Publications by authors named "Chiara Riganti"

168 Publications

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons.

J Exp Clin Cancer Res 2021 Jan 11;40(1):28. Epub 2021 Jan 11.

Department of Oncology, University of Torino, via Santena 5/bis, 10126, Torino, Italy.

Solid tumors often grow in a micro-environment characterized by < 2% O tension. This condition, together with the aberrant activation of specific oncogenic patwhays, increases the amount and activity of the hypoxia-inducible factor-1α (HIF-1α), a transcription factor that controls up to 200 genes involved in neoangiogenesis, metabolic rewiring, invasion and drug resistance. Hypoxia also induces endoplasmic reticulum (ER) stress, a condition that triggers cell death, if cells are irreversibly damaged, or cell survival, if the stress is mild.Hypoxia and chronic ER stress both induce chemoresistance. In this review we discuss the multiple and interconnected circuitries that link hypoxic environment, chronic ER stress and chemoresistance. We suggest that hypoxia and ER stress train and select the cells more adapted to survive in unfavorable conditions, by activating pleiotropic mechanisms including apoptosis inhibition, metabolic rewiring, anti-oxidant defences, drugs efflux. This adaptative process unequivocally expands clones that acquire resistance to chemotherapy.We believe that pharmacological inhibitors of HIF-1α and modulators of ER stress, although characterized by low specificty and anti-cancer efficacy when used as single agents, may be repurposed as chemosensitizers against hypoxic and chemorefractory tumors in the next future.
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http://dx.doi.org/10.1186/s13046-020-01824-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798239PMC
January 2021

NAMPT Over-Expression Recapitulates the BRAF Inhibitor Resistant Phenotype Plasticity in Melanoma.

Cancers (Basel) 2020 Dec 20;12(12). Epub 2020 Dec 20.

Cancer Immunogenetics Lab, Department of Medical Sciences, University of Turin, 10126 Turin, Italy.

Serine-threonine protein kinase B-RAF -mutated metastatic melanoma (MM) is a highly aggressive type of skin cancer. Treatment of MM patients using BRAF/MEK inhibitors (BRAFi/MEKi) eventually leads to drug resistance, limiting any clinical benefit. Herein, we demonstrated that the nicotinamide adenine dinucleotide (NAD)-biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) is a driving factor in BRAFi resistance development. Using stable and inducible NAMPT over-expression systems, we showed that forced NAMPT expression in MM -mutated cell lines led to increased energy production, MAPK activation, colony-formation capacity, and enhance tumorigenicity in vivo. Moreover, NAMPT over-expressing cells switched toward an invasive/mesenchymal phenotype, up-regulating expression of ZEB1 and TWIST, two transcription factors driving the epithelial to mesenchymal transition (EMT) process. Consistently, within the NAMPT-overexpressing cell line variants, we observed an increased percentage of a rare, drug-effluxing stem cell-like side population (SP) of cells, paralleled by up-regulation of ABCC1/MRP1 expression and CD133-positive cells. The direct correlation between NAMPT expression and gene set enrichments involving metastasis, invasiveness and mesenchymal/stemness properties were verified also in melanoma patients by analyzing The Cancer Genome Atlas (TCGA) datasets. On the other hand, CRISPR/Cas9 full knock-out BRAFi-resistant MM cells are not viable, while inducible partial silencing drastically reduces tumor growth and aggressiveness. Overall, this work revealed that NAMPT over-expression is both necessary and sufficient to recapitulate the BRAFi-resistant phenotype plasticity.
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http://dx.doi.org/10.3390/cancers12123855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766175PMC
December 2020

Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance.

Cells 2020 Dec 4;9(12). Epub 2020 Dec 4.

Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy.

