RESUMO
Fragile X syndrome (FXS) is a genetic disorder characterized by mutation in the FMR1 gene, leading to the absence or reduced levels of fragile X Messenger Ribonucleoprotein 1 (FMRP). This results in neurodevelopmental deficits, including autistic spectrum conditions. On the other hand, Fragile X-associated tremor/ataxia syndrome (FXTAS) is a distinct disorder caused by the premutation in the FMR1 gene. FXTAS is associated with elevated levels of FMR1 mRNA, leading to neurodegenerative manifestations such as tremors and ataxia.Mounting evidence suggests a link between both syndromes and mitochondrial dysfunction (MDF). In this minireview, we critically examine the intricate relationship between FXS, FXTAS, and MDF, focusing on potential therapeutic avenues to counteract or mitigate their adverse effects. Specifically, we explore the role of mitochondrial cofactors and antioxidants, with a particular emphasis on alpha-lipoic acid (ALA), carnitine (CARN) and Coenzyme Q10 (CoQ10). Findings from this review will contribute to a deeper understanding of these disorders and foster novel therapeutic strategies to enhance patient outcomes.
Assuntos
Síndrome do Cromossomo X Frágil , Doenças Mitocondriais , Humanos , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/genética , Tremor/tratamento farmacológico , Tremor/genética , Antioxidantes/uso terapêutico , Ataxia/tratamento farmacológico , Ataxia/genética , Proteína do X Frágil da Deficiência Intelectual/genéticaRESUMO
Retinitis pigmentosa (RP) is a group of mitochondrial diseases characterized by progressive degeneration of rods and cones leading to retinal loss of light sensitivity and, consequently, to blindness. To date, no cure is available according to the clinical literature. As a disease associated with pigmentation-related, pro-oxidant state, and mitochondrial dysfunction, RP may be viewed at the crossroads of different pathogenetic pathways involved in adverse health outcomes, where mitochondria play a preeminent role. RP has been investigated in a number of experimental and clinical studies aimed at delaying retinal hyperpigmentation by means of a number of natural and synthetic antioxidants, as well as mitochondrial cofactors, also termed mitochondrial nutrients (MNs), such as alpha-lipoic acid, coenzyme Q10 and carnitine. One should consider that each MN plays distinct-and indispensable-roles in mitochondrial function. Thus, a logical choice would imply the administration of MN combinations, instead of individual MNs, as performed in previous studies, and with limited, if any, positive outcomes. A rational study design aimed at comparing the protective effects of MNs, separately or in combinations, and in association with other antioxidants, might foresee the utilization of animal RP models. The results should verify a comparative optimization in preventing or effectively contrasting retinal oxidative stress in mouse RP models and, in prospect, in human RP cases.
Assuntos
Antioxidantes/farmacologia , Melaninas/metabolismo , Melanócitos/citologia , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/complicações , Nutrientes/farmacologia , Retinose Pigmentar/prevenção & controle , Animais , Humanos , Melanócitos/metabolismo , Mitocôndrias/metabolismo , Retinose Pigmentar/etiologia , Retinose Pigmentar/metabolismo , Retinose Pigmentar/patologiaRESUMO
BACKGROUND: The mitochondrial cofactors α-lipoic acid (ALA), coenzyme Q10 (CoQ10) and carnitine (CARN) play distinct and complementary roles in mitochondrial functioning, along with strong antioxidant actions. Also termed mitochondrial nutrients (MNs), these cofactors have demonstrated specific protective actions in a number of chronic disorders, as assessed in a well-established body of literature. METHODS: Using PubMed, the authors searched for articles containing information on the utilization of MNs in inflammatory disorders as assessed from in vitro and animal studies, and in clinical trials, in terms of exerting anti-inflammatory actions. RESULTS: The retrieved literature provided evidence relating acute pathologic conditions, such as sepsis and pneumonia, with a number of redox endpoints of biological and clinical relevance. Among these findings, both ALA and CARN were effective in counteracting inflammation-associated redox biomarkers, while CoQ10 showed decreased levels in proinflammatory conditions. MN-associated antioxidant actions were applied in a number of acute disorders, mostly using one MN. The body of literature assessing the safety and the complementary roles of MNs taken together suggests an adjuvant role of MN combinations in counteracting oxidative stress in sepsis and other acute disorders, including COVID-19-associated pneumonia. CONCLUSIONS: The present state of art in the use of individual MNs in acute disorders suggests planning adjuvant therapy trials utilizing MN combinations aimed at counteracting proinflammatory conditions, as in the case of pneumonia and the COVID-19 pandemic.
