Multidrug resistance (MDR) presents a serious challenge to the efficiency of cancer treatment, and may be associated with the overexpression of drug efflux pumps. P-glycoprotein (P-gp) is a drug ...efflux pump often found overexpressed in cases of acquired MDR. Nevertheless, there are no P-gp inhibitors being used in the current clinical practice, due to toxicity problems, drug interactions, or pharmacokinetic issues. Therefore, it is important to identify novel inhibitors of P-gp activity or expression. Curcumin is a secondary metabolite isolated from the turmeric of
L. which has been associated with several biological activities, particularly P-gp modulatory activity (by inhibiting both P-gp function and expression). However, curcumin shows extensive metabolism and instability, which has justified the recent and intensive search for analogs of curcumin that maintain the P-gp modulatory activity but have enhanced stability. This review summarizes and compares the effects of curcumin and several curcumin analogs on P-glycoprotein function and expression, emphasizing the potential of these molecules for the possible development of safe and effective inhibitors of P-gp to overcome MDR in human cancer.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Due to an aging population and illnesses related to current lifestyles, health-related concerns are becoming increasingly more important. Moreover, today's society is more aware of the potential side ...effects of medicines and is looking for innovative therapeutic alternatives. Hence, the use of natural compounds in the prevention of various diseases and health maintenance has been studied. Among the natural products studied are mushrooms, which are well known for their nutritional value and health-promoting properties. These have been considered as both functional foods and a source of nutraceuticals.
The present review is aimed at collecting and critically examining current data on the bioactive properties of mushrooms as well as their classification as functional foods and source of nutraceuticals. It also intended to describe the state of the art regarding mushroom formulations currently available on the market, and to highlight what could be done to improve this market in order to make a variety of quality and duly-certified products that promote human well-being available.
Mushrooms are natural matrices of excellence. Their bioactivity has been proved and therefore, their incorporation in foods has been studied. However, these new food products have not yet gone to market and most of the mushrooms and their compounds are mainly consumed in their natural form or in dietary supplements. Despite interest in such products having grown over the years, in Western countries, mushroom products are not as common as in Asia and legislation needs to be implemented to permit an increase in their consumption.
•Mushrooms are natural matrices of excellence, given their bioactive potential.•Their incorporation in foods allows the obtaining of new functional foods.•Mushrooms are consumed mostly in their natural form or in dietary supplements (DSs).•Mushroom intake through diverse formulations is an area that needs further expansion.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Multiple myeloma (MM) is the second most common blood cancer. Treatments for MM include corticosteroids, alkylating agents, anthracyclines, proteasome inhibitors, immunomodulatory drugs, histone ...deacetylase inhibitors and monoclonal antibodies. Survival outcomes have improved substantially due to the introduction of many of these drugs allied with their rational use. Nonetheless, MM patients successively relapse after one or more treatment regimens or become refractory, mostly due to drug resistance. This review focuses on the main drugs used in MM treatment and on causes of drug resistance, including cytogenetic, genetic and epigenetic alterations, abnormal drug transport and metabolism, dysregulation of apoptosis, autophagy activation and other intracellular signaling pathways, the presence of cancer stem cells, and the tumor microenvironment. Furthermore, we highlight the areas that need to be further clarified in an attempt to identify novel therapeutic targets to counteract drug resistance in MM patients.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
SARS-CoV-2 Spike protein was predicted by molecular docking to bind the host cell surface GRP78, which was suggested as a putative good molecular target to inhibit Covid-19. We aimed to confirm that ...GRP78 gene expression was increased in blood of SARS-CoV-2 (+) versus SARS-CoV-2 (-) pneumonia patients. In addition, we aimed to identify drugs that could be repurposed to inhibit GRP78, thus with potential anti-SARS-CoV-2 activity. Gene expression studies were performed in 10 SARS-CoV-2 (-) and 24 SARS-CoV-2 (+) pneumonia patients. A structure-based virtual screen was performed with 10,761 small molecules retrieved from DrugBank, using the GRP78 nucleotide binding domain and substrate binding domain as molecular targets. Results indicated that GRP78 mRNA levels were approximately four times higher in the blood of SARS-CoV-2 (+) versus SARS-CoV-2 (-) pneumonia patients, further suggesting that GRP78 might be a good molecular target to treat Covid-19. In addition, a total of 409 compounds were identified with potential as GRP78 inhibitors. In conclusion, we found preliminary evidence that further proposes GRP78 as a possible molecular target to treat Covid-19 and that many clinically approved drugs bind GRP78 as an off-target effect. We suggest that further work should be urgently carried out to confirm if GRP78 is indeed a good molecular target and if some of those drugs have potential to be repurposed for SARS-CoV-2 antiviral activity.