Resistance to chemotherapy still remains a major challenge in the clinic, impairing the quality of life and survival rate of patients. The identification of unconventional chemosensitizing agents is ...therefore an interesting aspect of cancer research. Resveratrol has emerged in the last decades as a fascinating molecule, able to modulate several cancer-related molecular mechanisms, suggesting a possible application as an adjuvant in cancer management. This review goes deep into the existing literature concerning the possible chemosensitizing effect of resveratrol associated with the most conventional chemotherapeutic drugs. Despite the promising effects observed in different cancer types in in vitro studies, the clinical translation still presents strong limitations due to the low bioavailability of resveratrol. Recently, efforts have been moved in the field of drug delivery to identifying possible strategies/formulations useful for a more effective administration. Despite the necessity of a huge implementation in this research area, resveratrol appears as a promising molecule able to sensitize resistant tumors to drugs, suggesting its potential use in therapy-refractory cancer patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Resveratrol in Cancer Patients: From Bench to Bedside Berretta, Massimiliano; Bignucolo, Alessia; Di Francia, Raffaele ...
International journal of molecular sciences,
04/2020, Volume:
21, Issue:
8
Journal Article
Peer reviewed
Open access
Resveratrol (3,5,4'-trihydroxystilbene) is a natural phytoalexin that accumulates in several vegetables and fruits like nuts, grapes, apples, red fruits, black olives, capers, red rice as well as red ...wines. Being both an extremely reactive molecule and capable to interact with cytoplasmic and nuclear proteins in human cells, resveratrol has been studied over the years as complementary and alternative medicine (CAM) for the therapy of cancer, metabolic and cardiovascular diseases like myocardial ischemia, myocarditis, cardiac hypertrophy and heart failure. This review will describe the main biological targets, cardiovascular outcomes, physico-chemical and pharmacokinetic properties of resveratrol in preclinical and clinical models implementing its potential use in cancer patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We conducted a prospective phase II multicentric trial to determine if radical radiation therapy to all metastatic sites might improve the progression-free survival (PFS) in oligometastatic breast ...cancer patients. Secondary endpoints were local control (LC), overall survival (OS) and toxicity.
Inclusion criteria were the following: oligometastatic breast cancer with ≤5 metastatic sites, FDG-PET/CT staging, no brain metastases, primary tumor controlled. Radiotherapy could be delivered using stereotactic body radiotherapy (SBRT) technique or fractionated intensity modulated radiotherapy (IMRT). SBRT consisted of 30–45Gy in 3 fractions, while IMRT was delivered to a total dose of 60Gy in 25 fractions. We hypothesized that radical radiation therapy could increase the PFS from 30% (according to the published literature) to 50% at two years.
54 Patients with 92 metastatic lesions were enrolled. Forty-four were treated with SBRT, and 10 with IMRT. Forty-eight (89%) patients received a form of systemic therapy concomitantly to radiation therapy. Sites of metastatic disease were the following: bones 60 lesions, lymph nodes 23 lesions, lung 4 lesions, liver 5 lesions. After a median follow-up of 30months (range, 6–55months), 1- and 2-year PFS was 75% and 53%, respectively. Two-year LC and OS were 97% and 95%, respectively. Radiation therapy was well tolerated, and no Grade ≥3 toxicity was documented. Grade 2 toxicity were pain and fatigue in 2 cases.
Patients with oligometastatic breast cancer treated with radical radiotherapy to all metastatic sites may achieve long-term progression-free survival, without significant treatment-related toxicity. While waiting for data from randomized trials, the use of radical radiation therapy to all metastatic sites in patients with oligometastatic breast cancer should be considered a valuable option, and its recommendation should be individualized.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Gut microbiota, a group of 10
bacteria, eukaryotes and virus living in gastrointestinal tract, is crucial for many physiological processes in particular plays an important role in inflammatory and ...immune reactions. Several internal and external factors can influence this population, and shifts in their composition, have been demonstrated to contribute and affect different diseases. During dysbiosis several bacteria related to inflammation, one of the most necessary factors in carcinogenesis; it has been shown that some bacterial strains through deregulation of different signals/pathways may affect tumor development through the production of many factors. Gut microbiota might be considered as a holistic hub point for cancer development: direct and indirect involvements have been studying in several neoplasms such as colon rectal cancer, hepatocellular carcinoma and breast cancer. This review discuss over the evidence of crosstalk between gut microbiota and cancer, its ability to modulate chemotherapy, radiotherapy and immunotherapy, and the possibility that the intestinal microbial is a new target for therapeutic approaches to improve the prognosis and quality of life of cancer patients.