Assuntos
Anti-Inflamatórios/uso terapêutico , Tratamento Farmacológico da COVID-19 , Carnitina/uso terapêutico , SARS-CoV-2 , Sepse/tratamento farmacológico , Ácido Tióctico/uso terapêutico , Ubiquinona/análogos & derivados , Doença Aguda , Animais , Quimioterapia Adjuvante , Humanos , Mitocôndrias/metabolismo , Ubiquinona/uso terapêuticoRESUMO
Cancer cells are known to reprogram their metabolism to adapt to adverse conditions dictated by tumor growth and microenvironment. A subtype of cancer cells with stem-like properties, known as cancer stem cells (CSC), is thought to be responsible for tumor recurrence. In this study, we demonstrated that CSC and chemoresistant cells derived from triple negative breast cancer cells display an enrichment of up- and downregulated proteins from metabolic pathways that suggests their dependence on mitochondria for survival. Here, we selected antibiotics, in particular - linezolid, inhibiting translation of mitoribosomes and inducing mitochondrial dysfunction. We provided the first in vivo evidence demonstrating that linezolid suppressed tumor growth rate, accompanied by increased autophagy. In addition, our results revealed that bactericidal antibiotics used in combination with autophagy blocker decrease tumor growth. This study puts mitochondria in a spotlight for cancer therapy and places antibiotics as effective agents for eliminating CSC and resistant cells.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Linezolida/administração & dosagem , Redes e Vias Metabólicas , Mitocôndrias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linezolida/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Transplante de Neoplasias , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Microambiente Tumoral/efeitos dos fármacosRESUMO
A number of aging-related disorders (ARD) have been related to oxidative stress (OS) and mitochondrial dysfunction (MDF) in a well-established body of literature. Most studies focused on cardiovascular disorders (CVD), type 2 diabetes (T2D), and neurodegenerative disorders. Counteracting OS and MDF has been envisaged to improve the clinical management of ARD, and major roles have been assigned to three mitochondrial cofactors, also termed mitochondrial nutrients (MNs), i.e., α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and carnitine (CARN). These cofactors exert essential-and distinct-roles in mitochondrial machineries, along with strong antioxidant properties. Clinical trials have mostly relied on the use of only one MN to ARD-affected patients as, e.g., in the case of CoQ10 in CVD, or of ALA in T2D, possibly with the addition of other antioxidants. Only a few clinical and pre-clinical studies reported on the administration of two MNs, with beneficial outcomes, while no available studies reported on the combined administration of three MNs. Based on the literature also from pre-clinical studies, the present review is to recommend the design of clinical trials based on combinations of the three MNs.
Assuntos
Envelhecimento , Antioxidantes , Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Mitocôndrias/metabolismo , Doenças Neurodegenerativas , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Carnitina/farmacologia , Carnitina/uso terapêutico , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácido Tióctico/farmacologia , Ácido Tióctico/uso terapêutico , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Ubiquinona/uso terapêuticoRESUMO
Mitochondrial dysfunction (MDF) has been identified as an important factor in various diseases ranging from neurological disorders, to diseases of the cardiovascular system and metabolic syndromes. MDF was also found in cancer as well as in cancer predisposition syndromes with defective DNA damage response (DDR) machinery. Moreover, a recent highlight arises from the detection of MDF in eukaryotic cells upon treatment with antibiotics. In this review, we focus on recent studies of MDF in pathological conditions with a particular emphasis on the effects of various classes of antibiotics on mitochondria. Special attention is given to the role of autophagy/mitophagy in MDF and repurposing antibiotics as anticancer drugs.