Hypoxia is a condition commonly observed in the core of solid tumors. The hypoxia-inducible factors (HIF) act as hypoxia sensors that orchestrate a coordinated response increasing the pro-survival and pro-invasive phenotype of cancer cells, and determine a broad metabolic rewiring. These events favor tumor progression and chemoresistance. The increase in glucose and amino acid uptake, glycolytic flux, and lactate production; the alterations in glutamine metabolism, tricarboxylic acid cycle, and oxidative phosphorylation; the high levels of mitochondrial reactive oxygen species; the modulation of both fatty acid synthesis and oxidation are hallmarks of the metabolic rewiring induced by hypoxia. This review discusses how metabolic-dependent factors (e.g., increased acidification of tumor microenvironment coupled with intracellular alkalinization, and reduced mitochondrial metabolism), and metabolic-independent factors (e.g., increased expression of drug efflux transporters, stemness maintenance, and epithelial-mesenchymal transition) cooperate in determining chemoresistance in hypoxia. Specific metabolic modifiers, however, can reverse the metabolic phenotype of hypoxic tumor areas that are more chemoresistant into the phenotype typical of chemosensitive cells. We propose these metabolic modifiers, able to reverse the hypoxia-induced metabolic rewiring, as potential chemosensitizer agents against hypoxic and refractory tumor cells.
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http://dx.doi.org/10.3390/cells9122598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761956PMC
December 2020

Joining European Scientific Forces to Face Pandemics.

Trends Microbiol 2021 02 4;29(2):92-97. Epub 2020 Dec 4.

Department of Oncology, University of Turin, IT-10126, Turin, Italy. Electronic address:

Despite the international guidelines on the containment of the coronavirus disease 2019 (COVID-19) pandemic, the European scientific community was not sufficiently prepared to coordinate scientific efforts. To improve preparedness for future pandemics, we have initiated a network of nine European-funded Cooperation in Science and Technology (COST) Actions that can help facilitate inter-, multi-, and trans-disciplinary communication and collaboration.
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http://dx.doi.org/10.1016/j.tim.2020.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716745PMC
February 2021

Impedance-based drug-resistance characterization of colon cancer cells through real-time cell culture monitoring.

Talanta 2021 Jan 25;222:121441. Epub 2020 Aug 25.

Department of Electronics and Telecommunications (DET), Politecnico di Torino, Turin, Italy.

Interest in impedance-based cellular assays is rising due to their remarkable advantages, including label-free, low cost, non-invasive, non-destructive, quantitative and real-time monitoring. In order to test their potential in cancer treatment decision and early detection of chemoresistance, we devised a new custom-made impedance measuring system based on electric cell-substrate impedance sensing (ECIS), optimized for long term impedance measurements. This device was employed in a proof of concept cell culture impedance analysis for the characterization of chemo-resistant colon cancer cells. Doxorubicin-resistant HT-29 cells were used for this purpose and monitored for 140 h. Analysis of impedance-based curves reveal different trends from chemo-sensitive and chemo-resistant cells. An impedance-based cytoxicity assay with different concentrations of doxorubicin was also performed using ECIS. The obtained results confirm the feasibility of ECIS in the study of drug resistance and show promises for studies of time-dependent factors related to physiological and behavioral changes in cells during resistance acquisition. The methodology presented herein, allows the continuous monitoring of cells under normal culture conditions as well as upon drug exposure. The ECIS device used, sets the basis for high-throughput early detection of resistance to drugs, administered in the clinical practice to cancer patients, and for the screening of new drugs in vitro, on patient-derived cells.
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http://dx.doi.org/10.1016/j.talanta.2020.121441DOI Listing
January 2021

Cholesterol metabolism: At the cross road between cancer cells and immune environment.

Int J Biochem Cell Biol 2020 Dec 6;129:105876. Epub 2020 Nov 6.

Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy. Electronic address:

Mevalonate pathway is a highly conserved pathway that produces isoprenoids and cholesterol, and it is often increased in cancer cells. Cholesterol, upstream metabolites including isoprenoids and cholesterol derivatives such as oxysterols modulate cell proliferation, motility, stemness and drug resistance. Moreover, when produced by cancer cells or immune infiltrating cells, they modulate the activity of immune populations of the tumor microenvironment. In this review, we will focus on the recent findings demonstrating that cholesterol derivatives may regulate tumor immune recognition or immune escape, playing a critical role in the immune surveillance. Since the mevalonate pathway is druggable, a deeper knowledge of the metabolic cross talks existing between the mevalonate pathway of cancer cells and immune cells may help to identify novel agents targeting cholesterol metabolism, able to boost the anti-tumor activity of the immune populations.
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http://dx.doi.org/10.1016/j.biocel.2020.105876DOI Listing
December 2020

Calcitriol Inhibits Viability and Proliferation in Human Malignant Pleural Mesothelioma Cells.

