ABSTRACT
Physical activity (PA) has an established role in the promotion of health and fitness and the prevention of disease. Expected overall benefits include reduction of all-cause morbidity and death, weight control, improved quality of life, improved bone health and decreased falls of elderly subjects, , deeper cognition, and reduced risk of depression, anxiety, and sleeplessness. Currently, PA is a mainstay in the management of cardiovascular diseases, metabolic syndrome, diabetes, and bone health. Recently, the perception of its role in primary and secondary prevention, interception, and treatment of cancer, however, is also gaining importance. Regular walking, the simplest type of PA, is associated with reduced all-cause and cardiovascular disease mortality, and a role in cancer prevention is of increasing interest. Furthermore, PA improves the quality of life of cancer patients, attenuating side effects of chemotherapy, decreasing sarcopenia, increasing fitness, and inhibiting the recurrence and progression of some cancer types. It promotes emotional and psychological benefits in patients, inducing positive changes. While mechanisms, effective levels and useful amount of PA practice are well established in cardiology, they are yet to be fully determined in oncology. Nevertheless, PA is recommended to reduce cancer risk in the general population, and it has been introduced in programs for the prevention of second cancers. In perspective, it will help as integrative therapy in cancer patients and for cancer survivors. The number of beneficial effects in the cancer continuum is highlighted in this review.
ABSTRACT
Invasive lobular cancer (ILC) is the most common of the breast cancer special types, accounting for up to 15% of all breast malignancies. The distinctive biological features of ILC include the loss of the cell adhesion molecule E-cadherin, which drives the tumor's peculiar discohesive growth pattern, with cells arranged in single file and dispersed throughout the stroma. Typically, such tumors originate in the lobules, are more commonly bilateral compared to invasive ductal cancer (IDC) and require a more accurate diagnostic examination through imaging. They are luminal in molecular subtype, and exhibit estrogen and progesterone receptor positivity and HER2 negativity, thus presenting a more unpredictable response to neoadjuvant therapies. There has been a significant increase in research focused on this distinctive breast cancer subtype, including studies on its pathology, its clinical and surgical management, and the high-resolution definition of its genomic profile, as well as the development of new therapeutic perspectives. This review will summarize the heterogeneous pattern of this unique disease, focusing on challenges in its comprehensive clinical management and on future insights and research objectives.
Subject(s)
Breast Neoplasms , Carcinoma, Lobular , Humans , Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Breast Neoplasms/therapy , Breast Neoplasms/pathology , Breast Neoplasms/prevention & control , Female , Carcinoma, Lobular/diagnosis , Carcinoma, Lobular/therapy , Carcinoma, Lobular/genetics , Carcinoma, Lobular/pathologyABSTRACT
Cancer growth is dependent on angiogenesis, the formation of new blood vessels, which represents a hallmark of cancer. After this concept was established in the 1970s, inhibition of tumor development and metastases by blocking the neoangiogenic process has been an important approach to the treatment of tumors. However, antiangiogenic therapies are often administered when cancer has already progressed. The key to reducing the cancer burden is prevention. We noticed 20 years ago that a series of possible cancer chemopreventive agents showed antiangiogenic properties when tested in experimental models. This article reviews the relevant advances in the understanding of the rationale for targeting angiogenesis for cancer therapy, prevention, and interception and recently investigated substances with antiangiogenic activity that may be suitable for such strategies. Many compounds, either dietary derivatives or repurposed drugs, with antiangiogenic activity are possible tools for cancer angioprevention. Such molecules have a favorable safety profile and are likely to allow the prolonged duration necessary for an efficient preventive strategy. Recent evidence on mechanisms and possible use is described here for food derivatives, including flavonoids, retinoids, triterpenoids, omega fatty acids, and carotenoids from marine microorganisms. As examples, a number of compounds, including epigallocatechin, resveratrol, xanthohumol, hydroxytyrosol, curcumin, fenretinide, lycopene, fucoxanthin, and repurposed drugs, such as aspirin, ß blockers, renin-angiotensin-aldosterone inhibitors, carnitines, and biguanides, are reviewed.
