolytic method and subsequently purified using a membrane. UC-1 was determined to contain 2000 ppm of gaseous chlorine dioxide in water. The efficacy and safety of UC-1 were evaluated. The antimicrobial activity was more than 98.2% reduction when UC-1 concentrations were 5 and 20 ppm for bacteria and fungi, respectively. The half maximal inhibitory concentrations (IC50) of H1N1, influenza virus B/TW/71718/04, and EV71 were 84.65 ± 0.64, 95.91 ± 11.61, and 46.39 ± 1.97 ppm, respectively. A 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test revealed that the cell viability of mouse lung fibroblast L929 cells was 93.7% at a 200 ppm UC-1 concentration that is over that anticipated in routine use. Moreover, 50 ppm UC-1 showed no significant symptoms in a rabbit ocular irritation test. In an inhalation toxicity test, treatment with 20 ppm UC-1 for 24 h showed no abnormality and no mortality in clinical symptoms and normal functioning of the lung and other organs. A ClO2 concentration of up to 40 ppm in drinking water did not show any toxicity in a subchronic oral toxicity test. Herein, UC-1 showed favorable disinfection activity and a higher safety profile tendency than in previous reports.
The use of a family of chemical agents, releasing active species of oxygen, effective against infectious microorganisms and viruses is described with emphasis on Chlorine Dioxide (CLO2), one of the oxides of chlorine. Also discussed are ozone, hypochlorite, periodate and the known mechanisms of action by which certain white blood cells attach and eradicate infectious microorganisms and primitive bacteria also known as viruses. Explanation of the biochemical mechanisms of acid of CLO 2 as an antimicrobial agent, is presented. Particular attention is given to Candida albicans, cytomegalovirus, polio virus, Herpes I and II, HTLV-III and Pseudomonas responding to the clinical application of CLO2. It is implied that these biochemical mechanisms are so fundamental that the development of resistant strains of bacteria and/or yeast would not occur with other anti-infectious agents. Limited lists of health abnormalities that respond to CLO2 are discussed.
Ascorbic acid (A) has been demonstrated to exhibit anti-cancer activity in association with chemotherapeutic agents. Potassium (K) is a regulator of cellular proliferation. In the present study, the biological effects of A and K bicarbonate, alone or in combination (A+K), on breast cancer cell lines were evaluated. The survival of cancer cells was determined by sulforhodamine B cell proliferation assay, while analysis of the cell cycle distribution was conducted via fluorescence-activated cell sorting. In addition, the expression of signaling proteins was analyzed upon treatment. The results indicated that there was a heterogeneous response of the different cell lines to A and K, and the best effects were achieved by A+K and A treatment. The interaction between A+K indicated an additive or synergistic effect. In addition, A+K increased the percentage of cells in the sub-G1 phase of the cell cycle, and was the most effective treatment in activating the degradation of poly(adenosine diphosphate-ribose) polymerase-1. In the breast cancer cell line MCF-7, A+K induced the appearance of the 18 kDa isoform of B-cell lymphoma-2-associated X protein (Bax), which is a more potent inducer of apoptosis than the full-length Bax-p21. The effects of A and K on the phosphorylation of extracellular signal-regulated kinase (ERK)1 and ERK2 were heterogeneous. In addition, treatment with K, A and A+K inhibited the expression of nuclear factor-κB. Overall, the results of the present study indicated that K potentiated the anti-tumoral effects of A in breast cancer cells in vitro.
Chlorine dioxide has been used for a disinfectant by exhibiting antimicrobial activity and is also potent to kill insect pests infesting stored grains. This study aimed to extend the usefulness of chlorine dioxide with respect to anticancer and antiviral activities. Cytotoxicity of chlorine dioxide was assessed against five different human cancer cell lines. Chlorine dioxide exhibited significant cytotoxicity against two breast cancer cell lines (MCF-7, MDA-MB-231) and three colorectal cancer cell lines (LoVo, HCT-116, SW-480). This cytotoxicity appeared to be associated with the capacity of chlorine dioxide to induce the production of reactive oxygen species (ROS). Compared to control insect cell lines, the cancer cell lines possessed much higher levels of ROS. On the other hand, a treatment of an antioxidant, vitamin E, significantly reduced the cytotoxicity, suggesting that the cytotoxicity was induced by high levels of ROS production. Chlorine dioxide exhibited antiviral activity against different viruses. A baculovirus, Autographa californica nuclear polyhedrosis virus (AcNPV), is a dsDNA insect virus and lost its viral activity to form polyhedral viral particles in response to chlorine dioxide. The antiviral activity against AcNPV was dependent on the incubation time with chlorine dioxide. Tobacco mosaic virus is a ssRNA plant virus and was reduced in its population after exposure to chlorine dioxide along with significant decrease of viral symptoms. These results indicate that chlorine dioxide possesses anticancer and antiviral activities probably due to its inducing activity of ROS production.