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cancer-derived extracellular vesicles (EVs) have been detected in the bloodstream and other biofluids of cancer patients. They carry various tumor-derived molecules such as mutated DNA and RNA ...fragments, oncoproteins as well as miRNA and protein signatures associated with various phenotypes. The molecular cargo of EVs partially reflects the intracellular status of their cellular origin, however various sorting mechanisms lead to the enrichment or depletion of EVs in specific nucleic acids, proteins or lipids. It is becoming increasingly clear that cancer-derived EVs act in a paracrine and systemic manner to promote cancer progression by transferring aggressive phenotypic traits and drug-resistant phenotypes to other cancer cells, modulating the anti-tumor immune response, as well as contributing to remodeling the tumor microenvironment and formation of pre-metastatic niches. These findings have raised the idea that cancer-derived EVs may serve as analytes in liquid biopsies for real-time monitoring of tumor burden and drug resistance. In this review, we have summarized recent longitudinal clinical studies describing promising EV-associated biomarkers for cancer progression and tracking cancer evolution as well as pre-clinical and clinical evidence on the relevance of EVs for monitoring the emergence or progression of drug resistance. Furthermore, we outlined the state-of-the-art in the development and commercialization of EV-based biomarkers and discussed the scientific and technological challenges that need to be met in order to translate EV research into clinically applicable tools for precision medicine.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Curative cancer therapy remains a major challenge particularly in cancers displaying multidrug resistance (MDR). The MDR phenotype is characterized by cross-resistance to a wide array of anticancer ...drugs harboring distinct structures and mechanisms of action. The multiple factors involved in mediating MDR may include host factors, tumor factors as well as tumor-host interactions. Among the host factors are genetic variants and drug-drug interactions. The plethora of tumor factors involves decreased drug uptake primarily via impaired influx transporters, increased drug efflux predominantly due to the overexpression of MDR efflux transporters of the ATP-binding cassette superfamily or due to drug efflux mediated by extracellular vesicles (EVs) or drug-loaded lysosomes undergoing exocytosis, deregulation of cell death mechanisms (i.e. anti-apoptotic modalities), enhanced DNA damage repair, epigenetic alterations and/or deregulation of microRNAs. The intratumor heterogeneity and dynamics, along with cancer stem cell plasticity, are important tumor factors. Among the tumor-host interactions are the role of the tumor microenvironment, selective pressure of various stressor conditions and agents, acidic pH and the intracellular transfer of traits mediated by EVs. The involvement of these diverse factors in MDR, highlights the need for precision medicine and real-time personalized treatments of individual cancer patients. In this review, written by a group of researchers from COST Action STRATAGEM “New diagnostic and therapeutic tools against multidrug resistant tumors”, we aim to bring together these multidisciplinary and interdisciplinary features of MDR cancers. Importantly, it is becoming increasingly clear that deciphering the molecular mechanisms underlying anticancer drug resistance, will pave the way towards the development of novel precision medicine treatment modalities that are able to surmount distinct and well-defined mechanisms of anticancer drug resistance.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tumour-associated macrophages have been implicated in pancreatic ductal adenocarcinoma (PDAC) therapy response and Extracellular vesicles (EVs) shed by macrophages might have a role in this process. ...Here, we demonstrated that large EVs released by anti-inflammatory human macrophages decreased PDAC cellular sensitivity to gemcitabine. Using proteomic analysis, chitinase 3-like-1 (CHI3L1) and fibronectin (FN1) were identified as two of the most abundant proteins in the cargo of macrophages-derived EVs. Overexpression of CHI3L1 and FN1, using recombinant human proteins, induced PDAC cellular resistance to gemcitabine through ERK (extracellular-signal-regulated kinase) activation. Inhibition of CHI3L1 and FN1 by pentoxifylline and pirfenidone, respectively, partially reverted gemcitabine resistance. In PDAC patient samples, CHI3L1 and FN1 were expressed in the stroma, associated with the high presence of macrophages. The Cancer Genome Atlas analysis revealed an association between CHI3L1 and FN1 gene expression, overall survival of PDAC patients, gemcitabine response, and macrophage infiltration. Altogether, our data identifies CHI3L1 and FN1 as potential targets for pharmacological inhibition in PDAC. Further pre-clinical in vivo work is warranted to study the possibility of repurposing pentoxifylline and pirfenidone as adjuvant therapies for PDAC treatment.
