RESUMO
Chemotherapy-induced cognitive impairment (CICI) has been observed in a large fraction of cancer survivors. Although many of the chemotherapeutic drugs do not cross the blood-brain barrier, following treatment, the structure and function of the brain are altered and cognitive dysfunction occurs in a significant number of cancer survivors. The means by which CICI occurs is becoming better understood, but there still remain unsolved questions of the mechanisms involved. The hypotheses to explain CICI are numerous. More than 50% of FDA-approved cancer chemotherapy agents are associated with reactive oxygen species (ROS) that lead to oxidative stress and activate a myriad of pathways as well as inhibit pathways necessary for proper brain function. Oxidative stress triggers the activation of different proteins, one in particular is tumor necrosis factor alpha (TNFα). Following treatment with various chemotherapy agents, this pro-inflammatory cytokine binds to its receptors at the blood-brain barrier and translocates to the parenchyma via receptor-mediated endocytosis. Once in brain, TNFα initiates pathways that may eventually lead to neuronal death and ultimately cognitive impairment. TNFα activation of the c-jun N-terminal kinases (JNK) and Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathways may contribute to both memory decline and loss of higher executive functions reported in patients after chemotherapy treatment. Chemotherapy also affects the brain's antioxidant capacity, allowing for accumulation of ROS. This review expands on these topics to provide insights into the possible mechanisms by which the intersection of oxidative stress and TNFΑ are involved in chemotherapy-induced cognitive impairment.
Assuntos
Antineoplásicos/efeitos adversos , Comprometimento Cognitivo Relacionado à Quimioterapia/metabolismo , Estresse Oxidativo/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Humanos , Transdução de Sinais/efeitos dos fármacosRESUMO
Aberrant levels of reactive oxygen species (ROS) are potential mechanisms that contribute to both cancer therapy efficacy and the side effects of cancer treatment. Upregulation of the non-canonical redox-sensitive NF-kB family member, RelB, confers radioresistance in prostate cancer (PCa). We screened FDA-approved compounds and identified betamethasone (BET) as a drug that increases hydrogen peroxide levels in vitro and protects non-PCa tissues/cells while also enhancing radiation killing of PCa tissues/cells, both in vitro and in vivo. Significantly, BET increases ROS levels and exerts different effects on RelB expression in normal cells and PCa cells. BET induces protein expression of RelB and RelB target genes, including the primary antioxidant enzyme, manganese superoxide dismutase (MnSOD), in normal cells, while it suppresses protein expression of RelB and MnSOD in LNCaP cells and PC3 cells. RNA sequencing analysis identifies B-cell linker protein (BLNK) as a novel RelB complementary partner that BET differentially regulates in normal cells and PCa cells. RelB and BLNK are upregulated and correlate with the aggressiveness of PCa in human samples. The RelB-BLNK axis translocates to the nuclear compartment to activate MnSOD protein expression. BET promotes the RelB-BLNK axis in normal cells but suppresses the RelB-BLNK axis in PCa cells. Targeted disruptions of RelB-BLNK expressions mitigate the radioprotective effect of BET on normal cells and the radiosensitizing effect of BET on PCa cells. Our study identified a novel RelB complementary partner and reveals a complex redox-mediated mechanism showing that the RelB-BLNK axis, at least in part, triggers differential responses to the redox-active agent BET by stimulating adaptive responses in normal cells but pushing PCa cells into oxidative stress overload.
Assuntos
Neoplasias da Próstata , Fator de Transcrição RelB , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Betametasona/farmacologia , Betametasona/uso terapêutico , Humanos , Masculino , Oxirredução , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/radioterapia , Tolerância a Radiação , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição RelB/genética , Fator de Transcrição RelB/metabolismoRESUMO
Generation of mitochondrial reactive oxygen species (ROS), lipid peroxidation, 4-hydroxy-2-nonenal, and heat-shock protein (HSP) 47 after electron and X-ray irradiations were detected in the human neuroblastoma cell line SK-N-SH. After 10 Gy electron irradiation and 15 Gy X-ray irradiation, mitochondrial ROS production and lipid peroxidation were significantly increased. Additionally, we observed a significant increase in the levels of HSP47 after 3 and 10 Gy electron irradiation as well as 15 Gy X-ray irradiation. Furthermore, myristoylation and farnesylation were increased after 10 Gy electron and 15 Gy X-ray irradiations. We found that the level of HSP47 increased in the mitochondria after 10 Gy electron and 15 Gy X-ray irradiations. HSP47 coexisted with myristoylation and farnesylation. Furthermore, HSP47 overexpression increased mitochondrial ROS production. These results suggest that HSP47 plays an important role in mitochondria and induces mitochondrial ROS production in SK-N-SH cells.