Tumors contain a distinct small subpopulation of cells that possess stem cell-like characteristics. These cells have been called cancer stem cells (CSCs) and are thought to be responsible for anticancer drug resistance and tumor relapse after therapy. Emerging evidence indicates that CSCs share many properties, such as self-renewal and quiescence, with normal stem cells. In particular, CSCs and normal stem cells retain low levels of reactive oxygen species (ROS), which can contribute to stem cell maintenance and resistance to stressful tumor environments. Current literatures demonstrate that the activation of ataxia telangiectasia mutated (ATM) and forkhead box O3 (FoxO3) is associated with the maintenance of low ROS levels in normal stem cells such as hematopoietic stem cells. However, the importance of ROS signaling in CSC biology remains poorly understood. Recent studies demonstrate that nuclear factor-erythroid 2-related factor 2 (NRF2), a master regulator of the cellular antioxidant defense system, is involved in the maintenance of quiescence, survival, and stress resistance of CSCs. Here, we review the recent findings on the roles of NRF2 in maintenance of the redox state and multidrug resistance in CSCs, focusing on how NRF2-mediated ROS modulation influences the growth and resistance of CSCs.
Glioblastoma multiforme (GBM), like most cancers, possesses a unique bioenergetic state of aerobic glycolysis known as the Warburg Effect. Here, we documented that methylene blue (MB) reverses the Warburg effect evidenced by the increasing of oxygen consumption and reduction of lactate production in GBM cell lines. MB decreases GBM cell proliferation and halts the cell cycle in S phase. Through activation of AMP- activated protein kinase (AMPK), MB inactivates downstream acetyl-CoA carboxylase and decreases cyclin expression. Structure-activity relationship analysis demonstrated that toluidine blue O, an MB derivative with similar bioenergetic actions, exerts similar action in GBM cell proliferation. In contrast, two other MB derivatives, 2-chlorophenothiazine and promethazine, exert no effect on cellular bioenergetics and do not inhibit GBM cell proliferation. MB inhibits cell proliferation in both temozolomide sensitive and insensitive GBM cell lines. In a human GBM xenograft model, a single daily dosage of MB does not activate AMPK signaling and no tumor regression was observed. In summary, the current study provides the first in vitro proof of concept that reversal of Warburg effect might be a novel therapy for GBM.
Methylene blue (MB), the first lead chemical structure of phenothiazine and other derivatives, is commonly used in diagnostic procedures and as a treatment for methemoglobinemia. We have previously demonstrated that MB could function as an alternative mitochondrial electron transfer carrier, enhance cellular oxygen consumption, and provide protection in vitro and in rodent models of Parkinson's disease and stroke. In the present study, we investigated the structure-activity relationships of MB in vitro using MB and six structurally related compounds. MB reduces mitochondrial superoxide production via alternative electron transfer that bypasses mitochondrial complexes I-III. MB mitigates reactive free radical production and provides neuroprotection in HT-22 cells against glutamate, IAA and rotenone toxicity. Distinctly, MB provides no protection against direct oxidative stress induced by glucose oxidase. Substitution of a side chain at MB's 10-nitrogen rendered a 1000-fold reduction of the protective potency against glutamate neurototoxicity. Compounds without side chains at positions 3 and 7, chlorophenothiazine and phenothiazine, have distinct redox potentials compared to MB and are incapable of enhancing mitochondrial electron transfer, while obtaining direct antioxidant actions against glutamate, IAA, and rotenone insults. Chlorophenothiazine exhibited direct antioxidant actions in mitochondria lysate assay compared to MB, which required reduction by NADH and mitochondria. MB increased complex IV expression and activity, while 2-chlorphenothiazine had no effect. Our study indicated that MB could attenuate superoxide production by functioning as an alternative mitochondrial electron transfer carrier and as a regenerable anti-oxidant in mitochondria.