Front Endocrinol (Lausanne) 2020 8;11:559586. Epub 2020 Oct 8.

Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy.

Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor, often associated with exposure to asbestos and characterized by poor prognosis and limited treatment options. The biologically active form of vitamin D, calcitriol, exerts anticancer effects in many cell types, both alone and in combination with chemotherapy drugs, through binding to vitamin D receptor (VDR); however, the role of calcitriol in MPM is still unknown. This study aimed to determine the potential antitumor role of calcitriol in MPM. The results showed that calcitriol reduces cell viability and proliferation in human MPM cells lines, which express both cytoplasmic and nuclear VDR; furthermore, calcitriol potentiated the inhibitory activity of the chemotherapy drug PEM. These effects were paralleled by cell cycle arrest and inhibition in expression of c-Myc and cyclins involved in cell cycle progression. Exposure of MPM cells to calcitriol also produced an alteration in mitochondrial function and inhibition in the expression of respiratory chain complex subunits. Finally, the inhibitory effects of calcitriol were also observed on viability of human primary MPM cells. Collectively, these results indicate a novel anticancer role for calcitriol in MPM, suggesting potential for vitamin D derivatives, alone or in combination with chemotherapy, in the treatment of this malignancy.
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http://dx.doi.org/10.3389/fendo.2020.559586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579995PMC
October 2020

Induced expression of P-gp and BCRP transporters on brain endothelial cells using transferrin functionalized nanostructured lipid carriers: A first step of a potential strategy for the treatment of Alzheimer's disease.

Int J Pharm 2020 Dec 22;591:120011. Epub 2020 Oct 22.

Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", Orabona St. 4, 70125 Bari, Italy. Electronic address:

P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are two transporters expressed in human neural stem/progenitor cells and at the Blood-Brain Barrier (BBB) level with decreased activity in the early stage of Alzheimer's disease (AD). Both proteins, have a protective role for the embryonic stem cells in the early developmental step, maintaining them in an undifferentiated state, and limit the access of exogenous and endogenous agents to the brain. Recently, MC111 selected from a P-gp/BCRP ligands library was investigated as multitarget strategy for AD treatment, considering its ability to induce the expression and activity of both proteins. However, MC111 clinical use could be limited for the ubiquitous physiological expression of efflux transporters and its moderate toxicity towards endothelial cells. Therefore, a selective MC111 delivery system based on nanostructured lipid carriers (NLC) functionalized with transferrin were developed. The results proved the formation of NLC with average size about 120 nm and high drug encapsulation efficiency (EE% greater than 50). In vitro studies on hCMEC/D3 cells revealed that the MC111 was selectively released by NLC at BBB level and then inducing the activity and expression of BCRP and P-gp, involved in the clearance of amyloid β peptide on brain endothelial cells.
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http://dx.doi.org/10.1016/j.ijpharm.2020.120011DOI Listing
December 2020

One molecule two goals: A selective P-glycoprotein modulator increases drug transport across gastro-intestinal barrier and recovers doxorubicin toxicity in multidrug resistant cancer cells.

Eur J Med Chem 2020 Dec 17;208:112843. Epub 2020 Sep 17.

Dipartimento di Farmacia-Scienze Del Farmaco, Università Degli Studi di Bari ALDO MORO, Via Orabona 4, 70125, Bari, Italy; Biofordrug s.r.l., Spin-off Dell'Università Degli Studi di Bari ALDO MORO, Via Orabona 4, 70125, Bari, Italy.

