RESUMO
ABSTRACT: Treatment resistance of leukemia stem cells (LSCs) and suppression of the autologous immune system represent major challenges to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38pos), LSCs are frequently enriched in the CD34posCD38neg blast fraction. Here, we report that interferon gamma (IFN-γ) reduces LSCs clonogenic activity and induces CD38 upregulation in both CD38pos and CD38neg LSC-enriched blasts. IFN-γ-induced CD38 upregulation depends on interferon regulatory factor 1 transcriptional activation of the CD38 promoter. To leverage this observation, we created a novel compact, single-chain CD38-CD3 T-cell engager (BN-CD38) designed to promote an effective immunological synapse between CD38pos AML cells and both CD8pos and CD4pos T cells. We demonstrate that BN-CD38 engages autologous CD4pos and CD8pos T cells and CD38pos AML blasts, leading to T-cell activation and expansion and to the elimination of leukemia cells in an autologous setting. Importantly, BN-CD38 engagement induces the release of high levels of IFN-γ, driving the expression of CD38 on CD34posCD38neg LSC-enriched blasts and their subsequent elimination. Critically, although BN-CD38 showed significant in vivo efficacy across multiple disseminated AML cell lines and patient-derived xenograft models, it did not affect normal hematopoietic stem cell clonogenicity and the development of multilineage human immune cells in CD34pos humanized mice. Taken together, this study provides important insights to target and eliminate AML LSCs.
Assuntos
Interferon gama , Leucemia Mieloide Aguda , Linfócitos T , Animais , Humanos , Camundongos , ADP-Ribosil Ciclase 1/imunologia , ADP-Ribosil Ciclase 1/metabolismo , Antígenos CD34/metabolismo , Linhagem Celular Tumoral , Células-Tronco Hematopoéticas/metabolismo , Interferon gama/efeitos dos fármacos , Interferon gama/metabolismo , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Neoplásicas/metabolismo , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Ativação Linfocitária/efeitos dos fármacosRESUMO
OBJECTIVES: Rapidly growing evidence suggests that immune cells play a key role in determining tumor progression. Tumor cells are surrounded by a microenvironment composed of different cell populations including immune cells. The cross talk between tumor cells and the neighboring microenvironment is an important factor to take into account while designing tumor therapies. Despite significant advances in immunotherapy strategies, a relatively small proportion of patients have successfully responded to them. Therefore, the search for safe and efficient drugs, which could be used alongside conventional therapies to boost the immune system against tumors, is an ongoing need. In the present work, the modulatory effects of melatonin on different components of tumor immune microenvironment are reviewed. METHODS: A thorough literature review was performed in PubMed, Scopus, and Web of Science databases. All published papers in English on tumor immune microenvironment and the relevant modulatory effects of melatonin were scrutinized. RESULTS: Melatonin modulates macrophage polarization and prevents M2 induction. Moreover, it prevents the conversion of fibroblasts into cancer-associated fibroblasts (CAFs) and prevents cancer cell stemness. In addition, it can affect the payload composition of tumor-derived exosomes (TEXs) and their secretion levels to favor a more effective anti-tumor immune response. Melatonin is a safe molecule that affects almost all components of the tumor immune microenvironment and prevents them from being negatively affected by the tumor. CONCLUSION: Based on the effects of melatonin on normal cells, tumor cells and microenvironment components, it could be an efficient compound to be used in combination with conventional immune-targeted therapies to increase their efficacy.
Assuntos
Fibroblastos Associados a Câncer , Melatonina , Neoplasias , Humanos , Melatonina/farmacologia , Melatonina/uso terapêutico , Fibroblastos/patologia , Fibroblastos Associados a Câncer/patologia , Imunoterapia , Microambiente TumoralRESUMO
Venetoclax (VEN), the first selective Bcl-2 inhibitor, has shown efficacy and safety both as monotherapy and in combination with other agents in the treatment of newly diagnosed acute myeloid leukemia (AML), while its role in relapsed or refractory (R/R) disease is not well defined. Here, we reviewed the latest advances of VEN-based therapy for R/R AML from the 2022 American Society of Hematology (ASH) Annual Meeting, including some novel and encouraging regimes, such as VCA, VAH, and HAM regimes, etc. Further research is still needed to fully understand the optimal use of these agents in R/R AML treatment.