Airborne influenza virus infection of mice can be prevented by gaseous chlorine dioxide (ClO2). Here, I demonstrate that ClO2 abolishes the function of hemagglutinin (HA) of influenza A virus (H1N1) in a concentration-, time- and temperature-dependent manner. The half-inhibitory concentration (IC50) during a 2-min reaction with ClO2 at 25°C was 13.7 μM, and the. half-inactivation time (t1/2) with 100 μM ClO2 at 25°C was 19.5 s. Peptides generated from a tryptic digest of ClO2-treated virus were analyzed by mass spectrometry. A HA fragment, H2N-NLLWLTGK-COOH (residues 150 - 157) was identified in which the tryptophan 153 residue (W153) was 32 mass units greater than expected. This peptide, which is derived from the central region of the receptor binding site of HA, includes a highly conserved W153. It is shown that W153 was oxidized to N-formylkynurenine in the ClO2-treated virus. It is concluded that the inactivation of influenza virus by ClO2 is caused by oxidation of W153 in HA, thereby abolishing its receptor-binding ability.
Vitamin D system is a complex pathway that includes precursors, active metabolites, enzymes, and receptors. This complex system actives several molecular pathways and mediates a multitude of functions. In addition to the classical role in calcium and bone homeostasis, vitamin D plays “non-calcemic” effects in host defense, inflammation, immunity, and cancer processes as recognized in vitro and in vivo studies. The aim of this review is to highlight the relationship between vitamin D and cancer, summarizing several mechanisms proposed to explain the potential protective effect of vitamin D against the development and progression of cancer. Vitamin D acts like a transcription factor that influences central mechanisms of tumorigenesis: growth, cell differentiation, and apoptosis. In addition to cellular and molecular studies, epidemiological surveys have shown that sunlight exposure and consequent increased circulating levels of vitamin D are associated with reduced reduced occurrence and a reduced mortality in different histological types of cancer. Another recent field of interest concerns polymorphisms of vitamin D receptor (VDR); in this context, preliminary data suggest that VDR polymorphisms more frequently associated with tumorigenesis are Fok1, Bsm1, Taq1, Apa1, EcoRV, Cdx2; although further studies are needed to clarify their role in the cancer. In this review, the relationship between vitamin D and cancer is discussed.
Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer. Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is predominantly regulated by the transcription factor Nrf2 (also known as Nfe2l2) and its repressor protein Keap1 (refs 2-5). In contrast to the acute physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2-Keap1 interaction to stabilize Nrf2 and increase the constitutive transcription of Nrf2 target genes were recently identified, indicating that enhanced ROS detoxification and additional Nrf2 functions may in fact be pro-tumorigenic. Here, we investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of Kras, Braf and Myc, and found that ROS are actively suppressed by these oncogenes. K-Ras(G12D), B-Raf(V619E) and Myc(ERT2) each increased the transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogene-directed increased expression of Nrf2 is a new mechanism for the activation of the Nrf2 antioxidant program, and is evident in primary cells and tissues of mice expressing K-Ras(G12D) and B-Raf(V619E), and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impairs K-Ras(G12D)-induced proliferation and tumorigenesis in vivo. Thus, the Nrf2 antioxidant and cellular detoxification program represents a previously unappreciated mediator of oncogenesis.