Assuntos
Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neoplasias/patologia , Neoplasias/terapia , Animais , Humanos , Neoplasias/metabolismoRESUMO
Given the key role of mitochondria in various cellular events, it is not surprising that mitochondrial dysfunction (MDF) is seen in many pathological conditions, in particular cancer. The mechanisms defining MDF are not clearly understood and may involve genetic defects, misbalance of reactive oxygen species (ROS), impaired autophagy (mitophagy), acquired mutations in mitochondrial or nuclear DNA and inability of cells to cope with the consequences. The importance of MDF arises from its detection in the syndromes with defective DNA damage response (DDR) and cancer predisposition. Here, we will focus on the dual role of these syndromes in cancer predisposition and MDF with specific emphasis on impaired autophagy.
Assuntos
Dano ao DNA , Mitocôndrias/fisiologia , Neoplasias/etiologia , Autofagia , Humanos , SíndromeRESUMO
Fanconi anemia (FA) is a rare autosomal recessive genetic disorder associated with a bone-marrow failure, genome instability, hypersensitivity to DNA crosslinking agents and a predisposition to cancer. Mutations have been documented in 16 FA genes that participate in the FA-BRCA DNA repair pathway, a fundamental pathway in the development of the disease and the presentation of its symptoms. FA cells have been characterized by an overproduction of cytokines, MAPKs, and Interleukins. Through this study we have identified the overexpression of additional secretory factors such as IL-6, IL-8, MMP-2, and MMP-9 in FA cells and in cells depleted of FANCA or FANCC and proved that their expression is under the control of NF-κB/TNF-α signaling pathways. We also demonstrated that these overexpressed secretory factors were effective in promoting the proliferation, migration, and invasion of surrounding tumor cells a fundamental event in the process of epithelial mesenchymal transition (EMT) and that they also modulated the expression of EMT markers such as E-cadherin and SNAIL. Overall our data suggest that the upregulation of EMT promoting factors in FA may contribute to predisposing FA patients to cancer, thereby providing new insights into possible therapeutic interventions.
Assuntos
Anemia de Fanconi/genética , Interleucina-6/genética , Interleucina-8/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , NF-kappa B/genética , Fator de Necrose Tumoral alfa/genética , Caderinas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Proteína do Grupo de Complementação C da Anemia de Fanconi/genética , Humanos , Células MCF-7 , Invasividade Neoplásica/genética , Transdução de Sinais/genética , Fatores de Transcrição da Família Snail , Fatores de Transcrição/genéticaRESUMO
Malignant tumors have increased energy requirements due to growth, differentiation or response to stress. A significant number of studies in recent years have described upregulation of mitochondrial genes responsible for oxidative phosphorylation (OXPHOS) in some tumors. Although OXPHOS is replaced by glycolysis in some tumors (Warburg effect), both processes can occur simultaneously during the evolution of the same malignancies. In particular, chemoresistant and/or cancer stem cells appear to find a way to activate OXPHOS and metastasize. In this paper, we discuss recent work showing upregulation of OXPHOS in chemoresistant tumors and cell models. In addition, we show an inverse correlation of OXPHOS gene expression with the survival time of cancer patients after chemotherapy and discuss combination therapies for resistant tumors.
Assuntos
Neoplasias , Fosforilação Oxidativa , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , GlicóliseRESUMO
Triple negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer with the worst prognosis after chemo- or radiation therapy. This is mainly due to the development of cancer chemoresistance accompanied by tumor recurrence. In this work, we investigated a new mechanism of acquired chemoresistance of TNBC cells. We showed that extracellular vehicles (EVs) of chemoresistant TNBC cells can transfer mitochondria to sensitive cancer cells, thus increasing their chemoresistance. Such transfer, but with less efficiency, can be carried out over short distances using tunneling nanotubes. In addition, we showed that exosome fractions carrying mitochondria from resistant TNBC cells contribute to acquired chemoresistance by increasing mtDNA levels with mutations in the mtND4 gene responsible for tumorigenesis. Blocking mitochondrial transport by exosome inhibitors, including GW4869, reduced acquired TNBC chemoresistance. These results could lead to the identification of new molecular targets necessary for more effective treatment of this type of cancer.