RESUMO
PURPOSE: Exosomes are membrane-derived nano-vesicles upregulated in pathological conditions like cancer. Therefore, inhibiting their release is a potential strategy for the development of more efficient combination therapies. Neutral sphingomyelinase 2 (nSMase2) is a key component in exosome release; however, a clinically safe yet efficient nSMase2 inhibitor remains to be used discovered. Accordingly, we made an effort to identify potential nSMase2 inhibitor(s) among the approved drugs. METHODS: Virtual screening was performed and aprepitant was selected for further investigation. To evaluate the reliability of the complex, molecular dynamics were performed. Finally, using the CCK-8 assay in HCT116 cells, the highest non-toxic concentrations of aprepitant were identified and the nSMase2 activity assay was performed to measure the inhibitory activity of aprepitant, in vitro. RESULTS: To validate the screening results, molecular docking was performed, and the retrieved scores were in line with the screening results. The root-mean-square deviation (RMSD) plot of aprepitant-nSMase2 showed proper convergence. Following treatment with different concentrations of aprepitant in both cell-free and cell-dependent assays, nSMase2 activity was remarkably decreased. CONCLUSION: Aprepitant, at a concentration as low as 15 µM, was able to inhibit nSmase2 activity in HCT116 cells without any significant effects on their viability. Aprepitant is therefore suggested to be a potentially safe exosome release inhibitor.
Assuntos
Exossomos , Neoplasias , Humanos , Esfingomielina Fosfodiesterase , Aprepitanto/farmacologia , Simulação de Acoplamento Molecular , Reprodutibilidade dos Testes , Detecção Precoce de CâncerRESUMO
Aims: To study the association between miR-31 expression and clinical outcomes in colorectal cancer. Methods: A systematic search was performed and 16 studies were found eligible. To calculate the combined hazard ratio (HR), the DerSimonian and Laird random-effects model was used. Results: Pooled analysis revealed significant associations between high miR-31 expression and poor overall (HR: 0.68; 95% CI: 0.47-0.97; I2: 68.6%) and progression-free survival (HR: 0.49; 95% CI: 0.33-0.73; I2: 81.1%). High expressers were more likely to have a BRAF mutation. Therapeutic regimen and the mutational status significantly affected the observed associations. Conclusion: We identified that high miR-31 expression is associated with poor overall survival and progression-free survival and has a significant predictive value for anti-EGFR response.
Lay abstract We aim to investigate whether the molecular marker miR-31 is useful in predicting clinical outcomes in colorectal cancer (CRC). We conducted a systematic search in the major scientific databases was performed and 16 studies were found eligible for data extraction.The analysis revealed that high levels of miR-31 in CRC patients are indicative of a shorter survival time. Patients with high miR-31 levels were also more likely to have a mutation in BRAF, an important gene in the pathogenesis and response to treatment of CRC patients. We showed that high levels of miR-31 are associated with shorter survival with a significant predictive value for anti-EGFR response.
Assuntos
Antineoplásicos , Neoplasias Colorretais , MicroRNAs , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Cetuximab/genética , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Receptores ErbB/uso terapêutico , Humanos , MicroRNAs/metabolismo , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/uso terapêuticoRESUMO
The current era of cancer research has been continuously advancing upon identifying novel aspects of tumorigenesis and the principal mechanisms behind the unleashed proliferation, invasion, drug resistance and immortality of cancer cells in hopes of exploiting these findings to achieve a more effective treatment for cancer. In pursuit of this goal, the identification of the first components of an extremely important regulatory pathway in Drosophila melanogaster that largely determines cell fate during the developmental stages, ended up in the discovery of the highly sophisticated Hippo signaling cascade. Soon after, it was revealed that deregulation of the components of this pathway either via mutations or through epigenetic alterations can be observed in a vast variety of tumors and these alterations greatly contribute to the neoplastic transformation of cells, their survival, growth and resistance to therapy. As more hidden aspects of this pathway such as its widespread entanglement with other major cellular signaling pathways are continuously being uncovered, many researchers have sought over the past decade to find ways of therapeutic interventions targeting the major components of the Hippo cascade. To date, various approaches such as the use of exogenous targeting miRNAs and different molecular inhibitors have been recruited herein, among which naturally occurring compounds have shown a great promise. On such a basis, in the present work we review the current understanding of Hippo pathway and the most recent evidence on targeting its components using natural plant-derived phytochemicals.