Neuroprotective strategies, including free radical scavengers, ion channel modulators, and anti-inflammatory agents, have been extensively explored in the last 2 decades for the treatment of neurological diseases. Unfortunately, none of the neuroprotectants has been proved effective in clinical trails. In the current study, we demonstrated that methylene blue (MB) functions as an alternative electron carrier, which accepts electrons from NADH and transfers them to cytochrome c and bypasses complex I/III blockage. A de novo synthesized MB derivative, with the redox center disabled by N-acetylation, had no effect on mitochondrial complex activities. MB increases cellular oxygen consumption rates and reduces anaerobic glycolysis in cultured neuronal cells. MB is protective against various insults in vitro at low nanomolar concentrations. Our data indicate that MB has a unique mechanism and is fundamentally different from traditional antioxidants. We examined the effects of MB in two animal models of neurological diseases. MB dramatically attenuates behavioral, neurochemical, and neuropathological impairment in a Parkinson disease model. Rotenone caused severe dopamine depletion in the striatum, which was almost completely rescued by MB. MB rescued the effects of rotenone on mitochondrial complex I-III inhibition and free radical overproduction. Rotenone induced a severe loss of nigral dopaminergic neurons, which was dramatically attenuated by MB. In addition, MB significantly reduced cerebral ischemia reperfusion damage in a transient focal cerebral ischemia model. The present study indicates that rerouting mitochondrial electron transfer by MB or similar molecules provides a novel strategy for neuroprotection against both chronic and acute neurological diseases involving mitochondrial dysfunction.
Unlike normal cells, tumor cells survive in a specific redox environment where the elevated reactive oxygen species contribute to enhance cell proliferation and to suppress apoptosis. Alpha-lipoic acid, a naturally occurring reactive oxygen species scavenger, has been shown to possess anticancer activity, due to its ability to suppress proliferation and to induce apoptosis in different cancer cell lines. Since at the moment little information is available regarding the potential effects of alpha-lipoic acid on breast cancer, in the present study we addressed the question whether alpha-lipoic acid induces cell cycle arrest and apoptosis in the human breast cancer cell line MCF-7. Moreover, we investigated some molecular mechanisms which mediate alpha-lipoic acid actions, focusing on the role of the PI3-K/Akt signalling pathway. We observed that alpha-lipoic acid is able to scavenge reactive oxygen species in MCF-7 cells and that the reduction of reactive oxygen species is followed by cell growth arrest in the G1 phase of the cell cycle, via the specific inhibition of Akt pathway and the up-regulation of the cyclin-dependent kinase inhibitor p27(kip1), and by apoptosis, via changes of the ratio of the apoptotic-related protein Bax/Bcl-2. Thus, the anti-tumor activity of alpha-lipoic acid observed in MCF-7 cells further stresses the role of redox state in regulating cancer initiation and progression.
Chlorine dioxide (ClO2) is a disinfectant gas with strong antifungal, antibacterial, and antiviral activities. Applied on hard non-porous surfaces as an aqueous solution or gas, the ClO2 exerts antimicrobial activity through its interaction and destabilization of cell membrane proteins, as well as through DNA/RNA oxidation, triggering cell death. As for viruses, the ClO2 promotes protein denaturalization mechanisms preventing the union between the human cells and the viral envelope. Currently, ClO2 has been pointed out as a potential anti-SARS-CoV-2 clinical treatment for use in humans with the ability to oxidize the cysteine residues in the spike protein of SARS-CoV-2, inhibiting the subsequent binding with the Angiotensin-converting enzyme type 2 receptor, located in the alveolus cells. Orally administered ClO2 reaches the gut tract and exacerbates the symptoms of COVID-19 generating a dysbiosis with gut inflammation and diarrhea as side effects, and once absorbed, produces toxic effects including methemoglobinemia and hemoglobinuria which can trigger respiratory diseases. These effects are dose-dependent and may not be entirely consistent between individuals since the gut microbiota composition is highly heterogeneous. However, to support the use of ClO2 as an anti-SARS-CoV-2 agent, further studies focused on its effectiveness and safety both in healthy and immunocompromised individuals, are needed.
Gaseous chlorine dioxide (ClO2) is one of the most promising air disinfectants. In this study, an ultra-low concentration of ClO2 gas (< 1.2 mg/m3) was generated in an office at various levels of humidity and illuminance to investigate the decay law. The disinfection efficiency and metal corrosiveness of ultra-low concentrations of ClO2 gas were also studied using an experimental chamber. At 48% and 75% humidity, the decay rate constants of ClO2 gas were 0.0034 min-1 and 0.0036 min-1, respectively. The rate of decline of the ClO2 concentration increased as the humidity of the environment increased. The decay rate constant of ClO2 gas at an illuminance of 76 lux and 3429 lux was 0.0034 min-1 and 0.00427 min-1, respectively; hence, the decay rate increased with increased illumination. At a humidity of 72% and illuminance of 2112 lux, the decay rate constant reached 0.00880 min-1. The effects of humidity and illuminance on the attenuation of the ClO2 concentration were strongly synergistic. When the gas concentration was maintained below 0.9 mg/m3, the disinfection rate of ClO2 on bacteria (P. aeruginosa, V. mimicus and S. aureus) exceeded 99.9%; thus, ClO2 gas exhibited a high disinfection efficiency. In addition, there was no corrosion to various metals by ClO2 under the same conditions. Consequently, gaseous ClO2 at ultra-low concentrations has a high sterilization efficiency and is non-corrosive to metals.