Assuntos
Elétrons , Proteínas de Choque Térmico HSP47/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , Neuroblastoma/patologia , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Humanos , Processamento de Proteína Pós-Traducional/efeitos da radiação , Transporte Proteico/efeitos da radiação , Raios XRESUMO
Cardiotoxicity is a major dose-limiting adverse effect of doxorubicin (DOX), mediated in part by overproduction of reactive oxygen species and oxidative stress. Abcc1 (Mrp1) mediates the efflux of reduced and oxidized glutathione (GSH, GSSG) and is also a major transporter that effluxes the GSH conjugate of 4-hydroxy-2-nonenal (HNE; GS-HNE), a toxic product of lipid peroxidation formed during oxidative stress. To assess the role of Mrp1 in protecting the heart from DOX-induced cardiac injury, wild-type (WT) and Mrp1 null (Mrp1(-/-)) C57BL/6 littermate mice were administered DOX (15 mg/kg) or saline (7.5 ml/kg) i.v., and heart ventricles were examined at 72 hours. Morphometric analysis by electron microscopy revealed extensive injuries in cytosol, mitochondria, and nuclei of DOX-treated mice in both genotypes. Significantly more severely injured nuclei were observed in Mrp1(-/-) versus WT mice (P = 0.031). GSH and the GSH/GSSG ratio were significantly increased in treatment-naïve Mrp1(-/-) versus WT mice; GSH remained significantly higher in Mrp1(-/-) versus WT mice after saline and DOX treatment, with no changes in GSSG or GSH/GSSG. GS-HNE, measured by mass spectrometry, was lower in the hearts of treatment-naïve Mrp1(-/-) versus WT mice (P < 0.05). DOX treatment decreased GS-HNE in WT but not Mrp1(-/-) mice, so that GS-HNE was modestly but significantly higher in Mrp1(-/-) versus WT hearts after DOX. Expression of enzymes mediating GSH synthesis and antioxidant proteins did not differ between genotypes. Thus, despite elevated GSH levels in Mrp1(-/-) hearts, DOX induced significantly more injury in the nuclei of Mrp1(-/-) versus WT hearts.
Assuntos
Antibióticos Antineoplásicos/toxicidade , Núcleo Celular/efeitos dos fármacos , Doxorrubicina/toxicidade , Glutationa/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Miocárdio/metabolismo , Miocárdio/ultraestrutura , Animais , Cardiotoxicidade/metabolismo , Glutationa/análogos & derivados , Dissulfeto de Glutationa/metabolismo , Peroxidação de Lipídeos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse OxidativoRESUMO
Oxidative stress plays a significant role in cancer development and cancer therapy, and is a major contributor to normal tissue injury. The unique characteristics of extracellular vesicles (EVs) have made them potentially useful as a diagnostic tool in that their molecular content indicates their cell of origin and their lipid membrane protects the content from enzymatic degradation. In addition to their possible use as a diagnostic tool, their role in how normal and diseased cells communicate is of high research interest. The most exciting area is the association of EVs, oxidative stress, and pathogenesis of numerous diseases. However, the relationship between oxidative stress and oxidative modifications of EVs is still unclear, which limits full understanding of the clinical potential of EVs. Here, we discuss how EVs, oxidative stress, and cancer therapy relate to one another; how oxidative stress can contribute to the generation of EVs; and how EVs' contents reveal the presence of oxidative stress. We also point out the potential promise and limitations of using oxidatively modified EVs as biomarkers of cancer and tissue injury with a focus on pediatric oncology patients.