Assuntos
DNA Mitocondrial/metabolismo , Vesículas Extracelulares/metabolismo , Mitocôndrias/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/genética , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Vesículas Extracelulares/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais CultivadasRESUMO
Traditional cancer treatments based on chemo- and/or radiotherapy effectively kill only differentiated cancer cells, while metastasis and recurrences are caused by surviving cancer resistant cells (CRC) or a special subpopulation of cancer cells known as cancer stem cells (CSC). Both of these cell types compromise anticancer treatment through various mechanisms, including withdrawal of the anticancer drug through ATP-binding cassette transporters, increased expression of DNA repair genes, or transition to a quiescent phenotype. In contrast to many cancers, where energy consumption is due to glycolysis (Warburg effect), the bioenergetics of CSC and CRC is most often related to oxidative phosphorylation, that is, dependent on mitochondrial function. Therefore, compounds that induce mitochondrial dysfunction (MDF), such as some antibiotics, may represent an alternative approach to anticancer therapy. This review summarizes the major recent works on the use of antibiotics to target tumors via CSC and suggests next steps for developing this approach.
Assuntos
Antibacterianos , Neoplasias , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Humanos , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Células-Tronco Neoplásicas , Fosforilação OxidativaRESUMO
A growing body of evidence supports the notion that cancer resistance is driven by a small subset of cancer stem cells (CSC), responsible for tumor initiation, growth, and metastasis. Both CSC and chemoresistant cancer cells may share common qualities to activate a series of self-defense mechanisms against chemotherapeutic drugs. Here, we aimed to identify proteins in chemoresistant triple-negative breast cancer (TNBC) cells and corresponding CSC-like spheroid cells that may contribute to their resistance. We have identified several candidate proteins representing the subfamilies of DNA damage response (DDR) system, the ATP-binding cassette, and the 26S proteasome degradation machinery. We have also demonstrated that both cell types exhibit enhanced DDR when compared to corresponding parental counterparts, and identified RAD50 as one of the major contributors in the resistance phenotype. Finally, we have provided evidence that depleting or blocking RAD50 within the Mre11-Rad50-NBS1 (MRN) complex resensitizes CSC and chemoresistant TNBC cells to chemotherapeutic drugs.
Assuntos
Hidrolases Anidrido Ácido/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Homóloga a MRE11/genética , Proteínas Nucleares/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Dano ao DNA/efeitos dos fármacos , Enzimas Reparadoras do DNA/genética , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Neoplasias de Mama Triplo Negativas/genéticaRESUMO
Friedreich's Ataxia is an autosomal recessive genetic disease causing the defective gene product, frataxin. A body of literature has been focused on the attempts to counteract frataxin deficiency and the consequent iron imbalance, in order to mitigate the disease-associated pro-oxidant state and clinical course. The present mini review is aimed at evaluating the basic and clinical reports on the roles and the use of a set of iron chelators, antioxidants and some cofactors involved in the key mitochondrial functions. Extensive literature has focused on the protective roles of iron chelators, coenzyme Q10 and analogs, and vitamin E, altogether with varying outcomes in clinical studies. Other studies have suggested mitoprotective roles for other mitochondrial cofactors, involved in Krebs cycle, such as alpha-lipoic acid and carnitine, involved in acyl transport across the mitochondrial membrane. A body of evidence points to the strong antioxidant properties of these cofactors, and to their potential contribution in mitoprotective strategies in Friedreich's Ataxia clinical evolution. Thus, we suggest the rationale for planning combination strategies based on the 3 mitochondrial cofactors and of some antioxidants and iron binders as mitoprotective cocktails in Friedreich Ataxia patients, calling attention to clinical practitioners of the importance to implement clinical trials.