Platinum agents, which include cisplatin, oxaliplatin and carboplatin, are chemotherapeutic drugs that represent the first-line treatment for different types of solid tumors, such as ovarian, head ...and neck, testicular, and bladder cancers. Their beneficial effect is limited by the onset of drug resistance and severe toxicities, involving mainly ototoxicity, neurotoxicity and nephrotoxicity. Recent studies highlight the supplementation of herbal products, vitamins and minerals with antioxidant properties to prevent and protect from side effects. In particular, the introduction of nutraceuticals associated with chemotherapy has improved the patients' quality of life. However, if from one side, complementary and alternative medicine ameliorates chemotherapeutics-induced toxicities, from the other side, it is important to take into consideration the possible interference with drug metabolism. This review aims to consider the current literature focusing on clinical trials that report an association between nutraceutical supplementation and platinum- based chemotherapy to prevent toxicities, highlighting both beneficial and side effects.
Cholesterol is a ubiquitous sterol with many biological functions, which are crucial for proper cellular signaling and physiology. Indeed, cholesterol is essential in maintaining membrane physical ...properties, while its metabolism is involved in bile acid production and steroid hormone biosynthesis. Additionally, isoprenoids metabolites of the mevalonate pathway support protein-prenylation and dolichol, ubiquinone and the heme
a
biosynthesis. Cancer cells rely on cholesterol to satisfy their increased nutrient demands and to support their uncontrolled growth, thus promoting tumor development and progression. Indeed, transformed cells reprogram cholesterol metabolism either by increasing its uptake and
de novo
biosynthesis, or deregulating the efflux. Alternatively, tumor can efficiently accumulate cholesterol into lipid droplets and deeply modify the activity of key cholesterol homeostasis regulators. In light of these considerations, altered pathways of cholesterol metabolism might represent intriguing pharmacological targets for the development of exploitable strategies in the context of cancer therapy. Thus, this work aims to discuss the emerging evidence of
in vitro
and
in vivo
studies, as well as clinical trials, on the role of cholesterol pathways in the treatment of cancer, starting from already available cholesterol-lowering drugs (statins or fibrates), and moving towards novel potential pharmacological inhibitors or selective target modulators.
Colorectal cancer(CRC) represents one of the most commonly diagnosed cancers worldwide.It is the second leading cause of cancer death in Western Countries.In the last decade the survival of patients ...with metastatic CRC has improved dramatically.Due to the advent of new drugs(irinotecan and oxaliplatin) and target therapies(i.e.,bevacizumab,cetuximab and panitumab),the median overall survival has risen from about 12 mo in the mid nineties to 30 mo recently.Many questions needing of right collocations and more clearness still exist regarding the prognostic factors and the predictive factors of response to therapy.Despite advances in dosing and scheduling of chemotherapy in both adjuvant and advanced settings,and a greater emphasis on early detection,the outlook still remains poor for most patients.Molecular analyses have shown that the natural history of all CRCs is not the same.Individual patients with same stage tumours may have different long term prognosis and response to therapy.In addition,some prognostic variables are likely to be more important than others.Here we review the role of prognostic factors and predictive factors according to the recently published English literature.