RESUMO
We have employed a redox-active MnP (MnTnBuOE-2-PyP5+, Mn(III) meso-tetrakis (N-n-butoxyethylpyridinium-2-yl) porphyrin) frequently identified as superoxide dismutase mimic or BMX-001, to explore the redox status of normal ovarian cell in relation to two ovarian cancer cell lines: OV90 human serous ovarian cancer cell and chemotherapy-resistant OV90 cell (OVCD). We identified that OVCD cells are under oxidative stress due to high hydrogen peroxide (H2O2) levels and low glutathione peroxidase and thioredoxin 1. Furthermore, OVCD cells have increased glycolysis activity and mitochondrial respiration when compared to immortalized ovarian cells (hTER7) and parental cancer cells (OV90). Our goal was to study how ovarian cell growth depends upon the redox state of the cell; hence, we used MnP (BMX-001), a redox-active MnSOD mimetic, as a molecular tool to alter ovarian cancer redox state. Interestingly, OVCD cells preferentially uptake MnP relative to OV90 cells which led to increased inhibition of cell growth, glycolytic activity, OXPHOS, and ATP, in OVCD cells. These effects were further increased when MnP was combined with carboplatin. The effects were discussed with regard to the elevation in H2O2 levels, increased oxidative stress, and reduced Nrf2 levels and its downstream targets when cells were exposed to either MnP or MnP/carboplatin. It is significant to emphasize that MnP protects normal ovarian cell line, hTER7, against carboplatin toxicity. Our data demonstrate that the addition of MnP-based redox-active drugs may be used (via increasing excessively the oxidative stress of serous ovarian cancer cells) to improve cancer patients' chemotherapy outcomes, which develop resistance to platinum-based drugs.
Assuntos
Metaloporfirinas , Neoplasias Ovarianas , Porfirinas , Antioxidantes , Carboplatina/farmacologia , Carboplatina/uso terapêutico , Linhagem Celular , Feminino , Humanos , Peróxido de Hidrogênio , Metaloporfirinas/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Oxirredução , Superóxido DismutaseRESUMO
In spite of extensive successes, cancer recurrence after radiation treatment (RT) remains one of the significant challenges in the cure of localized prostate cancer (PCa). This study focuses on elucidating a novel adaptive response to RT that could contribute to cancer recurrence. Here, we used PC3 cell line, an adenocarcinoma from a bone metastasis and radio-resistant clone 695 cell line, which survived after total radiation dose of 66 Gy (2 Gy × 33) and subsequently regrew in nude mice after exposure to fractionated radiation at 10 Gy (2 Gy × 5). Clone 695 cells not only showed an increase in surviving fraction post-radiation but also an increase in hydrogen peroxide (H2O2) production when compared to PC3 cells. At the single cell level, confocal microscope images coupled with IMARIS rendering software demonstrate an increase in mitochondrial mass and membrane potential in clone 695 cells. Utilizing the Seahorse XF96 instrument to investigate mitochondrial respiration, clone 695 cells demonstrated a higher basal Oxygen Consumption Rate (OCR), ATP-linked OCR, and proton leak compared to PC3 cells. The elevation of mitochondrial function in clone 695 cells is accompanied by an increase in mitochondrial H2O2 production. These data suggest that H2O2 could reprogram PCa's mitochondrial homeostasis, which allows the cancer to survive and regrow after RT. Upon exposure to RT, in addition to ROS production, we found that RT induces the release of extracellular vesicles (EVs) from PC3 cells (p < 0.05). Importantly, adding H2O2 to PC3 cells promotes EVs production in a dose-dependent manner and pre-treatment with polyethylene glycol-Catalase mitigates H2O2-mediated EV production. Both RT-derived EVs and H2O2-derived EVs carried higher levels of mitochondrial antioxidant proteins including, Peroxiredoxin 3, Glutathione Peroxidase 4 as well as mitochondrial-associated oxidative phosphorylation proteins. Significantly, adding isolated functional mitochondria 24 h prior to RT shows a significant increase in surviving fractions of PC3 cells (p < 0.05). Together, our findings reveal that H2O2 promotes the production of EVs carrying mitochondrial proteins and that functional mitochondria enhance cancer survival after RT.
RESUMO
Cranial radiation is important for treating both primary brain tumors and brain metastases. A potential delayed side effect of cranial radiation is neurocognitive function decline. Early detection of CNS injury might prevent further neuronal damage. Extracellular vesicles (EVs) have emerged as a potential diagnostic tool because of their unique membranous characteristics and cargos. We investigated whether EVs can be an early indicator of CNS injury by giving C57BJ/6 mice 10 Gy cranial IR. EVs were isolated from sera to quantify: 1) number of EVs using nanoparticle tracking analysis (NTA); 2) Glial fibrillary acidic protein (GFAP), an astrocyte marker; and 3) protein-bound 4-hydroxy-2-nonenal (HNE) adducts, an oxidative damage marker. Brain tissues were prepared for immunohistochemistry staining and protein immunoblotting. The results demonstrate: 1) increased GFAP levels (p < 0.05) in EVs, but not brain tissue, in the IR group; and 2) increased HNE-bound protein adduction levels (p < 0.05). The results support using EVs as an early indicator of cancer therapy-induced neuronal injury.