Subject(s)
Angiogenesis Inhibitors , Neoplasms , Neovascularization, Pathologic , Humans , Neoplasms/drug therapy , Neoplasms/prevention & control , Neoplasms/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/prevention & control , Neovascularization, Pathologic/pathology , Angiogenesis Inhibitors/therapeutic use , Angiogenesis Inhibitors/pharmacology , Animals , AngiogenesisABSTRACT
A hybrid cellulose-based programmable nanoplatform for applications in precision radiation oncology is described. Here, sugar heads work as tumor targeting moieties and steer the precise delivery of radiosensitizers, i.e. gold nanoparticles (AuNPs) into triple negative breast cancer (TNBC) cells. This "Trojan horse" approach promotes a specific and massive accumulation of radiosensitizers in TNBC cells, thus avoiding the fast turnover of small-sized AuNPs and the need for high doses of AuNPs for treatment. Application of X-rays resulted in a significant increase of the therapeutic effect while delivering the same dose, showing the possibility to use roughly half dose of X-rays to obtain the same radiotoxicity effect. These data suggest that this hybrid nanoplatform acts as a promising tool for applications in enhancing cancer radiotherapy effects with lower doses of X-rays.
Subject(s)
Cellulose , Gold , Metal Nanoparticles , Radiation-Sensitizing Agents , Triple Negative Breast Neoplasms , Triple Negative Breast Neoplasms/drug therapy , Radiation-Sensitizing Agents/chemistry , Gold/chemistry , Cellulose/chemistry , Humans , Metal Nanoparticles/chemistry , Metal Nanoparticles/therapeutic use , Metal Nanoparticles/radiation effects , Cell Line, Tumor , Female , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Nanoparticles/chemistry , Cell Survival/drug effectsABSTRACT
INTRODUCTION: The emergence of anaplastic lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC) has revolutionized targeted therapy. This dynamic landscape, featuring novel ALK inhibitors and combination therapies, necessitates a profound understanding of resistance mechanisms for effective treatment strategies. Recognizing two primary categories - on-target and off-target resistance - underscores the need for comprehensive assessment. AREAS COVERED: This review delves into the intricacies of resistance to ALK inhibitors, exploring complexities in identification and management. Molecular testing, pivotal for early detection and accurate diagnosis, forms the foundation for patient stratification and resistance management. The literature search methodology involved comprehensive exploration of Pubmed and Embase. The multifaceted perspective encompasses new therapeutic horizons, ongoing clinical trials, and their clinical implications post the recent approval of lorlatinib. EXPERT OPINION: Our expert opinion encapsulates the critical importance of understanding resistance mechanisms in the context of ALK inhibitors for shaping successful treatment approaches. With a focus on molecular testing and comprehensive assessment, this review contributes valuable insights to the evolving landscape of NSCLC therapy.
Subject(s)
Aminopyridines , Anaplastic Lymphoma Kinase , Carcinoma, Non-Small-Cell Lung , Drug Resistance, Neoplasm , Lactams, Macrocyclic , Lactams , Lung Neoplasms , Protein Kinase Inhibitors , Pyrazoles , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/genetics , Anaplastic Lymphoma Kinase/genetics , Anaplastic Lymphoma Kinase/antagonists & inhibitors , Lactams/pharmacology , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/genetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/administration & dosage , Aminopyridines/pharmacology , Aminopyridines/administration & dosage , Lactams, Macrocyclic/pharmacology , Lactams, Macrocyclic/administration & dosage , Pyrazoles/pharmacology , Pyrazoles/administration & dosage , Molecular Targeted Therapy , Antineoplastic Agents/pharmacology , Antineoplastic Agents/administration & dosage , Gene RearrangementABSTRACT
Little is known as to whether there may be any pathogenetic link between pulmonary carcinoids and neuroendocrine carcinomas (NECs). A gene signature we previously found to cluster pulmonary carcinoids, large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), and which encompassed MEN1, MYC, MYCL1, RICTOR, RB1, SDHA, SRC and TP53 mutations or copy number variations (CNVs), was used to reclassify an independent cohort of 54 neuroendocrine neoplasms (NENs) [31 typical carcinoids (TC), 11 atypical carcinoids (AC) and 12 SCLC], by means of transcriptome and mutation data. Unsupervised clustering analysis identified two histology-independent clusters, namely CL1 and CL2, where 17/42 (40.5%) carcinoids and all the SCLC samples fell into the latter. CL2 carcinoids affected survival adversely, were enriched in T to G transversions or T > C/C > T transitions in the context of specific mutational signatures, presented with at least 1.5-fold change (FC) increase of gene mutations including TSC2, SMARCA2, SMARCA4, ERBB4 and PTPRZ1, differed for gene expression and showed epigenetic changes in charge of MYC and MTORC1 pathways, cellular senescence, inflammation, high-plasticity cell state and immune system exhaustion. Similar results were also found in two other independent validation sets comprising 101 lung NENs (24 carcinoids, 21 SCLC and 56 LCNEC) and 30 carcinoids, respectively. We herein confirmed an unexpected sharing of molecular traits along the spectrum of lung NENs, with a subset of genomically distinct aggressive carcinoids sharing molecular features of high-grade neuroendocrine neoplasms.