In the present study a series of tetrahydroisoquinoline derivatives were synthesized and evaluated for their activity towards three ABC transporters, P-gp, MRP1 and BCRP. The compounds proved to be selective against P-gp. One of them, 8b, displayed activity in the nanomolar range (EC = 94 nM). Thus, compound 8b was tested for its ability to restore the cytotoxic activity of a well-known anti-cancer agent and P-gp substrate, doxorubicin, as first proof of concept. Moreover, compound 8b was also tested in an in vitro model of competent gastro-intestinal (GI) barrier (Caco-2 cells) for its ability to inhibit P-gp, present on luminal side, and increase the apical-to-basolateral transport of several structurally uncorrelated drugs, belonging to different therapeutic areas but actively excreted by P-gp. Notably the transport of the drugs across the GI barrier was increased by a concentration of 8b devoid of toxicity and of perturbing effects on barrier function. An in vitro simulated digestion process was set up: interestingly the effect of 8b on the transport of digoxin was preserved also after the simulated digestion process. This result may suggest 8b as a safe and effective P-gp modulator that can increase the bioavailability of a wide spectrum of drugs administered per os, improving their transport across the GI barrier.
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http://dx.doi.org/10.1016/j.ejmech.2020.112843DOI Listing
December 2020

Synthesis of defined oligohyaluronates-decorated liposomes and interaction with lung cancer cells.

Carbohydr Polym 2020 Nov 21;248:116798. Epub 2020 Jul 21.

Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources CNRS UMR 7378, Université de Picardie Jules Verne, 33 rue Saint Leu, 80039 Amiens, France. Electronic address:

In this work hyaluronic acid (HA) oligosaccharides with degree of polymerization (DP) 4, 6 and 8, obtained by enzymatic depolymerization of HA, were conjugated to a PEG-phospholipid moiety. The products (HA-DP4, HA-DP6 and HA-DP8) were used to prepare decorated liposomes. The cellular uptake of HA-DP4, HA-DP6 and HA-DP8-decorated fluorescently labelled liposomes was significantly higher (12 to 14-fold) in lung cancer cell lines with high CD44 expression than in those with low CD44 expression, suggesting a receptor-mediated entry of HA-conjugated formulations. Competition assays showed that the uptake followed this rank order: HA-DP8>HA-DP6>HA-DP4 liposomes. Moreover, they are capable of a faster interaction with CD44, followed by phagocytosis, than HA liposomes obtained from HA of higher molecular weight (4800 and 14800 Da). HA-DP4, HA-DP6 and HA-DP8-liposomes did not show cytotoxicity or inflammatory effects. Overall, we propose our new HA-DP oligosaccharides as biocompatible and effective tools for a potential drug delivery to CD44-positive cells.
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http://dx.doi.org/10.1016/j.carbpol.2020.116798DOI Listing
November 2020

MRP5 nitration by NO-releasing gemcitabine encapsulated in liposomes confers sensitivity in chemoresistant pancreatic adenocarcinoma cells.

Biochim Biophys Acta Mol Cell Res 2020 12 21;1867(12):118824. Epub 2020 Aug 21.

Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Italy. Electronic address:

Pancreatic ductal adenocarcinoma (PDAC) is a therapy recalcitrant disease characterized by the aberrations in multiple genes that drive pathogenesis and drug chemoresistance. In this study, we synthesize a library of seven novel nitric oxide-releasing gemcitabine pro-drugs (NO-GEMs) in order to improve the effectiveness of GEM by exploiting the therapeutic effects of NO. Among these NO-GEM pro-drugs we select 5b as the most effective compound in GEM-resistant PDAC cells. After its encapsulation in liposomes for drug delivery the intracellular NO level increases and nitration associated to activity inhibition of the multidrug resistance associated protein 5 (MRP5; ABCC5) occurs. This results in GEM intracellular accumulation and enhanced apoptotic cell death in GEM-resistant PDAC cells, which express MRP5 at higher levels than GEM-sensitive cells. Our results support the development of a new anti-tumoral strategy to efficiently affect GEM-resistant PDAC cells based on the usage of NO-GEM pro-drugs.
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http://dx.doi.org/10.1016/j.bbamcr.2020.118824DOI Listing
December 2020

Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma.

Int J Mol Sci 2020 Jun 24;21(12). Epub 2020 Jun 24.

Department of Oncology, University of Torino, 1026 Torino, Italy.