Assuntos
Lesões Encefálicas , Vesículas Extracelulares , Animais , Astrócitos/metabolismo , Encéfalo/metabolismo , Lesões Encefálicas/etiologia , Lesões Encefálicas/metabolismo , Vesículas Extracelulares/metabolismo , Camundongos , Neurônios/metabolismo , Proteínas/metabolismoRESUMO
Increasing numbers of cancer patients survive and live longer than five years after therapy, but very often side effects of cancer treatment arise at same time. One of the side effects, chemotherapy-induced cognitive impairment (CICI), also called "chemobrain" or "chemofog" by patients, brings enormous challenges to cancer survivors following successful chemotherapeutic treatment. Decreased abilities of learning, memory, attention, executive function and processing speed in cancer survivors with CICI, are some of the challenges that greatly impair survivors' quality of life. The molecular mechanisms of CICI involve very complicated processes, which have been the subject of investigation over the past decades. Many mechanistic candidates have been studied including disruption of the blood-brain barrier (BBB), DNA damage, telomere shortening, oxidative stress and associated inflammatory response, gene polymorphism of neural repair, altered neurotransmission, and hormone changes. Oxidative stress is considered as a vital mechanism, since over 50% of FDA-approved anti-cancer drugs can generate reactive oxygen species (ROS) or reactive nitrogen species (RNS), which lead to neuronal death. In this review paper, we discuss these important candidate mechanisms, in particular oxidative stress and the cytokine, TNF-alpha and their potential roles in CICI.
Assuntos
Antineoplásicos/efeitos adversos , Encéfalo/efeitos dos fármacos , Sobreviventes de Câncer/estatística & dados numéricos , Disfunção Cognitiva/fisiopatologia , Neoplasias/fisiopatologia , Qualidade de Vida , Antineoplásicos/uso terapêutico , Encéfalo/patologia , Encéfalo/fisiopatologia , Sobreviventes de Câncer/psicologia , Disfunção Cognitiva/induzido quimicamente , Humanos , Memória/efeitos dos fármacos , Modelos Biológicos , Neoplasias/tratamento farmacológico , Neoplasias/psicologia , Estresse Oxidativo/efeitos dos fármacosRESUMO
Cancer treatments are developing fast and the number of cancer survivors could arise to 20 million in United State by 2025. However, a large fraction of cancer survivors demonstrate cognitive dysfunction and associated decreased quality of life both shortly, and often long-term, after chemotherapy treatment. The etiologies of chemotherapy induced cognitive impairment (CICI) are complicated, made more so by the fact that many anti-cancer drugs cannot cross the blood-brain barrier (BBB). Multiple related factors and confounders lead to difficulties in determining the underlying mechanisms. Chemotherapy induced, oxidative stress-mediated tumor necrosis factor-alpha (TNF-α) elevation was considered as one of the main candidate mechanisms underlying CICI. Doxorubicin (Dox) is a prototypical reactive oxygen species (ROS)-generating chemotherapeutic agent used to treat solid tumors and lymphomas as part of multi-drug chemotherapeutic regimens. We previously reported that peripheral Dox-administration leads to plasma protein damage and elevation of TNF-α in plasma and brain of mice. In the present study, we used TNF-α null (TNFKO) mice to investigate the role of TNF-α in Dox-induced, oxidative stress-mediated alterations in brain. We report that Dox-induced oxidative stress in brain is ameliorated and brain mitochondrial function assessed by the Seahorse-determined oxygen consumption rate (OCR) is preserved in brains of TNFKO mice. Further, we show that Dox-decreased the level of hippocampal choline-containing compounds and brain phospholipases activity are partially protected in TNFKO group in MRS study. Our results provide strong evidence that Dox-targeted mitochondrial damage and levels of brain choline-containing metabolites, as well as phospholipases changes decreased in the CNS are associated with oxidative stress mediated by TNF-α. These results are consistent with the notion that oxidative stress and elevated TNF-α in brain underlie the damage to mitochondria and other pathological changes that lead to CICI. The results are discussed with reference to our identifying a potential therapeutic target to protect against cognitive problems after chemotherapy.