Subject(s)
Carcinoid Tumor , Carcinoma, Large Cell , Carcinoma, Neuroendocrine , Lung Neoplasms , Neuroendocrine Tumors , Humans , DNA Copy Number Variations/genetics , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Neuroendocrine Tumors/genetics , Neuroendocrine Tumors/pathology , Carcinoma, Neuroendocrine/genetics , Carcinoid Tumor/genetics , Carcinoid Tumor/pathology , Carcinoma, Large Cell/genetics , Carcinoma, Large Cell/pathology , Lung/pathology , DNA Helicases/genetics , Nuclear Proteins/genetics , Transcription Factors/genetics , Receptor-Like Protein Tyrosine Phosphatases, Class 5/geneticsABSTRACT
Since antiquity, numerous advantages of olive oil and its by-products have been recognized in various domains, including cooking, skincare, and healthcare. Extra virgin olive oil is a crucial component of the Mediterranean diet; several of its compounds exert antioxidant, anti-proliferative, anti-angiogenic and pro-apoptotic effects against a variety of cancers, and also affect cellular metabolism, targeting cancer cells through their metabolic derangements. Numerous olive tree parts, including leaves, can contribute metabolites useful to human health. Olive mill waste water (OMWW), a dark and pungent liquid residue produced in vast amounts during olive oil extraction, contains high organic matter concentrations that may seriously contaminate the soil and surrounding waters if not managed properly. However, OMWW is a rich source of phytochemicals with various health benefits. In ancient Rome, the farmers would employ what was known as amurca, a mulch-like by-product of olive oil production, for many purposes and applications. Several studies have investigated anti-angiogenic and chemopreventive activities of OMWW extracts. The most prevalent polyphenol in OMWW extracts is hydroxytyrosol (HT). Verbascoside and oleuperin are also abundant. We assessed the impact of one such extract, A009, on endothelial cells (HUVEC) and cancer cells. A009 was anti-angiogenic in several in vitro assays (growth, migration, adhesion) and inhibited angiogenesis in vivo, outperforming HT alone. A009 inhibited cells from several tumors in vitro and in vivo and showed potential cardioprotective effects mitigating cardiotoxicity induced by chemotherapy drugs, commonly used in cancer treatment, and reducing up-regulation of pro-inflammatory markers in cardiomyocytes. Extracts from OMWW and other olive by-products have been evaluated for biological activities by various international research teams. The results obtained make them promising candidates for further development as nutraceutical and cosmeceutical agents or dietary supplement, especially in cancer prevention or even in co-treatments with anti-cancer drugs. Furthermore, their potential to offer cardioprotective benefits opens up avenues for application in the field of cardio-oncology.
ABSTRACT
Interleukin-10 (IL-10) is a pleiotropic cytokine that has a fundamental role in modulating inflammation and in maintaining cell homeostasis. It primarily acts as an anti-inflammatory cytokine, protecting the body from an uncontrolled immune response, mostly through the Jak1/Tyk2 and STAT3 signaling pathway. On the other hand, IL-10 can also have immunostimulating functions under certain conditions. Given the pivotal role of IL-10 in immune modulation, this cytokine could have relevant implications in pathologies characterized by hyperinflammatory state, such as cancer, or infectious diseases as in the case of COVID-19 and Post-COVID-19 syndrome. Recent evidence proposed IL-10 as a predictor of severity and mortality for patients with acute or post-acute SARS-CoV-2 infection. In this context, IL-10 can act as an endogenous danger signal, released by tissues undergoing damage in an attempt to protect the organism from harmful hyperinflammation. Pharmacological strategies aimed to potentiate or restore IL-10 immunomodulatory action may represent novel promising avenues to counteract cytokine storm arising from hyperinflammation and effectively mitigate severe complications. Natural bioactive compounds, derived from terrestrial or marine photosynthetic organisms and able to increase IL-10 expression, could represent a useful prevention strategy to curb inflammation through IL-10 elevation and will be discussed here. However, the multifaceted nature of IL-10 has to be taken into account in the attempts to modulate its levels.