Doxorubicin (Dox) is one of the most important first-line drugs used in osteosarcoma therapy. Multiple and not fully clarified mechanisms, however, determine resistance to Dox. With the aim of identifying new markers associated with Dox-resistance, we found a global up-regulation of small nucleolar RNAs (snoRNAs) in human Dox-resistant osteosarcoma cells. We investigated if and how snoRNAs are linked to resistance. After RT-PCR validation of snoRNAs up-regulated in osteosarcoma cells with different degrees of resistance to Dox, we overexpressed them in Dox-sensitive cells. We then evaluated Dox cytotoxicity and changes in genes relevant for osteosarcoma pathogenesis by PCR arrays. SNORD3A, SNORA13 and SNORA28 reduced Dox-cytotoxicity when over-expressed in Dox-sensitive cells. In these cells, GADD45A and MYC were up-regulated, TOP2A was down-regulated. The same profile was detected in cells with acquired resistance to Dox. GADD45A/MYC-silencing and TOP2A-over-expression counteracted the resistance to Dox induced by snoRNAs. We reported for the first time that snoRNAs induce resistance to Dox in human osteosarcoma, by modulating the expression of genes involved in DNA damaging sensing, DNA repair, ribosome biogenesis, and proliferation. Targeting snoRNAs or down-stream genes may open new treatment perspectives in chemoresistant osteosarcomas.
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http://dx.doi.org/10.3390/ijms21124500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349977PMC
June 2020

In vitro vascular toxicity assessment of NitDOX, a novel NO-releasing doxorubicin.

Eur J Pharmacol 2020 Aug 11;880:173164. Epub 2020 May 11.

Dipartimento di Scienze della Vita, Università di Siena, Siena, Italy. Electronic address:

The conjugation of doxorubicin (DOX) with nitric oxide (NO)-releasing groups gave rise to novel anthracyclines, such as nitrooxy-DOX (NitDOX), capable to overcome multidrug resistance. The widely described anthracycline cardiovascular toxicity, however, might limit their clinical use. This study aimed to investigate NitDOX-induced effects, as potential hazard, on vascular smooth muscle A7r5 and endothelial EA.hy926 cell viability, on the mechanical activity of freshly and cultured rat aorta rings, as well as on Ca1.2 channels of A7r5 cells. DOX was used as a reference compound. Although an increase in intracellular radicals and a reduction in mitochondrial potential occurred upon treatment with both drugs, A7r5 and EA.hy926 cells proved to be more sensitive to DOX than to NitDOX. Both compounds promoted comparable effects in A7r5 cells, whereas NitDOX was less active than DOX in inducing DNA damage and in eliciting apoptotic-mediated cell death revealed as an increase in sub-diploid-, DAPI- and annexin V-positive- EA.hy926 cell percentage. Moreover, in EA.hy926 cells, NitDOX doubled basal NO content, while preincubation with the NO-scavenger PTIO increased NitDOX-induced cytotoxicity. DOX exhibited a negligible contracturing effect in endothelium-intact rings, while NitDOX induced a significant ODQ-sensible, vasodilation in endothelium-denuded rings. In arteries cultured with both drugs for 7 days, NitDOX prevented either phenylephrine- or KCl-induced contraction at a concentration 10-fold higher than that of DOX. These results demonstrate that NitDOX displays a more favourable vascular toxicity profile than DOX. Taking into account its greater efficacy against drug-resistant cells, NitDOX is worth of further investigations in preclinical and clinical settings.
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http://dx.doi.org/10.1016/j.ejphar.2020.173164DOI Listing
August 2020

MRP1-Collateral Sensitizers as a Novel Therapeutic Approach in Resistant Cancer Therapy: An In Vitro and In Vivo Study in Lung Resistant Tumor.

Int J Mol Sci 2020 May 8;21(9). Epub 2020 May 8.

Department of Pharmacy-Drug Sciences, University of Bari "A. Moro", Via Orabona 4, 70125 Bari, Italy.