Assuntos
Ataxia de Friedreich/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Carnitina/farmacologia , Deferiprona/uso terapêutico , Ataxia de Friedreich/patologia , Humanos , Quelantes de Ferro/uso terapêutico , Ácidos Linoleicos/farmacologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Ubiquinona/análogos & derivados , Ubiquinona/farmacologiaRESUMO
Fanconi anemia (FA) has been investigated since early studies based on two definitions, namely defective DNA repair and proinflammatory condition. The former definition has built up the grounds for FA diagnosis as excess sensitivity of patients' cells to xenobiotics as diepoxybutane and mitomycin C, resulting in typical chromosomal abnormalities. Another line of studies has related FA phenotype to a prooxidant state, as detected by both in vitro and ex vivo studies. The discovery that the FA group G (FANCG) protein is found in mitochondria (Mukhopadhyay et al., 2006) has been followed by an extensive line of studies providing evidence for multiple links between other FA gene products and mitochondrial dysfunction. The fact that FA proteins are encoded by nuclear, not mitochondrial DNA does not prevent these proteins to hamper mitochondrial function, as it is recognized that most mitochondrial proteins are of nuclear origin. This body of evidence supporting a central role of mitochondrial dysfunction, along with redox imbalance in FA, should lead to the re-definition of FA as a mitochondrial disease. A body of literature has demonstrated the beneficial effects of mitochondrial cofactors, such as α-lipoic acid, coenzyme Q10, and carnitine on patients affected by mitochondrial diseases. Altogether, this re-definition of FA as a mitochondrial disease and the prospect use of mitochondrial nutrients may open new gateways toward mitoprotective strategies for FA patients. These strategies are expected to mitigate the mitochondrial dysfunction and prooxidant state in FA patients, and potentially protect transplanted FA patients from post-transplantation malignancies.
Assuntos
Anemia de Fanconi , Doenças Mitocondriais , Anemia de Fanconi/genética , Humanos , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/genética , Mitomicina , Fenótipo , ProteínasRESUMO
Fanconi anemia (FA) is a chromosomal instability disorder of bone marrow associated with aplastic anemia, congenital abnormalities and a high risk of malignancies. The identification of more than two dozen FA genes has revealed a plethora of interacting proteins that are mainly involved in repair of DNA interstrand crosslinks (ICLs). Other important findings associated with FA are inflammation, oxidative stress response, mitochondrial dysfunction and mitophagy. In this work, we performed quantitative proteomic and metabolomic analyses on defective FA cells and identified a number of metabolic abnormalities associated with cancer. In particular, an increased de novo purine biosynthesis, a high concentration of fumarate, and an accumulation of purinosomal clusters were found. This was in parallel with decreased OXPHOS and altered glycolysis. On the whole, our results indicate an association between the need for nitrogenous bases upon impaired DDR in FA cells with a subsequent increase in purine metabolism and a potential role in oncogenesis.
Assuntos
Anemia de Fanconi/metabolismo , Redes e Vias Metabólicas , Metabolômica/métodos , Proteômica/métodos , Linhagem Celular , Cromatografia Líquida , Reparo do DNA , Glicólise , Humanos , Fosforilação Oxidativa , Espectrometria de Massas em TandemRESUMO
In the current work, in continuation of our recent research, we synthesized and studied new chimeric compounds, including the ribosome-targeting antibiotic chloramphenicol (CHL) and the membrane-penetrating cation triphenylphosphonium (TPP), which are linked by alkyl groups of different lengths. Using various biochemical assays, we showed that these CAM-Cn-TPP compounds bind to the bacterial ribosome, inhibit protein synthesis in vitro and in vivo in a way similar to that of the parent CHL, and significantly reduce membrane potential. Similar to CAM-C4-TPP, the mode of action of CAM-C10-TPP and CAM-C14-TPP in bacterial ribosomes differs from that of CHL. By simulating the dynamics of CAM-Cn-TPP complexes with bacterial ribosomes, we proposed a possible explanation for the specificity of the action of these analogs in the translation process. CAM-C10-TPP and CAM-C14-TPP more strongly inhibit the growth of the Gram-positive bacteria, as compared to CHL, and suppress some CHL-resistant bacterial strains. Thus, we have shown that TPP derivatives of CHL are dual-acting compounds targeting both the ribosomes and cellular membranes of bacteria. The TPP fragment of CAM-Cn-TPP compounds has an inhibitory effect on bacteria. Moreover, since the mitochondria of eukaryotic cells possess qualities similar to those of their prokaryotic ancestors, we demonstrate the possibility of targeting chemoresistant cancer cells with these compounds.