Assuntos
Drosophila melanogaster , Neoplasias , Animais , Transformação Celular Neoplásica , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Via de Sinalização Hippo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Proteínas Serina-Treonina Quinases , Transdução de Sinais/genéticaRESUMO
Rapidly growing interest in the study of extracellular vesicles (EVs) has led to the accumulation of evidence on their critical roles in various pathologies, as well as opportunities to design novel therapeutic EV-based applications. Efficiently exploiting the constantly expanding knowledge of the biology and function of EVs requires a deep understanding of the various possible strategies of using EVs for therapeutic purposes. Accordingly, in the present work, we have narrowed the broad therapeutic potential of EVs and consider the similarities and differences of various strategies as we articulate three major aspects (i.e., a triad) of their therapeutic uses: (i) EVs as drug targets, whereby we discuss therapeutic targeting of disease-promoting EVs; (ii) EVs as drugs, whereby we consider the natural medicinal properties of EVs and the available options for their optimization; and (iii) EVs as drug carriers, whereby we highlight the advantages of EVs as vehicles for efficacious drug delivery of natural compounds. Finally, after conducting a comprehensive review of the latest literature on each of these aspects, we outline opportunities, limitations, and potential solutions.
Assuntos
Fatores Biológicos/metabolismo , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Vesículas Extracelulares/metabolismo , Animais , Fatores Biológicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Exossomos/metabolismo , Humanos , Doenças Vasculares/sangue , Doenças Vasculares/tratamento farmacológicoRESUMO
Aims: Acute myeloblastic leukemia (AML) is the most common type of acute leukemia in adults. Despite numerous treatment strategies including chemotherapy and radiotherapy, a large number of patients do not respond to treatment and experience relapse. The main problem of these patients is the development of resistance to anti-cancer drugs. Therefore, any endeavor to reduce drug resistance in these patients is of high priority. In general, several mechanisms such as changes in drug metabolic pathways, drug inactivation, drug target alterations and reduced drug accumulation in the cells contribute to drug resistance of cancer cells. In this context, evidence suggests that exosomes could reduce drug resistance by removing drugs from their parent cells. In the present study, we aimed to investigate the effects of exosome release inhibition on the resistance of U937 cells to PEGylated liposomal doxorubicin (PLD). Main Methods: In order to find a suitable ABCG2 (ATP-binding cassette sub-family G member 2) transporter substrate, virtual screening was performed among a list of drugs used in leukemia and PLD was selected. U937 cells were treated with PLD with/without co-treatment with the exosome release inhibitor, GW4869. Released exosomes within different study groups were isolated and characterized to determine the differences between groups. Doxorubicin presence in the isolated exosomes was also measured by high performance liquid chromatography (HPLC) to confirm drug export through the exosomes. Finally, the effect of exosome inhibition on the cytotoxicity of PLD on U937 cells was determined using different cytotoxicity assays including the standard lactate dehydrogenase (LDH) release assay and the flow cytometric analysis of apoptotic and non-apoptotic cell death. Key Findings: GW4869 treatment caused a significant decrease in the exosome release of U937 cells compared to the untreated cells, as evidenced by the reduction of the protein content of the isolated exosomes (P<0.05). Co-treatment with GW4869 significantly increased cytotoxic cell death in the groups treated with 0.5 and 1 µM PLD, compared to the same groups without GW4869 co-treatment (P<0.05). Interestingly, co-treatment with GW4896 and 0.5 µM PLD was enough to induce the same cytotoxic effect as that of the sole 1 µM PLD group. Significance: Our findings showed that U937 cells increase their resistance against the cytotoxic effects of PLD through the exosome-mediated expelling of the drug. Inhibition of exosome release could prevent PLD efflux and consequently increase the vulnerability of the U937 cells to the cytotoxic effects of PLD. Our results along with prior studies indicate that the integration of exosome release inhibitors into the common PLD-containing chemotherapy regimens could significantly lower the required concentrations of the drug and consequently reduce its associated side effects. Further studies are warranted to identify clinically safe inhibitors and investigate their clinical efficacy.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Compostos de Anilina/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Compostos de Benzilideno/farmacologia , Doxorrubicina/análogos & derivados , Exossomos/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Morte Celular/efeitos dos fármacos , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Exossomos/metabolismo , Exossomos/patologia , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas de Neoplasias/metabolismo , Polietilenoglicóis/metabolismo , Polietilenoglicóis/farmacologia , Células U937RESUMO