Subject(s)
COVID-19 , Neoplasms , Humans , Post-Acute COVID-19 Syndrome , Interleukin-10 , SARS-CoV-2/metabolism , Inflammation/drug therapy , Cytokines/metabolismABSTRACT
Knowledge of aging biology needs to be expanded due to the continuously growing number of elderly people worldwide. Aging induces changes that affect all systems of the body. The risk of cardiovascular disease and cancer increases with age. In particular, the age-induced adaptation of the immune system causes a greater susceptibility to infections and contributes to the inability to control pathogen growth and immune-mediated tissue damage. Since the impact of aging on immune function, is still to be fully elucidated, this review addresses some of the recent understanding of age-related changes affecting key components of immunity. The emphasis is on immunosenescence and inflammaging that are impacted by common infectious diseases that are characterized by a high mortality, and includes COVID-19, HIV and tuberculosis.
Subject(s)
COVID-19 , HIV Infections , Tuberculosis , Humans , Aged , Inflammation , AgingABSTRACT
The exploration of natural preventive molecules for nutraceutical and pharmaceutical use has recently increased. In this scenario, marine microorganisms represent an underestimated source of bioactive products endowed with beneficial effects on health that include anti-oxidant, anti-inflammatory, differentiating, anti-tumor, and anti-angiogenic activities. Here, we tested the potential chemopreventive and anti-angiogenic activities of an extract from the marine coastal diatom Skeletonema marinoi Sarno and Zingone (Sm) on prostate cancer (PCa) and endothelial cells. We also tested one of the main carotenoids of the diatom, the xanthophyll pigment fucoxanthin (Fuco). Fuco from the literature is a potential candidate compound involved in chemopreventive activities. Sm extract and Fuco were able to inhibit PCa cell growth and hinder vascular network formation of endothelial cells. The reduced number of cells was partially due to growth inhibition and apoptosis. We studied the molecular targets by qPCR and membrane antibody arrays. Angiogenesis and inflammation molecules were modulated. In particular, Fuco downregulated the expression of Angiopoietin 2, CXCL5, TGFß, IL6, STAT3, MMP1, TIMP1 and TIMP2 in both prostate and endothelial cells. Our study confirmed microalgae-derived drugs as potentially relevant sources of novel nutraceuticals, providing candidates for potential dietary or dietary supplement intervention in cancer prevention approaches.
Subject(s)
Diatoms , Prostatic Neoplasms , Male , Humans , Diatoms/physiology , Endothelial Cells , Xanthophylls/pharmacology , Carotenoids/pharmacology , Prostatic Neoplasms/drug therapy , Plant Extracts/pharmacologyABSTRACT
Xanthophylls, a group of carotenoids, have attracted attention as human health benefit compounds thanks to their functionality and bioavailability. The great antioxidant and anti-inflammatory abilities of diatoxanthin (Dt), a photoprotective xanthophyll synthetized by diatoms, were recently documented. This study investigates the capacity of Dt to intercept prostate cancer progression in vitro on different human cell lines, exploring its role against cancer proliferation and angiogenesis. Our results highlighted the chemopreventive role of Dt already at low concentration (44.1 pM) and suggest that the Dt-induced cancer cell death occurred through oxidative stress mechanisms. This hypothesis was supported by variations on the expression of key genes and proteins. Oxidative stress cell deaths (e.g., ferroptosis) are recently described types of cell death that are closely related to the pathophysiological processes of many diseases, such as tumors. Nonetheless, the interest of Dt was further strengthened by its ability to inhibit angiogenesis. The results are discussed considering the actual progress and requirements in cancer therapy, notably for prostate cancer.