Implications:
Humidity and illuminance can influence decay laws of extremely low concentration ClO2 gas. The gaseous ClO2 at ultra-low concentrations has a high sterilisation efficiency and is non-corrosive to metals.
We discuss how lipoic acid (LA), a natural antioxidant, induces apoptosis and inhibits proliferation, EMT, metastasis and stemness of cancer cells. Furthermore, owing to its ability to reduce chemotherapy-induced side effects and chemoresistance, LA appears to be a promising compound for cancer treatment.
Drug delivery via the rectum is a useful alternative route of administration to the oral route for patients who cannot swallow. Traditional rectal dosage forms have been traditionally used for localised treatments including delivery of laxatives, treatment of haemorrhoids and for delivery of antipyretics. However, the recent trend is showing an increased incline for development of novel rectal delivery systems to deliver drug directly into the systemic circulation by taking advantage of porto-systemic shunting. The present review is based on research studies carried out between years 1969-2017. Data for this review have been derived from keyword searches using Scopus and Medline databases. Novel rectal drug delivery systems including hollow type suppositories, thermo-responsive and muco-adhesive liquid suppositories, and nanoparticulate systems incorporated into an appropriate vehicle have offered more control over delivery of drug molecules for local or systemic actions. In addition, various methods for in vitro - in vivo evaluation of rectal drug delivery systems are covered which is as important as the formulation, and must be carried out using appropriate methodology. Continuous research and development in this field of drug delivery may unleash the hidden potential of the rectal drug delivery systems.
Aims:
Invasion and metastasis are the main cause of mortality in breast cancer. Hence, novel therapeutic interventions with high specificity toward invasion and metastasis are necessary. α-Lipoic acid showed antiproliferative and cytotoxic effects on several cancers including breast cancer. However, the effect of lipoic acid on breast cancer metastasis remains unclear.
Main methods:
In the present study, we examined the effects of lipoic acid on the migration and invasion of MDA-MB-231 and 4T1 breast cancer cells.
Key findings:
Our data showed that lipoic acid effectively inhibited the colony forming ability of highly invasive MDA-MB-231 and 4T1 cells. Moreover, the nontoxic concentrations of lipoic acid significantly reduced the migration of breast cancer cells. Lipoic acid also inhibited the TGFβ-induced angiopoietin-like 4 (ANGPTL4) expression and reduced the activity of matrix metalloproteinase-9 (MMP-9), an enzyme involved in invasion and metastasis, in both the cell lines. The inhibition of cell migration by lipoic acid is accompanied by the downregulation of FAK, ERK1/2 and AKT phosphorylation, and inhibition of nuclear translocation of β-catenin.
Significance:
Our data demonstrated that lipoic acid inhibited the migration and invasion of metastatic breast cancer cells at least in part through inhibiting ERK1/2 and AKT signaling. Thus, our findings show that the inhibition of TGFβ signaling is a potential mechanism for the anti-invasive effects of lipoic acid.
Reactive oxygen species (ROS) are generated in the cell through multiple mechanisms. Intracellular ROS are rapidly detoxified by various enzymatic and non-enzymatic mechanisms; however, disruption of the oxidant-antioxidant balance causes oxidative stress and elicits cell damage. The oxidative stress induced by chemotherapy is known to cause side effects in patients with cancer. However, few studies have examined whether anticancer drugs induce oxidative stress in cancer cells. Furthermore, the precise mechanism by which anticancer drugs induce the generation of ROS remains unclear. In the present study, to investigate whether anticancer drugs induce oxidative stress, DLD-1 human colorectal cancer cells were treated with 20 different anticancer drugs and then stained with CellROX(®) ROS detection reagent. Furthermore, an oxygen radical absorbance capacity assay in the presence of copper was performed to estimate the oxidative activities of the anticancer drugs in the absence of cells. The data of the present study using assay methods in the presence and absence of cells suggest that nimustine, actinomycin D, doxorubicin, mitomycin C, mitoxantrone, carmofur, gemcitabine, mercaptopurine, camptothecin, paclitaxel, vinblastine, and vinorelbine are able to induce oxidative stress.