Assuntos
Encéfalo/patologia , Colina/metabolismo , Disfunção Cognitiva/induzido quimicamente , Doxorrubicina/farmacologia , Mitocôndrias/patologia , Neurônios/patologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Antibióticos Antineoplásicos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacosRESUMO
Extracellular vesicles (EVs) generated from redox active anticancer drugs are released into the extracellular environment. These EVs contain oxidized molecules and trigger inflammatory responses by macrophages. Using a mouse model of doxorubicin (DOX)-induced tissue injury, we previously found that the major sources of circulating EVs are from heart and liver, organs that are differentially affected by DOX. Here, we investigated the effects of EVs from cardiomyocytes and those from hepatocytes on macrophage activation. EVs from H9c2 rat cardiomyocytes (H9c2 EVs) and EVs from FL83b mouse hepatocytes (FL83â¯bâ¯EVs) have different levels of protein-bound 4-hydroxynonenal and thus different immunostimulatory effects on mouse RAW264.7 macrophages. H9c2 EVs but not FL83â¯bâ¯EVs induced both pro-inflammatory and anti-inflammatory macrophage activation, mediated by NFκB and Nrf-2 pathways, respectively. DOX enhanced the effects of H9c2 EVs but not FL83â¯bâ¯EVs. While EVs from DOX-treated H9c2 cells (H9c2 DOXEVs) suppressed mitochondrial respiration and increased glycolysis of macrophages, EVs from DOX-treated FL83b cells (FL83b DOXEVs) enhanced mitochondrial reserve capacity. Mechanistically, the different immunostimulatory functions of H9c2 EVs and FL83â¯bâ¯EVs are regulated, in part, by the redox status of the cytoplasmic thioredoxin 1 (Trx1) of macrophages. H9c2 DOXEVs lowered the level of reduced Trx1 in cytoplasm while FL83b DOXEVs did the opposite. Trx1 overexpression alleviated the effect of H9c2 DOXEVs on NFκB and Nrf-2 activation and prevented the upregulation of their target genes. Our findings identify EVs as a novel Trx1-mediated redox mediator of immune response, which greatly enhances our understanding of innate immune responses during cancer therapy.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Vesículas Extracelulares/imunologia , Hepatócitos/química , Miócitos Cardíacos/química , Tiorredoxinas/imunologia , Aldeídos/imunologia , Aldeídos/metabolismo , Aldeídos/farmacologia , Animais , Linhagem Celular , Meios de Cultivo Condicionados/química , Vesículas Extracelulares/química , Regulação da Expressão Gênica , Glicólise/efeitos dos fármacos , Hepatócitos/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Oxirredução , Células RAW 264.7 , Ratos , Tiorredoxinas/genéticaRESUMO
Peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) are two major antioxidant proteins that play a critical role in maintaining redox homeostasis for tumor progression. Here, we identify the prototypical pyranonaphthoquinone natural product frenolicin B (FB) as a selective inhibitor of Prx1 and Grx3 through covalent modification of active-site cysteines. FB-targeted inhibition of Prx1 and Grx3 results in a decrease in cellular glutathione levels, an increase of reactive oxygen species (ROS), and concomitant inhibition of cancer cell growth, largely by activating the peroxisome-bound tuberous sclerosis complex to inhibit mTORC1/4E-BP1 signaling axis. FB structure-activity relationship studies reveal a positive correlation between inhibition of 4E-BP1 phosphorylation, ROS-mediated cancer cell cytotoxicity, and suppression of tumor growth in vivo. These findings establish FB as the most potent Prx1/Grx3 inhibitor reported to date and also notably highlight 4E-BP1 phosphorylation status as a potential predictive marker in response to ROS-based therapies in cancer.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/química , Proteínas de Ciclo Celular/metabolismo , Glutarredoxinas/metabolismo , Peroxirredoxinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glutarredoxinas/antagonistas & inibidores , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Nus , Naftoquinonas/química , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Peroxirredoxinas/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transplante HeterólogoRESUMO
SIGNIFICANCE: Cancer cells that are resistant to radiation and chemotherapy are a major problem limiting the success of cancer therapy. Aggressive cancer cells depend on elevated intracellular levels of reactive oxygen species (ROS) to proliferate, self-renew, and metastasize. As a result, these aggressive cancers maintain high basal levels of ROS compared with normal cells. The prominence of the redox state in cancer cells led us to consider whether increasing the redox state to the condition of oxidative stress could be used as a successful adjuvant therapy for aggressive cancers. Recent Advances: Past attempts using antioxidant compounds to inhibit ROS levels in cancers as redox-based therapy have met with very limited success. However, recent clinical trials using pro-oxidant compounds reveal noteworthy results, which could have a significant impact on the development of strategies for redox-based therapies. CRITICAL ISSUES: The major objective of this review is to discuss the role of the redox state in aggressive cancers and how to utilize the shift in redox state to improve cancer therapy. We also discuss the paradox of redox state parameters; that is, hydrogen peroxide (H2O2) as the driver molecule for cancer progression as well as a target for cancer treatment. FUTURE DIRECTIONS: Based on the biological significance of the redox state, we postulate that this system could potentially be used to create a new avenue for targeted therapy, including the potential to incorporate personalized redox therapy for cancer treatment.
Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Humanos , Oxirredução , Espécies Reativas de Oxigênio/metabolismoRESUMO
Radiation therapy (RT) is commonly used for the treatment of localized prostate cancer (PCa). However, cancer cells often develop resistance to radiation through unknown mechanisms and pose an intractable challenge. Radiation resistance is highly unpredictable, rendering the treatment less effective in many patients and frequently causing metastasis and cancer recurrence. Understanding the molecular events that cause radioresistance in PCa will enable us to develop adjuvant treatments for enhancing the efficacy of RT. Radioresistant PCa depends on the elevated DNA repair system and the intracellular levels of reactive oxygen species (ROS) to proliferate, self-renew, and scavenge anti-cancer regimens, whereas the elevated heat shock protein 90 (HSP90) and the epithelial-mesenchymal transition (EMT) enable radioresistant PCa cells to metastasize after exposure to radiation. The up-regulation of the DNA repairing system, ROS, HSP90, and EMT effectors has been studied extensively, but not targeted by adjuvant therapy of radioresistant PCa. Here, we emphasize the effects of ionizing radiation and the mechanisms driving the emergence of radioresistant PCa. We also address the markers of radioresistance, the gene signatures for the predictive response to radiotherapy, and novel therapeutic platforms for targeting radioresistant PCa. This review provides significant insights into enhancing the current knowledge and the understanding toward optimization of these markers for the treatment of radioresistant PCa.
Assuntos
Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Tolerância a Radiação/genética , Biomarcadores , Dano ao DNA/efeitos da radiação , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Masculino , Oxirredução , Estresse Oxidativo/efeitos da radiação , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/radioterapia , Radioterapia/efeitos adversos , Radioterapia/métodos , Transdução de Sinais/efeitos da radiação , Fatores de Transcrição/metabolismoRESUMO
AIM: Extracellular superoxide dismutase (ECSOD) and the cysteine/glutamate transporter (Cys)/(xCT) are tumor microenvironment (TME) redox state homeostasis regulators. Altered expression of ECSOD and xCT can lead to imbalance of the TME redox state and likely have a profound effect on cancer invasion. In the present study, we investigated whether ECSOD and xCT could be therapeutic targets for prostate cancer (PCa) invasion. RESULTS: Immunohistochemistry of tumor microarray PCa tissues (N = 165) with high Gleason scores indicated that xCT protein expression is significantly increased while ECSOD protein expression is significantly decreased. Metastatic PCa indicated ECSOD protein expression is significantly decreased in epithelial area whereas xCT protein expression is significantly increased in stromal area. Furthermore, inhibition of extracellular O2â¢- by overexpression of ECSOD or alteration of the extracellular Cys/CySS ratio by knockdown of xCT protein inhibited PCa cell invasion. Simultaneous overexpression of ECSOD and knockdown xCT inhibited PCa cell invasion more than overexpression of ECSOD or knockdown of xCT alone. In the co-culturing system, simultaneous overexpression of ECSOD and knockdown of xCT in prostate stromal WPMY-1 cells inhibited PCa cell invasiveness more than overexpression of ECSOD alone. The decrease in PCa invasion correlated with increased of extracellular H2O2 levels. Notably, overexpression of catalase in TME reversed the inhibitory effect of ECSOD on cancer cell invasion. CONCLUSION: Impaired ECSOD activity and an upregulated of xCT protein expression may be clinical features of an aggressive PCa, particularly metastatic cancers and/or those with a high Gleason score. Therefore, shifting the extracellular redox state toward an oxidizing status by targeted modulation of ECSOD and xCT, in both cancer and stromal cells, may provide a greater strategy for potential therapeutic interventions of aggressive PCa.