ABSTRACT
High-dose standard-of-care chemotherapy is the only option for triple-negative breast cancer (TNBC) patients, which eventually die due to metastatic tumors. Recently, metronomic chemotherapy (mCHT) showed advantages in treating TNBCs leading us to investigate the anti-metastatic and anti-angiogenic potential of metronomic 5-Fluorouracil plus Vinorelbine (5-FU+VNR) on endothelial cells (ECs) and TNBCs in comparison to standard treatment (STD). We found that 10-fold lower doses of 5-FU+VNR given mCHT vs. STD inhibits cell proliferation and survival of ECs and TNBC cells. Both schedules strongly affect ECs migration and invasion, but in TNBC cells mCHT is significantly more effective than STD in impairing cell migration and invasion. The two treatments disrupt FAK/VEGFR/VEGF signaling in both ECs and TNBC cells. mCHT, and to a much lesser extent STD treatment, induces apoptosis in ECs, whereas it switches the route of cell death from apoptosis (as induced by STD) to autophagy in TNBC cells. mCHT-treated TNBCs-derived conditioned medium also strongly affects ECs' migration, modulates different angiogenesis-associated proteins, and hampers angiogenesis in matrix sponge in vivo. In conclusion, mCHT administration of 5-FU+VNR is more effective than STD schedule in controlling cell proliferation/survival and migration/invasion of both ECs and TNBC cells and has a strong anti-angiogenic effect. Our data suggest that the stabilization of tumor growth observed in TNBC patients treated with mCHT therapy schedule is likely due not only to direct cytotoxic effects but also to anti-metastatic and anti-angiogenic effects.
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Biobanks are biorepositories that collect, process, store, catalog, and distribute human biological samples, and record the associated data. The role and action field of these strategic infrastructures for implementing precision medicine in translational research is continuously evolving. To ensure the optimal quality at all stages of biobanking, specific protocols are required and should be elaborated according to updated guidelines, recommendations, laws, and rules. This article illustrates the standard operating procedures, including protocols, troubleshooting, and quality controls, of a fully certified biobank in a referral Cancer Center. This model involves all clinical departments and research groups to support the dual mission of academic cancer centers, i.e. to provide high-quality care and high-quality research. All biobanking activities based on the type of biological specimens are detailed and the most tricky methodological aspects are discussed, from patients' informed consent to specimen management.
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Objective: Several therapies with immune-modulatory functions have been proposed to reduce the overwhelmed inflammation associated with COVID-19. Here we investigated the impact of IL-10 in COVID-19, through the ex-vivo assessment of the effects of exogenous IL-10 on SARS-CoV-2-specific-response using a whole-blood platform. Methods: Two cohorts were evaluated: in "study population A", plasma levels of 27 immune factors were measured by a multiplex (Luminex) assay in 39 hospitalized "COVID-19 patients" and 29 "NO COVID-19 controls" all unvaccinated. In "study population B", 29 COVID-19 patients and 30 NO COVID-19-Vaccinated Controls (NO COVID-19-VCs) were prospectively enrolled for the IL-10 study. Whole-blood was stimulated overnight with SARS-COV-2 antigens and then treated with IL-10. Plasma was collected and used for ELISA and multiplex assay. In parallel, whole-blood was stimulated and used for flow cytometry analysis. Results: Baseline levels of several immune factors, including IL-10, were significantly elevated in COVID-19 patients compared with NO COVID-19 subjects in "study population A". Among them, IL-2, FGF, IFN-γ, and MCP-1 reached their highest levels within the second week of infection and then decreased. To note that, MCP-1 levels remained significantly elevated compared with controls. IL-10, GM-CSF, and IL-6 increased later and showed an increasing trend over time. Moreover, exogenous addition of IL-10 significantly downregulated IFN-γ response and several other immune factors in both COVID-19 patients and NO COVID-19-VCs evaluated by ELISA and a multiplex analysis (Luminex) in "study population B". Importantly, IL-10 did not affect cell survival, but decreased the frequencies of T-cells producing IFN-γ, TNF-α, and IL-2 (p<0.05) and down-modulated HLA-DR expression on CD8+ and NK cells. Conclusion: This study provides important insights into immune modulating effects of IL-10 in COVID-19 and may provide valuable information regarding the further in vivo investigations.