Hematological malignancies are classified as a heterogeneous category of cancers with various degrees of incidence and prognosis and different etiologies. Due to their aggressive essence they should be diagnosed as early as possible to improve prognosis, treatment outcome and survival. Bases on the limitations of previously identified biomarkers in terms of sensitivity, specificity and predictability, it is necessary to develop new diagnostic tools and biomarkers for the early diagnosis of hematological malignancies. Exosomes are nanovesicles secreted by almost all cell types in both physiological and pathological conditions. They play major roles in intercellular communication and are recently being considered as disease biomarkers. These nanovesicles carry proteins, lipids and nucleic acids like microRNAs (miRNAs). miRNAs are small noncoding RNAs, which act as translational suppressors via regulating protein-coding genes. The aberrant expression of miRNAs has been shown in various conditions including hematological malignancies. Moreover, it is now known that tumor cells secrete higher amounts of exosomes compared to normal cells. The idea of using exosomal miRNAs in serum as biomarkers is based on their surprisingly high stability and specificity. In the present paper, we reviewed and recommended exosomal miRNA panels including (miR-150, miR-155 and miR-1246), (miR-17-5p, miR-20a-5p, miR-16-5p and miR-5a-5p), (miR-18a, Let-7b) and (miR192-5p, miR21-5p, miR320b and Let-7d), for their potential to be used as non-invasive biomarkers in different hematological malignancies such as multiple myeloma, leukemia, and lymphoma.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Hematológicas/sangue , MicroRNAs/sangue , Exossomos/metabolismo , Exossomos/patologia , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , HumanosRESUMO
The biological functions of melatonin range beyond the regulation of the circadian rhythm. With regard to cancer, melatonin's potential to suppress cancer initiation, progression, angiogenesis and metastasis as well as sensitizing malignant cells to conventional chemo- and radiotherapy are among its most interesting effects. The targets at which melatonin initiates its anti-cancer effects are in common with those of a majority of existing anti-cancer agents, giving rise to the notion that this molecule is a pleiotropic agent sharing many features with other antineoplastic drugs in terms of their mechanisms of action. Among these common mechanisms of action are the regulation of several major intracellular pathways including mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) and protein kinase B (AKT/PKB) signaling. The important mediators affected by melatonin include cyclins, nuclear factor-κB (NF-κB), heat shock proteins (HSPs) and c-Myc, all of which can serve as potential targets for cancer drugs. Melatonin also exerts some of its anti-cancer effects via inducing epigenetic modifications, DNA damage and mitochondrial disruption in malignant cells. The regulation of these mediators by melatonin mitigates tumor growth and invasiveness via modulating their downstream responsive genes, housekeeping enzymes, telomerase reverse transcriptase, apoptotic gene expression, angiogenic factors and structural proteins involved in metastasis. Increasing our knowledge on how melatonin affects its target sites will help find ways of exploiting the beneficial effects of this ubiquitously-acting molecule in cancer therapy. Acknowledging this, here we reviewed the most studied target pathways attributed to the anti-cancer effects of melatonin, highlighting their therapeutic potential.
Assuntos
Melatonina/metabolismo , Melatonina/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Ritmo Circadiano/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Melatonina/fisiologia , NF-kappa B/metabolismo , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais/efeitos dos fármacos , Telomerase/metabolismoRESUMO
Mesenchymal stem cells (MSCs) are mesenchymal precursors of various origins, with well-known immunomodulatory effects. Natural killer (NK) cells, the major cells of the innate immune system, are critical for the antitumor and antiviral defenses; however, in certain cases, they may be the main culprits in the pathogenesis of some NK-related conditions such as autoimmunities and hematological malignancies. On the other hand, these cells seem to be the major responders in beneficial phenomena like graft versus leukemia. Substantial data suggest that MSCs can variably affect NK cells and can be affected by these cells. Accordingly, acquiring a profound understanding of the crosstalk between MSCs and NK cells and the involved mechanisms seems to be a necessity to develop therapeutic approaches based on such interactions. Therefore, in this study, we made a thorough review of the existing literature on the interactions between MSCs and NK cells with a focus on the underlying mechanisms. The current knowledge herein suggests that MSCs possess a great potential to be used as tools for therapeutic targeting of NK cells in disease context and that preconditioning of MSCs, as well as their genetic manipulation before administration, may provide a wider variety of options in terms of eliciting more specific and desirable therapeutic outcomes. Nevertheless, our knowledge regarding the effects of MSCs on NK cells is still in its infancy, and further studies with well-defined conditions are warranted herein.