Assuntos
Sistema y+ de Transporte de Aminoácidos/metabolismo , Neoplasias da Próstata/patologia , Superóxido Dismutase/metabolismo , Microambiente Tumoral/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Oxirredução , Neoplasias da Próstata/metabolismoRESUMO
Purpose: Cardiac injury is a major cause of death in cancer survivors, and biomarkers for it are detectable only after tissue injury has occurred. Extracellular vesicles (EV) remove toxic biomolecules from tissues and can be detected in the blood. Here, we evaluate the potential of using circulating EVs as early diagnostic markers for long-term cardiac injury.Experimental Design: Using a mouse model of doxorubicin (DOX)-induced cardiac injury, we quantified serum EVs, analyzed proteomes, measured oxidized protein levels in serum EVs released after DOX treatment, and investigated the alteration of EV content.Results: Treatment with DOX caused a significant increase in circulating EVs (DOX_EV) compared with saline-treated controls. DOX_EVs exhibited a higher level of 4-hydroxynonenal adducted proteins, a lipid peroxidation product linked to DOX-induced cardiotoxicity. Proteomic profiling of DOX_EVs revealed the distinctive presence of brain/heart, muscle, and liver isoforms of glycogen phosphorylase (GP), and their origins were verified to be heart, skeletal muscle, and liver, respectively. The presence of brain/heart GP (PYGB) in DOX_EVs correlated with a reduction of PYGB in heart, but not brain tissues. Manganese superoxide dismutase (MnSOD) overexpression, as well as pretreatment with cardioprotective agents and MnSOD mimetics, resulted in a reduction of EV-associated PYGB in mice treated with DOX. Kinetic studies indicated that EVs containing PYGB were released prior to the rise of cardiac troponin in the blood after DOX treatment, suggesting that PYGB is an early indicator of cardiac injury.Conclusions: EVs containing PYGB are an early and sensitive biomarker of cardiac injury. Clin Cancer Res; 24(7); 1644-53. ©2017 AACRSee related commentary by Zhu and Gius, p. 1516.
Assuntos
Biomarcadores/metabolismo , Doxorrubicina/farmacologia , Vesículas Extracelulares/metabolismo , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Miócitos Cardíacos/metabolismo , Aldeídos/metabolismo , Animais , Encéfalo/metabolismo , Cardiotoxicidade/metabolismo , Modelos Animais de Doenças , Cinética , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Proteoma/metabolismo , Proteômica/métodos , Superóxido Dismutase/metabolismoRESUMO
We characterized the redox profiles in two different human prostate carcinoma cell lines (LNCaP vs PC3) that are known to exhibit varying degrees of invasiveness/metastatic ability. We confirmed that PC3 cells were more invasive than LNCaP cells through an in vitro analysis. The present study documented higher 8-hydroxy-2'-deoxyguanosine levels in PC3 cells than in LNCaP cells. The levels of lipid peroxidation were higher in LNCaP cells than in PC3 cells. The reduced glutathione (GSH)/glutathione disulfide (GSSG) ratio increased to a greater extent during cell growth in PC3 cells than in LNCaP cells, whereas both reduced GSH and GSSG levels were higher in the medium of PC3 cells than in that of LNCaP cells. The levels of reactive oxygen (ROS) and reactive nitrogen species (RNS), both intracellularly and in the medium, were higher for LNCaP cells than for PC3 cells during cell growth. In addition, our results demonstrated higher ROS/RNS levels in LNCaP cells than in PC3 cells in S and G(2)/M phases of the cell cycle during logarithmic growth. Each cell type showed distinct cytotoxic responses to low-molecular-weight redox-modulating compounds. Our results document that human prostate cancer cell lines of varying degrees of aggressive behavior have distinct redox properties, findings that could lead to novel therapeutic interventions.
Assuntos
Peroxidação de Lipídeos , Neoplasias da Próstata/patologia , Divisão Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Invasividade Neoplásica , Oxirredução , Neoplasias da Próstata/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Tumorais CultivadasRESUMO
The tumor suppressor gene p53 is activated by reactive oxygen species-generating agents. After activation, p53 migrates to mitochondria and nucleus, a response that eventually leads to apoptosis, but how the two events are related is unknown. Herein, we show that p53 translocation to mitochondria precedes its translocation to nucleus in JB6 skin epidermal cells treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Translocation of p53 to mitochondria occurs within 10 minutes after TPA application. In the mitochondria, p53 interacts with the primary antioxidant enzyme, manganese superoxide dismutase (MnSOD), consistent with the reduction of its superoxide scavenging activity, and a subsequent decrease of mitochondrial membrane potential. In contrast to the immediate action on mitochondria, p53 transcriptional activity in the nucleus increases at 1 hour following TPA application, accompanied by an increase in the levels of its target gene bax at 15 hours following TPA treatment. Activation of p53 transcriptional activity is preventable by application of a SOD mimetic (MnTE-2-PyP5+). Thus, p53 translocation to mitochondria and subsequent inactivation of MnSOD explains the observed mitochondrial dysfunction, which leads to transcription-dependent mechanisms of p53-induced apoptosis.