Subject(s)
COVID-19 , Interleukin-10 , Granulocyte-Macrophage Colony-Stimulating Factor , HLA-DR Antigens/analysis , Humans , Interleukin-2 , Interleukin-6 , SARS-CoV-2 , Tumor Necrosis Factor-alphaABSTRACT
Purpose: To investigate the clinical predictors of in-hospital mortality in hospitalized patients with Coronavirus disease 2019 (COVID-19) infection during the Omicron period. Methods: All consecutive hospitalized laboratory-confirmed COVID-19 patients between January and May 2022 were retrospectively analyzed. All patients underwent accurate physical, laboratory, radiographic and echocardiographic examination. Primary endpoint was in-hospital mortality. Results: 74 consecutive COVID-19 patients (80.0 ± 12.6 yrs, 45.9% males) were included. Patients who died during hospitalization (27%) and those who were discharged alive (73%) were separately analyzed. Compared to patients discharged alive, those who died were significantly older, with higher comorbidity burden and greater prevalence of laboratory, radiographic and echographic signs of pulmonary and systemic congestion. Charlson comorbidity index (CCI) (OR 1.76, 95%CI 1.07-2.92), neutrophil-to-lymphocyte ratio (NLR) (OR 1.24, 95%CI 1.10-1.39) and absence of angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARBs) therapy (OR 0.01, 95%CI 0.00-0.22) independently predicted the primary endpoint. CCI ≥7 and NLR ≥9 were the best cut-off values for predicting mortality. The mortality risk for patients with CCI ≥7, NLR ≥9 and not in ACEI/ARBs therapy was high (86%); for patients with CCI <7, NLR ≥9, with (16.6%) or without (25%) ACEI/ARBs therapy was intermediate; for patients with CCI <7, NLR <9 and in ACEI/ARBs therapy was of 0%. Conclusions: High comorbidity burden, high levels of NLR and the undertreatment with ACEI/ARBs were the main prognostic indicators of in-hospital mortality. The risk stratification of COVID-19 patients at hospital admission would help the clinicians to take care of the high-risk patients and reduce the mortality.
Subject(s)
COVID-19 Drug Treatment , Renin-Angiotensin System , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Comorbidity , Female , Hospital Mortality , Humans , Lymphocytes , Male , Neutrophils , Retrospective StudiesABSTRACT
Scientific advances in the late 19th century set the stage for progress in understanding and treating cancer, a disease that was previously considered almost hopeless. One hundred years later, cancer prevention is becoming an increasingly important focus for oncology research. New tools and ideas bring to the field some extremely promising molecular, organizational, social, and political approaches, which were a focus of the American Association for Cancer Research 2022 Annual Meeting and of the newly launched AACR Cancer Prevention Working Group (CPWG). We are moving toward precision prevention, better tools for early detection and for risk assessment, the use of a Precancer Atlas, unveiling of new biomarkers. Besides improving lifestyle, by avoiding risk factors such as tobacco use, excessive UV exposure, infectious agents, as well as poor dietary habits, lack of exercise, overweight, and obesity, many other factors can impact cancer risk, which is a warning to consider a multifaceted molecular but also social approach. Gender, ethnicity, geographic, and economic lines are associated with disparities in prevention, which we want to overcome. Here we summarize some challenges and priorities in cancer prevention emerging from the work of AACR and CPWG.
Subject(s)
Medical Oncology , Neoplasms , Exercise , Humans , Life Style , Neoplasms/etiology , Obesity/complications , United States/epidemiologyABSTRACT
Contact between SARS-CoV-2 and human lung cells involves the viral spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor on epithelial cells, the latter being strongly involved in the regulation of inflammation as well as blood pressure homeostasis. SARS-CoV-2 infection is characterized by a strong inflammatory response defined as a "cytokine storm". Among recent therapeutic approaches against SARS-CoV-2 targeting the dramatic inflammatory reaction, some natural products are promising. Diatoms are microalgae able to produce bioactive secondary metabolites, such as the xanthophyll diatoxanthin (Dt). The aim of this study is to demonstrate the anti-inflammatory effects of Dt on the A549-hACE2 lung cell line, exploring its interaction with the ACE2 receptor, as well as depicting its role in inhibiting a cytokine storm induced by the SARS-CoV-2 spike glycoprotein. Results showed that Dt enhanced the cell metabolism, e.g., the percent of metabolically active cells, as well as the ACE2 enzymatic activity. Moreover, Dt strongly affected the response of the SARS-CoV-2 spike glycoprotein-exposed A549-hACE2 cells in decreasing the interleukin-6 production and increasing the interleukin-10 release. Moreover, Dt upregulated genes encoding for the interferon pathway related to antiviral defense and enhanced proteins belonging to the innate immunity response. The potential interest of Dt as a new therapeutic agent in the treatment and/or prevention of the severe inflammatory syndrome related to SARS-CoV-2 infection is postulated.