Assuntos
Comunicação Celular , Células Matadoras Naturais/metabolismo , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/cirurgia , Terapia Genética , Humanos , Células Matadoras Naturais/imunologia , Células-Tronco Mesenquimais/imunologia , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/cirurgia , Fenótipo , Transdução de Sinais , Microambiente TumoralRESUMO
BACKGROUND: Despite the advances in the treatment of multiple myeloma (MM), complete remission is usually challenging. The interactions between tumor and host cells, in which exosomes (EXs) play critical roles, have been shown to be among the major deteriorative tumor-promoting factors herein. Therefore, any endeavor to beneficially target these EX-mediated interactions could be of high importance. OBJECTIVES: a) To investigate the effects of myeloma EXs on natural killer (NK) cell functions. b) To check whether treatment of myeloma cells with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), two polyunsaturated omega-3 fatty acids with known anti-cancer effects, can modify myeloma EXs in terms of their effects on natural killer functions. METHODS: L363 cells were treated with either EPA or DHA or left untreated and the released EXs (designated as E-EX, D-EX and C-EX, respectively) were used to treat NK cells for functional studies. RESULTS: Myeloma EXs (C-EXs) significantly reduced NK cytotoxicity against K562 cells (P ≤ 0.05), while the cytotoxicity suppression was significantly lower (P ≤ 0.05) in the (E-EX)- and (D-EX)-treated NK cells compared to the (C-EX)-treated cells. The expression of the activating NK receptor NKG2D and NK degranulation, after treatment with the EXs, were both altered following the same pattern. However, C-EXs could increase IFN-γ production in NK cells (P < 0.01), which was not significantly affected by EPA/DHA treatment. This indicates a dual effect of myeloma EXs on NK cells functions. CONCLUSION: Our observations showed that myeloma EXs have both suppressive and stimulatory effects on different NK functions. Treatment of myeloma cells with EPA/DHA can reduce the suppressive effects of myeloma EXs while maintaining their stimulatory effects. These findings, together with the previous findings on the anti-cancer effects of EPA/DHA, provide stronger evidence for the repositioning of the currently existing EPA/DHA supplements to be used in the treatment of MM as an adjuvant treatment. EXs released from L363 (myeloma) cells in their steady state increase IFN-γ production of NK cells, while reduce their cytotoxicity against the K562 cell line (right blue trace). EXs from L363 cells pre-treated with either EPA or DHA are weaker stimulators of IFN-γ production. These EXs also increase NK cytotoxicity and NKG2D expression (left brown trace) compared to the EXs obtained from untreated L363 cells. Based on these findings, myeloma EXs have both suppressive and stimulatory effects on different NK functions depending on the properties of their cells of origin, which can be exploited in the treatment of myeloma.
Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Exossomos/fisiologia , Células Matadoras Naturais/citologia , Mieloma Múltiplo/metabolismo , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Exossomos/efeitos dos fármacos , Humanos , Interferon gama/metabolismo , Células K562 , Células Matadoras Naturais/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismoRESUMO
Melatonin is a ubiquitous indole amine that plays a fundamental role in the regulation of the biological rhythm. Disrupted circadian rhythm alters the expression of clock genes and deregulates oncogenes, which finally promote tumor development and progression. An evidence supporting this notion is the higher risk of developing malignancies among night shift workers. Circadian secretion of the pineal hormone also synchronizes the immune system via a reciprocal association that exists between the immune system and melatonin. Immune cells are capable of melatonin biosynthesis in addition to the expression of its receptors. Melatonin induces big changes in different immune cell proportions, enhances their viability and improves immune cell metabolism in the tumor microenvironment. These effects might be directly mediated by melatonin receptors or indirectly through alterations in hormonal and cytokine release. Moreover, melatonin induces apoptosis in tumor cells via the intrinsic and extrinsic pathways of apoptosis, while it protectsthe immune cells. In general, melatonin has a profound impact on immune cell trafficking, cytokine production and apoptosis induction in malignant cells. On such a basis, using melatonin and resynchronization of sleep cycle may have potential implications in immune function enhancement against malignancies, which will be the focus of the present paper.