Assuntos
Núcleo Celular/metabolismo , Mitocôndrias/metabolismo , Superóxido Dismutase/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/fisiologia , Materiais Biomiméticos/farmacologia , Linhagem Celular , DNA/metabolismo , Imuno-Histoquímica , Metaloporfirinas/farmacologia , Camundongos , Mitocôndrias/enzimologia , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , Pele/citologia , Pele/efeitos dos fármacos , Pele/metabolismo , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Superóxido Dismutase/antagonistas & inibidores , Acetato de Tetradecanoilforbol/farmacologia , Ativação Transcricional/fisiologia , Proteína Supressora de Tumor p53/genética , Proteína X Associada a bcl-2RESUMO
Studies in our laboratories showed that overexpression of manganese superoxide dismutase (MnSOD) reduced tumor incidence in a multistage skin carcinogenesis mouse model. However, reduction of MnSOD by heterozygous knockout of the MnSOD gene (MnSOD KO) did not lead to an increase in tumor incidence, because a reduction of MnSOD enhanced both cell proliferation and apoptosis. The present study extends our previous studies in the MnSOD KO mice and shows that apoptosis in mouse epidermis occurred prior to cell proliferation (6 versus 24 hours) when treated with tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). To investigate the possibility that a timed administration of SOD following apoptosis but before proliferation may lead to suppression of tumor incidence, we applied a SOD mimetic (MnTE-2-PyP(5+)) 12 hours after each TPA treatment. Biochemical studies showed that MnTE-2-PyP(5+) suppressed the level of protein carbonyls and reduced the activity of activator protein-1 and the level of proliferating cellular nuclear antigen, without reducing the activity of p53 or DNA fragmentation following TPA treatment. Histologic examination confirmed that MnTE-2-PyP(5+) suppressed mitosis without interfering with apoptosis. Remarkably, the incidence and multiplicity of skin tumors were reduced in mice that received MnTE-2-PyP(5+) before cell proliferation. These results show a novel strategy for an antioxidant approach to cancer intervention.
Assuntos
Metaloporfirinas/farmacologia , Neoplasias Cutâneas/prevenção & controle , Animais , Apoptose/fisiologia , Materiais Biomiméticos/química , Materiais Biomiméticos/metabolismo , Materiais Biomiméticos/farmacologia , Carcinógenos , Processos de Crescimento Celular/fisiologia , Feminino , Metaloporfirinas/química , Metaloporfirinas/metabolismo , Camundongos , Camundongos Endogâmicos DBA , Camundongos Knockout , Oxirredução , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Superóxido Dismutase/deficiência , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Acetato de TetradecanoilforbolRESUMO
OBJECTIVE: Treatment with adriamycin (ADR) is associated with cardiotoxicity mediated through the generation of superoxide (O2*-). Because nitric oxide (*NO) reacts with O2*-, generating peroxynitrite, we hypothesized that decreased *NO production would lead to protection in acute cardiac injury. METHODS: We investigated the role of decreased *NO levels in exacerbation of ADR-induced cardiotoxicity in vivo using iNOS (-/-) mice. Pathology, biochemical injury markers, and cardiac function were used to assess ADR-induced cardiac injury. RESULTS: Ultrastructural analysis demonstrated that iNOS (-/-) mice exhibited extensive cytoplasmic swelling and degeneration of mitochondria when compared to wildtype mice following treatment with ADR. Mice lacking iNOS exhibited a decrease in resting indices of cardiac function as well as an impairment in the positive inotropic actions of isoproterenol following treatment with ADR compared to nTg mice. Cardiac troponin, creatine phosphokinase, and lactate dehydrogenase levels were significantly increased after treatment in iNOS (-/-) mice as compared to controls and wildtype mice. CONCLUSIONS: These results indicate that a lack of *NO production by iNOS caused significantly enhanced cardiac injury. However, when iNOS (-/-) mice were crossed with manganese superoxide dismutase (MnSOD)-overexpressing animals, mitochondrial injury was ameliorated to the level of the wild type. These findings suggest that reduction of *NO levels mediated by ADR treatment leads to increased cardiac mitochondrial injury that can be attenuated by a compensatory increase in MnSOD.