RESUMO
The cancer stem cell (CSC) model defines tumors as hierarchically organized entities, containing a small population of tumorigenic CSC, or tumour-initiating cells, placed at the apex of this hierarchy. These cells may share common qualities with chemo- and radio-resistant cancer cells and contribute to self-renewal activities resulting in tumour formation, maintenance, growth and metastasis. Yet, it remains obscure what self-defense mechanisms are utilized by these cells against the chemotherapeutic drugs or radiotherapy. Recently, attention has been focused on the pivotal role of the DNA damage response (DDR) in tumorigenesis. In line with this note, an increased DDR that prevents CSC and chemoresistant cells from genotoxic pressure of chemotherapeutic drugs or radiation may be responsible for cancer metastasis. In this review, we focus on the current knowledge concerning the role of DDR in CSC and resistant cancer cells and describe the existing opportunities of re-sensitizing such cells to modulate therapeutic treatment effects.
Assuntos
Antineoplásicos/farmacologia , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia , Tolerância a Radiação , Animais , Apoptose , Humanos , Neoplasias/genética , Neoplasias/terapia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos da radiaçãoRESUMO
Oxidative stress (OS) and mitochondrial dysfunction (MDF) occur in a number of disorders, and several clinical studies have attempted to counteract OS and MDF by providing adjuvant treatments against disease progression. The present review is aimed at focusing on two apparently distant diseases, namely type 2 diabetes (T2D) and a rare genetic disease, Fanconi anemia (FA). The pathogenetic links between T2D and FA include the high T2D prevalence among FA patients and the recognized evidence for OS and MDF in both disorders. This latter phenotypic/pathogenetic feature-namely MDF-may be regarded as a mechanistic ground both accounting for the clinical outcomes in both diseases, and as a premise to clinical studies aimed at counteracting MDF. In the case for T2D, the working hypothesis is raised of evaluating any in vivo decrease of mitochondrial cofactors, or mitochondrial nutrients (MNs) such as α-lipoic acid, coenzyme Q10, and l-carnitine, with possibly combined MN-based treatments. As for FA, the established knowledge of MDF, as yet only obtained from in vitro or molecular studies, prompts the requirement to ascertain in vivo MDF, and to design clinical studies aimed at utilizing MNs toward mitigating or delaying FA's clinical progression. Altogether, this paper may contribute to building hypotheses for clinical studies in a number of OS/MDF-related diseases.
RESUMO
A novel differential in gel electrophoresis (DIGE)-based method has been developed and applied to measure telomere length and appearance of two-dimensional structural DNA changes. It can be applied to any area requiring quick and evident measurement of structural DNA changes.
Assuntos
DNA/química , Eletroforese em Gel Bidimensional/métodos , Telômero/química , Conformação de Ácido Nucleico , Relação Estrutura-AtividadeRESUMO
Significance: A fraction of tumorigenic cells, also known as tumor initiating or cancer stem cells (CSCs), is thought to drive tumor growth, metastasis, and chemoresistance. However, little is known regarding mechanisms that convey relevant pathways contributing to their self-renewal, proliferation, and differentiation abilities. Recent Advances: Recent works on CSCs provide evidence on the role of redox disruption and regulation of autophagic flux. This has been linked to increased DNA repair capacity and chemoresistance. Critical Issues: The current review summarizes the most recent studies assessing the role of redox homeostasis, autophagy, and chemoresistance in CSCs, including some novel findings on microRNAs and their role in horizontal transfer within cancer cell populations. Future Directions: Rational anticancer therapy and prevention should rely on the fact that cancer is a redox disease with the CSCs being the apex modulated by redox-mediated autophagy. Antioxid. Redox Signal. 28, 1066-1079.