ABSTRACT
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatments over the last 10 years, with even increasing indications in many neoplasms. Non-small cell lung cancer (NSCLC) is considered highly immunogenic, and ICIs have found a wide set of applications in this area, in both early and advanced lines of treatment, significantly changing the prognosis of these patients. Unfortunately, not all patients can benefit from the treatment, and resistance to ICIs can develop at any time. In addition to T lymphocytes, which are the major target, a variety of other cells present in the tumor microenvironment (TME) act in a complex cross-talk between tumor, stromal, and immune cells. An imbalance between activating and inhibitory signals can shift TME from an "anti-" to a "pro-tumorigenic" phenotype and vice versa. Natural killer cells (NKs) are able to recognize cancer cells, based on MHC I (self and non-self) and independently from antigen presentation. They represent an important link between innate and adaptive immune responses. Little data are available about the role of pro-inflammatory NKs in NSCLC and how they can influence the response to ICIs. NKs express several ligands of the checkpoint family, such as PD-1, TIGIT, TIM-3, LAG3, CD96, IL1R8, and NKG2A. We and others have shown that TME can also shape NKs, converting them into a pro-tumoral, pro-angiogenic "nurturing" phenotype through "decidualization." The features of these NKs include expression of CD56, CD9, CD49a, and CXCR3; low CD16; and poor cytotoxicity. During ICI therapy, tumor-infiltrating or associated NKs can respond to the inhibitors or counteract the effect by acting as pro-inflammatory. There is a growing interest in NKs as a promising therapeutic target, as a basis for adoptive therapy and chimeric antigen receptor (CAR)-NK technology. In this review, we analyzed current evidence on NK function in NSCLC, focusing on their possible influence in response to ICI treatment and resistance development, addressing their prognostic and predictive roles and the rationale for exploiting NKs as a tool to overcome resistance in NSCLC, and envisaging a way to repolarize decidual NK (dNK)-like cells in lung cancer.
ABSTRACT
Cardiovascular toxicity in cancer patients receiving chemotherapy remains one of the most undesirable side effects, limiting the choice of the most efficient therapeutic regimen, including combinations of different anticancer agents. Anthracyclines (doxorubicin) and antimetabolites (5-fluorouracil (5-FU), capecitabine) are among the most known agents used in breast cancer and other neoplasms and are associated with cardiotoxic effects. Extra-virgin olive oil (EVOO) is rich in polyphenols endowed with antioxidant cardioprotective activities. Olive mill wastewater (OMWW), a waste product generated by EVOO processing, has been reported to be enriched in polyphenols. In this study, we investigated the activities of polyphenol-rich extract from OMWW, A009, in cooperation with chemotherapy on two breast cancer cell lines, namely, BT459 and MDA-MB-231, in a cardio-oncology perspective. The effects of A009 on cardiac cells were also investigated with and without chemotherapeutic agents. Cell viability was determined on BT459 and MDA-MB-231 (i.e., breast cancer cells) and H9C2 (i.e., rat cardiomyocytes) cells, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. A spheroids assay was used as a 3D in vitro model on BT459 and MDA-MB-231 cells. For in vivo studies, the murine sponge assay of angiogenesis was used as a model of breast cancer-associated vascularization. The embryo of Danio rerio (zebrafish) was used to detect the cardioprotective activities of the OMWW. We found that the A009 extract exhibited antiangiogenic activities induced by breast cancer cell supernatants and increased T-cell recruitment in vivo. The combination of the OMWW extracts with doxorubicin or 5-FU limited BT459 and MDA-MB-231 cell viability and the diameter of 3D spheroids, while mitigating their toxic effects on the rat H9C2 cardiomyocytes. Cardioprotective effects were observed by the combination of OMWW extracts with doxorubicin in zebrafish embryos. Finally, in human cardio myocytes, we observed 5-FU-induced upregulation of the inflammatory, senescence-associated cytokine IL6 and p16 genes, which expression was reduced by OMWW treatment. Our study demonstrates that the polyphenol-rich purified OMWW extract A009 combined with cancer chemotherapy could represent a potential candidate for cardiovascular protection in breast cancer patients, while increasing the effects of breast cancer chemotherapy.