Assuntos
Ritmo Circadiano/fisiologia , Melatonina/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Microambiente Tumoral/imunologia , Apoptose/fisiologia , Movimento Celular/fisiologia , Citocinas/metabolismo , Exossomos/metabolismo , HumanosRESUMO
Poly-unsaturated fatty acids (PUFAs) have been shown to have cytotoxic effects in both solid and non-solid tumors. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are among the most studied PUFAs. The aim of the present study was to evaluate the cytotoxic effects of these two fatty acids (FAs) in the peripheral blood mononuclear cells (PBMCs) obtained from untreated patients (new cases) with confirmed symptomatic multiple myeloma (MM). Our results showed that EPA at the concentration of 100 µM and DHA at 50 and 100 µM induce potent apoptotic effects in the PBMCs of MM patients (P < 0.05) as evidenced by Annexin V and propidium iodide (PI) staining, while they have little or no effects on the PBMCs isolated from healthy donors (P > 0.05). The observed effects were concentration- and time-dependent and 72 h treatment with DHA at a concentration of 100 µM had the strongest effect (P < 0.01). CD138 + cells isolated from MM patients showed great sensitivity to EPA/DHA. EPA- and DHA-induced apoptosis was significantly inhibited by the pan-caspase inhibitor (Z-VAD-FMK), indicating that cell death was at least partly dependent on caspase activation. The results of the present study showed that EPA and DHA have selective toxicities for malignant human plasma cells from MM patients, but not for mononuclear cells of healthy donors. These results warrant further studies with larger study populations to investigate the usefulness of PUFAs as a promising adjunctive therapy in the treatment of MM.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Plasmócitos/efeitos dos fármacos , Estudos de Casos e Controles , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Leucócitos Mononucleares/enzimologia , Leucócitos Mononucleares/patologia , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/patologia , Plasmócitos/enzimologia , Plasmócitos/patologia , Fatores de TempoRESUMO
Our knowledge of the role of innate immunity in protecting against cancers has expanded greatly in recent years. An early focus was on the adoptive transfer of natural killer (NK) cells and, although this approach has demonstrated promising results in many patients, a few limitations including immune escape of tumors from cytotoxic killing by NK cells have caused treatment failures. Downregulation of the expression of activating ligands on the surface of cancer cells and prevention of the activity of soluble factors are among the mechanisms employed by cancer cells to overcome NK-mediated immunity. It has become evident that a class of small membranous structures of endosomal origin known as exosomes play a key role in regulating the local tumor microenvironment. Here we hypothesize that exosome secretion by cancer cells, which is greater than that of normal cells, is an important escape mechanism employed by cancer cells. Interruption of exosome release by various inhibitory agents in combination with the adoptive transfer of NK cells may overcome, at least in part, the treatment failures that occur with adoptive NK cell transfer. In this regard, repositioning of approved drugs with previously shown effects on exosome release may be a good strategy to bypass the safety issues of newly identified agents and will also dramatically reduce the huge costs of drug approval process.