Multidrug resistance (MDR) is the main obstacle to current chemotherapy and it is mainly due to the overexpression of some efflux transporters such as MRP1. One of the most studied strategies to overcome MDR has been the inhibition of MDR pumps through small molecules, but its translation into the clinic unfortunately failed. Recently, a phenomenon called collateral sensitivity (CS) emerged as a new strategy to hamper MDR acting as a synthetic lethality, where the genetic changes developed upon the acquisition of resistance towards a specific agent are followed by the development of hypersensitivity towards a second agent. Among our library of sigma ligands acting as MDR modulators, we identified three compounds, , , and acting as CS-promoting agents. We deepened their CS mechanisms in the "pure" model of MRP1-expressing cells (MDCK-MRP1) and in MRP1-expressing/drug resistant non-small cell lung cancer cells (A549/DX). The in vitro results demonstrated that (i) the three ligands are highly cytotoxic for MRP1-expressing cells; (ii) their effect is MRP1-mediated; (iii) they increase the cytotoxicity induced by cis-Pt, the therapeutic agent commonly used in the treatment of lung tumors; and (iv) their effect is ROS-mediated. Moreover, a preclinical in vivo study performed in lung tumor xenografts confirms the in vitro findings, making the three CS-promoting agents candidates for a novel therapeutic approach in lung resistant tumors.
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http://dx.doi.org/10.3390/ijms21093333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247425PMC
May 2020

Insights into P-Glycoprotein Inhibitors: New Inducers of Immunogenic Cell Death.

Cells 2020 04 22;9(4). Epub 2020 Apr 22.

Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy.

Doxorubicin is a strong inducer of immunogenic cell death (ICD), but it is ineffective in P-glycoprotein (Pgp)-expressing cells. Indeed, Pgp effluxes doxorubicin and impairs the immunesensitizing functions of calreticulin (CRT), an "eat-me" signal mediating ICD. It is unknown if classical Pgp inhibitors, designed to reverse chemoresistance, may restore ICD. We addressed this question by using Pgp-expressing cancer cells, treated with Tariquidar, a clinically approved Pgp inhibitor, and -3 compound, a ,-bis(alkanol)amine aryl ester derivative with the same potency of Tariquidar as Pgp inhibitor. In Pgp-expressing/doxorubicin-resistant cells, Tariquidar and -3 increased doxorubicin accumulation and toxicity, reduced Pgp activity, and increased CRT translocation and ATP and HMGB1 release. Unexpectedly, only -3 promoted phagocytosis by dendritic cells and activation of antitumor CD8T-lymphocytes. Although Tariquidar did not alter the amount of Pgp present on cell surface, -3 promoted Pgp internalization and ubiquitination, disrupting its interaction with CRT. Pgp knock-out restores doxorubicin-induced ICD in MDA-MB-231/DX cells that recapitulated the phenotype of -3-treated cells. Our work demonstrates that plasma membrane-associated Pgp prevents a complete ICD notwithstanding the release of ATP and HMGB1, and the exposure of CRT. Pharmacological compounds reducing Pgp activity and amount may act as promising chemo- and immunesensitizing agents.
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http://dx.doi.org/10.3390/cells9041033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226521PMC
April 2020

Searching the Link for Better Therapeutic Combination: The Case of Tumor Cells Migration Pattern and Modality of Immunosuppression Induction at the Metastatic Site.

Cureus 2020 Mar 21;12(3):e7353. Epub 2020 Mar 21.

Oncology, University of Torino, Torino, ITA.

Cancer is a disease characterized by its high morbidity and mortality, mainly due to its metastatic ability. Metastasis is a multi-step process beginning with detachment of tumor cells from the primary tumor and leading ultimately to the establishment of a new tumoral site. This cascade includes intravascular migration of tumor cells either individually or collectively and the expansion of cancer cells at metastatic sites that is dependent on certain conditions such as an immunosuppressive environment. In this paper, blockers of tumor cell migration and suppressors of immunotolerance at metastatic sites are reviewed as an illustration of early and later phases intervention, respectively. A combination of these two therapeutics will be advocated based on the proposition of correlation between the pattern of tumor cell migration and the mechanism of immunotolerance induction. By extension, the ''delayed complementarity'' will be introduced as an approach to formulate new anticancer drug combinations.
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http://dx.doi.org/10.7759/cureus.7353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170019PMC
March 2020

Overcoming Doxorubicin Resistance with Lipid-Polymer Hybrid Nanoparticles Photoreleasing Nitric Oxide.