•CHI3L1 and FN1: the most abundant cargo proteins released by human macrophage EVs.•Both CHI3L1 and FN1 cause PDAC resistance to gemcitabine through the ERK signalling.•Pentoxifylline and Pirfenidone revert CHI3L1 and FN1 induced gemcitabine resistance.•CHI3L1 and FN1 are expressed in PDAC macrophage-enriched stroma.•The genes CHI3L1 and FN1 are associated with low overall survival of PDAC patients.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Overexpression of oncomiR-21 has been observed in most cancer types, such as leukemia. This miR has been implicated in a number of cellular processes, including chemoresistance, possibly by directly ...modulating the expression of several apoptotic related proteins. It was recently shown to directly target Bcl-2 mRNA and upregulate Bcl-2 protein expression. Nevertheless, the possible effect of miR-21 in autophagy has never been addressed. This study investigates the effects of targeting miR-21 with antimiRs on chronic myeloid leukemia cellular autophagy and on associated drug sensitivity. We observed that miR-21 downregulation decreased cellular viability and proliferation, although no changes to the normal cell cycle profile were observed. miR-21 downregulation also caused increased programmed cell death and a decrease in the expression levels of Bcl-2 protein, although PARP cleavage was not affected, indicating that apoptosis was not the relevant mechanism underlying the observed results. Treatment with antimiR-21 caused an increase in the autophagy related proteins Beclin-1, Vps34 and LC3-II. Accordingly, autophagic vacuoles were visualized both by monodansylcadaverine (MDC) and acridine orange (AO) staining and also by transmission electron microscopy (TEM). Additionally, miR-21 downregulation increased K562 and KYO-1 cellular sensitivity to etoposide or doxorubicin. This chemosensitivity was reverted by pre-treating cells with 3-MA, an autophagy inhibitor. Finally, serum starvation (an autophagy inducer) also increased sensitivity to these drugs, confirming that autophagy sensitized these cells to the effect of these drugs. To the best of our knowledge, this is the first description of autophagy induction via miR-21 targeting and its involvement in drug sensitivity.
This review aims to contribute to the knowledge on bioactivity (antioxidant, antitumor and antimicrobial properties) of polysaccharides, glycoproteins and polysaccharidic extracts obtained from ...Ganoderma species. The chemical features were analyzed and related with the correspondent bioactivity. Display omitted
•Chemical features of Ganoderma bioactive polysaccharides were discussed.•Methods for extraction, isolation and identification were evaluated.•Bioactivity of polysaccharidic extracts and purified compounds are discussed.•Integration of data allowed deduction of structure–activity relationships.
Ganoderma genus comprises one of the most commonly studied species worldwide, Ganoderma lucidum. However, other Ganoderma species have been also reported as important sources of bioactive compounds. Polysaccharides are important contributors to the medicinal properties reported for Ganoderma species, as demonstrated by the numerous publications, including reviews, on this matter. Yet, what are the chemical features of Ganoderma polysaccharides that have bioactivity? In the present manuscript, the chemical features of Ganoderma polysaccharides with reported antioxidant, antitumor and antimicrobial activities (the most studied worldwide) are analyzed in detail. The composition of sugars (homo- versus hetero-glucans and other polysaccharides), type of glycosidic linkages, branching patterns, and linkage to proteins are discussed. Methods for extraction, isolation and identification are evaluated and, finally, the bioactivity of polysaccharidic extracts and purified compounds are discussed. The integration of data allows deduction of structure–activity relationships and gives clues to the chemical aspects involved in Ganoderma bioactivity.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Extracellular vesicles (EVs) are nanosized particles (100–1000 nm) enclosed by a phospholipid bilayer that have been described as important mediators of intercellular communication. The role of EVs ...in oncobiology has been extensively studied, including their contribution to the horizontal transfer of drug resistance from drug-resistant to drug-sensitive cancer cells. This review focuses on the EVs cargo responsible for this intercellular transfer of drug resistance; namely, drug-efflux pumps, miRNAs, long noncoding RNAs (lncRNAs), and other mediators. Additionally, the known molecular mechanisms and features of this transfer are discussed. This is an emerging area of research and we highlight topics that need to be further studied to fully understand and counteract the intercellular transfer of drug resistance mediated by EVs.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
PDF