Purpose:
Cancer stem cells (CSCs) that possess the ability of self-renewal and multi-potency have been shown to drive tumor progression and metastasis. The majority of recent studies has focused on potential molecules targeting CSCs so as to develop novel strategies for efficient cancer treatment or protection. Here, we show how alpha-lipoic acid (LA), an endogenous mitochondrial anti-oxidant, affects the CSC-like phenotypes of human non-small cell lung cancer-derived H23, H292 and H460 cells.
Methods:
CSC-like phenotypes were verified by anchorage-independent growth, three-dimensional (3D) spheroid formation and the expression of CSC markers. Enriched CSC populations were used to confirm the effects of LA. Protein ubiquitination and degradation were assessed using immunoprecipitation.
Results:
We found that treatment with LA reduced the CSC-like phenotype, as indicated by a decreased expression of known CSC markers (CD133, CD44, ALDH1A1, Oct-4 and Nanog) in H460 cells. In addition, we found that LA reduced the CSC-related abilities of anchorage-independent growth and 3D spheroid formation, and suppressed factors related to epithelial-mesenchymal transition, such as E-cadherin, Vimentin, Slug and Snail. Mechanistically, we found that LA suppresses CSC through depletion of the cellular stemness proteins β-catenin and Oct-4 via decreasing the level of active (phosphorylated) Akt. This resulted in the induction of GSK3β-dependent β-catenin ubiquitin-proteasomal degradation and a decrease in the stabilized (phosphorylated) form of Oct-4. The effects of LA on the CSC-like phenotypes were confirmed in CSC enriched H460, H292 and H23 non-small cell lung cancer-derived cells.
Conclusion:
Our data are indicative for a novel regulatory role and underlying mechanism of LA in the negative regulation of a CSC-like phenotype in non-small cell lung cancer-derived cells.
Reactive oxygen species (ROS), a group of highly reactive ions and molecules, are increasingly being appreciated as powerful signaling molecules involved in the regulation of a variety of biological processes. Indeed, their role is continuously being delineated in a variety of pathophysiological conditions. For instance, cancer cells are shown to have increased ROS levels in comparison to their normal counterparts. This is partly due to an enhanced metabolism and mitochondrial dysfunction in cancer cells. The escalated ROS generation in cancer cells contributes to the biochemical and molecular changes necessary for the tumor initiation, promotion and progression, as well as, tumor resistance to chemotherapy. Therefore, increased ROS in cancer cells may provide a unique opportunity to eliminate cancer cells via elevating ROS to highly toxic levels intracellularly, thereby, activating various ROS-induced cell death pathways, or inhibiting cancer cell resistance to chemotherapy. Such results can be achieved by using agents that either increase ROS generation, or inhibit antioxidant defense, or even a combination of both. In fact, a large variety of anticancer drugs, and some of those currently under clinical trials, effectively kill cancer cells and overcome drug resistance via enhancing ROS generation and/or impeding the antioxidant defense mechanism. This review focuses on our current understanding of the tumor promoting (tumorigenesis, angiogenesis, invasion and metastasis, and chemoresistance) and the tumor suppressive (apoptosis, autophagy, and necroptosis) functions of ROS, and highlights the potential mechanism(s) involved. It also sheds light on a very novel and an actively growing field of ROS-dependent cell death mechanism referred to as ferroptosis.
Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine
acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor
of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from
autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby
improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with
several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved
the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent
tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory
T cells from the tumor bed.
An AIE-based fluorescent nanoprobe (MTPE-M) has been developed and used for ratiometric detection of hypochlorite with high selectivity and sensitivity. More importantly, its application in live cells and zebrafish for ratiometric imaging of endogenous ClO(-) has also been achieved.