Hyperglycemia, obesity and metabolic syndrome are negative prognostic factors in breast cancer patients. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, achieving ...unprecedented efficacy in multiple malignancies. However, ICIs are associated with immune-related adverse events involving cardiotoxicity. We aimed to study if hyperglycemia could affect ipilimumab-induced anticancer efficacy and enhance its cardiotoxicity. Human cardiomyocytes and estrogen-responsive and triple-negative breast cancer cells (MCF-7 and MDA-MB-231 cell lines) were exposed to ipilimumab under high glucose (25 mM); low glucose (5.5 mM); high glucose and co-administration of SGLT-2 inhibitor (empagliflozin); shifting from high glucose to low glucose. Study of cell viability and the expression of new putative biomarkers of cardiotoxicity and resistance to ICIs (NLRP3, MyD88, cytokines) were quantified through ELISA (Cayman Chemical) methods. Hyperglycemia during treatment with ipilimumab increased cardiotoxicity and reduced mortality of breast cancer cells in a manner that is sensitive to NLRP3. Notably, treatment with ipilimumab and empagliflozin under high glucose or shifting from high glucose to low glucose reduced significantly the magnitude of the effects, increasing responsiveness to ipilimumab and reducing cardiotoxicity. To our knowledge, this is the first evidence that hyperglycemia exacerbates ipilimumab-induced cardiotoxicity and decreases its anticancer efficacy in MCF-7 and MDA-MB-231 cells. This study sets the stage for further tests on other breast cancer cell lines and primary cardiomyocytes and for preclinical trials in mice aimed to decrease glucose through nutritional interventions or administration of gliflozines during treatment with ipilimumab.
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In the era of precision medicine, the identification of several predictive biomarkers and the development of innovative therapies have dramatically increased the request of tests to identify specific ...targets on cytological or histological samples, revolutionizing the management of the tumoral biomaterials. The Food and Drug Administration (FDA) has recently approved a selective neurotrophic tyrosine receptor kinase (NTRK) inhibitor, larotrectinib. Contemporarily, the development of multi-kinase inhibitors with activity in tumors carrying TRK fusions is ongoing. Chromosomal translocations involving the NTRK1, NTRK2, and NTRK3 genes result in constitutive activation and aberrant expression of TRK kinases in numerous cancer types. In this context, the identification of tumors harboring TRK fusions is crucial. Several methods of detection are currently available. We revise the advantages and disadvantages of different techniques used for identifying TRK alterations, including immunohistochemistry, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, and next generation sequencing-based approaches. Finally, we propose a diagnostic algorithm based on histology and the relative frequency of TRK fusions in each specific tumor, considering also the economic feasibility in the clinical practice.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Renal cell carcinoma (RCC) represents the main renal tumors and are highly metastatic. Sunitinib, a recently-approved, multi-targeted Tyrosine Kinases Inhibitor (TKi), prolongs survival in patients ...with metastatic renal cell carcinoma and gastrointestinal stromal tumors, however a dose related cardiotoxicity was well described. Polydatin (3,4’,5-trihydroxystilbene-3-β-d-glucoside) is a monocrystalline compound isolated from Polygonum cuspidatum with consolidated anti-oxidant and anti-inflammatory properties, however no studies investigated on its putative cardioprotective and chemosensitizing properties during incubation with sunitinib. We investigated on the effects of polydatin on the oxidative stress, NLRP3 inflammasome and Myd88 expression, highlighting on the production of cytokines and chemokines (IL-1β, IL-6, IL-8, CXCL-12 and TGF-β) during treatment with sunitinib. Exposure of cardiomyocytes and cardiomyoblasts (AC-16 and H9C2 cell lines) and human renal adenocarcinoma cells (769‐P and A498) to polydatin combined to plasma-relevant concentrations of sunitinib reduces significantly iROS, MDA and LTB4 compared to only sunitinib-treated cells (P<0.001). In renal cancer cells and cardiomyocytes polydatin reduces expression of pro-inflammatory cytokines and chemokines involved in myocardial damages and chemoresistance and down-regulates the signaling pathway of NLRP3 inflammasome, MyD88 and NF-κB. Data of the present study, although
in vitro
, indicate that polydatin, besides reducing oxidative stress, reduces key chemokines involved in cancer cell survival, chemoresistance and cardiac damages of sunitinib through downregulation of NLRP3-MyD88 pathway, applying as a potential nutraceutical agent in preclinical studies of preventive cardio-oncology.
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