Assuntos
Antineoplásicos/uso terapêutico , Exossomos/efeitos dos fármacos , Neoplasias/terapia , Transferência Adotiva , Antineoplásicos/farmacologia , Reposicionamento de Medicamentos , Exossomos/imunologia , Humanos , Neoplasias/metabolismo , Evasão Tumoral/efeitos dos fármacos , Microambiente TumoralRESUMO
Multiple myeloma (MM), one of the most prevalent hematological malignancies, accounts for approximately 10% of all blood cancers. In spite of the recent advancements in MM therapy, this malignancy of terminally differentiated plasma cells (PCs) continues to remain a hard-to-cure disease due to the emergence of drug resistance and frequent relapses. It is now well-established that the tumor-supportive involvement of the bone marrow microenvironment (BMM) including the cellular and non-cellular elements are the major causes behind treatment failures of MM as well as its main complications such as osteolytic bone loss. Exosomes (EXs) are membranous structures that carry signaling molecules and have recently received a great deal of attention as important mediators of inter-cellular communication in health and disease. EXs involve in the growth and drug resistance of many tumors via delivering their rich contents of bioactive molecules including miRNAs, growth factors, cytokines, signaling molecules, etc. With regard to MM, many studies have reported that EXs are among the main culprits playing key roles in the vicious network within the BMM of these patients. The main producers of EXs that largely contribute to MM pathogenesis are bone marrow stromal cells (BMSCs) as well as MM cells themselves. These cell types produce large amounts of EXs that affect a variety of target cells including natural killer (NK) cells, osteoclasts (OCs) and osteoblasts (OBs) to the advantage of tumor survival and progression. These EXs contain a different profile of proteins and miRNAs from that of EXs obtained from their counterparts in healthy individuals. MM patients exhibit distinguishable elevations in some of their contents such as miR-21, miR-146a, let-7b and miR-18a, while some molecules like miR-15a are markedly downregulated in EXs of MM patients compared to healthy individuals. These findings make EXs desirable biomarkers for early prediction of disease progression and drug resistance in the context of MM. On the other hand, due to the tumor-supportive role of EXs, targeting these structures in parallel to the conventional therapeutic regimens may be a promising approach to a successful anti-MM therapy. In the present work, an extensive review of the literature has been carried out to highlight the recent advances in the field.
Assuntos
Exossomos/patologia , Mieloma Múltiplo/patologia , Animais , Comunicação Celular , Exossomos/genética , Exossomos/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Terapia de Alvo Molecular , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/terapia , Transdução de SinaisRESUMO
AIMS: Senescence is a state ensuing aging to eliminate age-associated damage with an irreversible cell-cycle arrest mechanism, which is historically believed to be one of the tumor responses to therapy. Doxorubicin as an anti-cancer drug has been used in cancer treatment for a long time. Liposomal doxorubicin (Ldox) is a liposomal formulation of doxorubicin, which increases the doxorubicin permanency. The aim of this study was to examine the toxicity of these two formulations by comparing them in terms of their ability to induce cellular senescence. MAIN METHODS: The study groups included a control group, three DOX (0.75, 0.5, 0.1â¯mg/kg/BW) and three Ldox groups (0.1, 0.05, 0.025â¯mg/kg/BW). Heart tissues were studied regarding oxidative stress assessment, mitochondrial function, inflammatory markers and biochemical and histopathological evaluation. Real-Time PCR was used for P53 and SA ß-gal expression. KEY FINDINGS: Based on the results, the highest doses of Dox and Ldox (0.75 and 0.1â¯mg/kg/BW respectively) significantly increased the level of inflammatory markers and according to other factors especially p53 and SA ß-gal expression, both were able to induce senescence but the changes in Ldox were less tangible than the Dox.
Assuntos
Senescência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/metabolismo , Animais , Biomarcadores/metabolismo , Doxorrubicina/análogos & derivados , Glutationa Peroxidase/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Polietilenoglicóis/farmacologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Exposure to environmental toxicants (ET) results in specific organ damage and auto-immune diseases, mostly mediated by inflammatory responses. The NLRP3 inflammasome has been found to be the major initiator of the associated pathologic inflammation. It has been found that ETs can trigger all the signals required for an NLRP3-mediated response. The exaggerated activation of the NLRP3 inflammasome and its end product IL-1ß, is responsible for the pathogenesis caused by many ETs including pesticides, organic pollutants, heavy metals, and crystalline compounds. Therefore, an extensive study of these chemicals and their mechanisms of inflammasome (INF) activation may provide the scientific evidence for possible targeting of this pathway by proposing possible protective agents that have been previously shown to affect INF compartments and its activation. Melatonin and polyunsaturated fatty acids (PUFA) are among the safest and the most studied of these agents, which affect a wide variety of cellular and physiological processes. These molecules have been shown to suppress the NLRP3 inflammasome mostly through the regulation of cellular redox status and the nuclear factor-κB (NF-κB) pathway, rendering them potential promising compounds to overcome ET-mediated organ damage. In the present review, we have made an effort to extensively review the ETs that exert their pathogenesis via the stimulation of inflammation, their precise mechanisms of action and the possible protective agents that could be potentially used to protect against such toxicants.