Dimethyl sulfoxide (CAS # 67-68-5) is a colorless organosulfur compound and is important as a polar aprotic solvent. It is readily absorbed by animals and humans by dermal and oral routes and enhances absorption of many other chemicals by those routes. In humans, it is an irritant of the eyes, skin, and respiratory system. In animals, reported effects include renal and hepatic lesions, corneal injury (opacities), teratogenicity, and repeated dermal application results in irritation and urticaria.
Cancer cells are characterized by altered glucose metabolism known as the Warburg effect in which aerobic glycolysis is increased. Glucose is converted to lactate even under sufficient oxygen tension. Interfering with this process may be a potential effective strategy to cause cancer cell death because these cells rely heavily on glucose metabolism for survival and proliferation. 2-Deoxy-D-glucose (2DG), a glucose analog, targets glucose metabolism to deplete cancer cells of energy. In addition, 2DG increases oxidative stress, inhibits N-linked glycosylation, and induces autophagy. It can efficiently slow cell growth and potently facilitate apoptosis in specific cancer cells. Although, 2DG itself has limited therapeutic effect in many types of cancers, it may be combined with other therapeutic agents or radiotherapy to exhibit a synergistic anticancer effect. In this review, we describe the Warburg effect and discuss 2DG and its underlying mechanisms and potential application for cancer treatment.
The effects of pH on the inorganic products formed during the reaction of chlorine dioxide with an etherified lignin model compound have been studied. Analyses of the inorganic species produced during the reaction at pH 8 revealed that 2 mol of chlorite are liberated for every 1 mol of oxidized nonphenolic lignin model compound formed, consistent with two consecutive one-electron-transfer processes. In contrast, the low-pH reactions produced mostly ring oxidation products and chlorinated organic material, accompanied by increased levels of hypochlorous acid. The transient hypochlorous acid rapidly reacted with chlorite to generate chloride ions, with a maximum chloride formation at pH 4. Chlorate formation was shown to increase with increasing reaction pH. These results are in contrast to those previously reported for reactions with wood pulps and are explained on the basis of the slow reaction kinetics of nonphenolic lignin moieties as compared to phenolic ones, thereby enabling hypochlorous acid to react with chlorine dioxide to produce chlorate.
In this paper, the disinfection effects of chlorine dioxide (ClO2) on some main bacteria in water and the influence of ClO2 on the inactivation of some microorganisms studied under various conditions such as the dose of disinfectant and the contact time, pH value, etc. were researched and reported, and it was compared with that of liquid chlorine. The results showed that the killing effect of the ClO2 on bacteria is similar to or better than that of liquid chlorine, the bacteria were effectively killed off by using ClO2 in a relatively wider range of pH value. Moreover, the investigation of the bactericidal mechanism of ClO2 was tentatively undertaken. Then, we concluded that ClO2 is an excellent disinfectant to substitute for the liquid chlorine.
Oxychlorine compounds, such as hypochlorous acid (HOCl) and chlorine dioxide (ClO2), have potent antimicrobial activity. Although the biochemical mechanism of the antimicrobial activity of HOCl has been extensively investigated, little is known about that of ClO2. Using bovine serum albumin and glucose-6-phosphate dehydrogenase of Saccharomyces cerevisiae as model proteins, here I demonstrate that the antimicrobial activity of ClO2 is attributable primarily to its protein-denaturing activity. By solubility analysis, circular dichroism spectroscopy, differential scanning calorimetry, and measurement of enzymatic activity, I demonstrate that protein is rapidly denatured by ClO2 with a concomitant decrease in the concentration of ClO2 in the reaction mixture. Circular dichroism spectra of the ClO2-treated proteins show a change in ellipticity at 220 nm, indicating a decrease in alpha-helical content. Differential scanning calorimetry shows that transition temperature and endothermic transition enthalpy of heat-induced unfolding decrease in the ClO2-treated protein. The enzymatic activity of glucose-6-phosphate dehydrogenase decreases to 10% within 15 s of treatment with 10 microM ClO2. Elemental analyses show that oxygen, but not chlorine, atoms are incorporated in the ClO2-treated protein, providing direct evidence that protein is oxidized by ClO2. Furthermore, mass spectrometry and nuclear magnetic resonance spectroscopy show that tryptophan residues become N-formylkynurenine and tyrosine residues become 3,4-dihydroxyphenylalanine (DOPA) or 2,4,5-trihydroxyphenylalanine (TOPA) in the ClO2-treated proteins. Taking these results together, I conclude that microbes are inactivated by ClO2 owing to denaturation of constituent proteins critical to their integrity and/or function, and that this denaturation is caused primarily by covalent oxidative modification of their tryptophan and tyrosine residues.
A low serum 25-hydroxyvitamin D [25(OH)D] level is a risk factor for many diseases, including musculoskeletal diseases, many types of cancer, cardiovascular diseases, diabetes mellitus, infectious diseases, autoimmune diseases, and brain diseases. This report estimates the reduction in mortality rates for the five Nordic countries for an increase in population mean serum 25-hydroxyvitamin D level to 105 nmol/L.
Serum vitamin D dose-incidence/prognosis relationships can be developed with significant levels of reliability for most vitamin D-sensitive diseases on the basis of ecological, cross-sectional, and observational studies, randomized controlled trials, and meta-analysis of such studies. These dose-response relations are used to estimate the population-wide benefit of raising mean serum 25(OH)D concentration to 105 nmol/L for the five Nordic countries.
From this study, the reductions in mortality rates possible by raising population mean serum 25(OH)D levels to 105 nmol/L are: Denmark, 17% (estimated range,11%-24%); Finland, 24% (17%-32%); Iceland, 24% (17%-32%); Norway, 18% (11%-26%); and Sweden, 18% (8%-25%).
Reaching these levels would require changes in health policies with respect to solar ultraviolet-B (UVB) irradiance, vitamin D fortification of food, availability of vitamin D and calcium supplements, and attitude toward use of UVB lamps. Adverse effects of oral vitamin D intake are limited, and those from UVB irradiance are minor compared with the benefits.
A profound difference between cancer and normal tissues is the preferential utilization of glycolysis by cancer cells. To translate this paradigm in the clinic, we completed a phase I study of 2-deoxyglucose (2DG), and assessed 2DG uptake with fluorodeoxyglucose (FDG) positron emission tomography (PET) and the autophagy substrate p62 as a marker of 2DG resistance.
Patients received 2DG orally on days 1-14 of a 21-day cycle in cohorts of three in a dose-escalating manner. Correlative assessments included PET scans at baseline and day 2 and p62 protein in peripheral blood mononuclear cells as a potential marker of 2DG resistance.
The dose of 45 mg/kg was defined as the recommended phase II dose, secondary to dose-limiting toxicity of grade 3 asymptomatic QTc prolongation at a dose of 60 mg/kg. PK evaluation of 2DG revealed linear pharmacokinetics with C(max) 45 microg/ml (277 microM), 73.7 microg/ml (449 microM), and 122 microg/ml (744 microM) in dose levels 30, 45, and 60 mg/kg, respectively. Five of eight patients assessed with FDG-PET scanning demonstrated decreased FDG uptake by day 2 of therapy, suggesting competition of 2DG with FDG. Five of six patients assessed for p62 had a decrease in p62 at 24 hr.
These data support the safety of 2DG, defined 2DG PK, demonstrated the effect of 2DG on FDG-PET imaging, and demonstrated the feasibility of assessment of p62 as an autophagic resistance marker. These data support future studies of 2DG alone or in combination with approaches to abrogate autophagy.
An important discovery of recent years has been that lifestyle and environmental factors affect cancer initiation, promotion and progression, suggesting that many malignancies are preventable. Epidemiological studies strongly suggest that excessive adiposity, decreased physical activity, and unhealthy diets are key players in the pathogenesis and prognosis of many common cancers. In addition, calorie restriction (CR), without malnutrition, has been shown to be broadly effective in cancer prevention in laboratory strains of rodents. Adult-onset moderate CR also reduces cancer incidence by 50% in monkeys. Whether the antitumorigenic effects of CR will apply to humans is unknown, but CR results in a consistent reduction in circulating levels of growth factors, anabolic hormones, inflammatory cytokines and oxidative stress markers associated with various malignancies. Here, we discuss the link between nutritional interventions and cancer prevention with focus on the mechanisms that might be responsible for these effects in simple systems and mammals with a view to developing chemoprevention agents.