Mol Pharm 2020 06 27;17(6):2135-2144. Epub 2020 Apr 27.

Laboratory of Photochemistry, Department of Drug Sciences, University of Catania, Viale Andrea Doria 6, I-95125 Catania, Italy.

We report on tailored lipid-polymer hybrid nanoparticles (NPs) delivering nitric oxide (NO) under the control of visible light as a tool for overcoming doxorubicin (DOX) resistance. The NPs consist of a polymeric core and a coating. They are appropriately designed to entrap DOX in the poly(lactide--glycolide) core and a NO photodonor (NOPD) in the phospholipid shell to avoid their mutual interaction both in the ground and excited states. The characteristic red fluorescence of DOX, useful for its tracking in cells, is well preserved upon incorporation within the NPs, even in the copresence of NOPD. The NP scaffold enhances the NO photoreleasing efficiency of the entrapped NOPD when compared with that of the free compound, and the copresence of DOX does not significantly affect such enhanced photochemical performance. Besides, the delivery of DOX and NOPD from NPs is also not mutually influenced. Experiments carried out in M14 DOX-resistant melanoma cells demonstrate that NO release from the multicargo NPs can be finely regulated by excitation with visible light, at a concentration level below the cytotoxic doses but sufficient enough to inhibit the efflux transporters mostly responsible for DOX cellular extrusion. This results in increased cellular retention of DOX with consequent enhancement of its antitumor activity. This approach, in principle, is not dependent on the type of chemotherapeutic used and may pave the way for new treatment modalities based on the photoregulated release of NO to overcome the multidrug resistance phenomenon and improve cancer chemotherapies.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00290DOI Listing
June 2020

6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline amides and corresponding ester isosteres as multidrug resistance reversers.

J Enzyme Inhib Med Chem 2020 Dec;35(1):974-992

NEUROFARBA Department, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Florence, Italy.

Aiming to deepen the structure-activity relationships of the two P-glycoprotein (P-gp) modulators elacridar and tariquidar, a new series of amide and ester derivatives carrying a 6,7-dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline scaffold linked to different methoxy-substituted aryl moieties were synthesised. The obtained compounds were evaluated for their P-gp interaction profile and selectivity towards the two other ABC transporters, multidrug-resistance-associated protein-1 and breast cancer resistance protein, showing to be very active and selective versus P-gp. Two amide derivatives, displaying the best P-gp activity, were tested in co-administration with the antineoplastic drug doxorubicin in different cancer cell lines, showing a significant sensitising activity towards doxorubicin. The investigation on the chemical stability of the derivatives towards spontaneous or enzymatic hydrolysis, showed that amides are stable in both models while some ester compounds were hydrolysed in human plasma. This study allowed us to identify two chemosensitizers that behave as non-transported substrates and are characterised by different selectivity profiles.
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http://dx.doi.org/10.1080/14756366.2020.1747449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178819PMC
December 2020

Consensus guidelines for the definition, detection and interpretation of immunogenic cell death.

J Immunother Cancer 2020 03;8(1)

Refuge Biotechnologies, Menlo Park, California, USA.

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.
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http://dx.doi.org/10.1136/jitc-2019-000337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064135PMC
March 2020

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma.

Cells 2020 03 6;9(3). Epub 2020 Mar 6.

Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy.

The ATP Binding Cassette transporter B1 (ABCB1) induces chemoresistance in osteosarcoma, because it effluxes doxorubicin, reducing the intracellular accumulation, toxicity, and immunogenic cell death induced by the drug. The ATP Binding Cassette transporter A1 (ABCA1) effluxes isopentenyl pyrophosphate (IPP), a strong activator of anti-tumor Vγ9Vδ2 T-cells. Recruiting this population may represent an alternative strategy to rescue doxorubicin efficacy in ABCB1-expressing osteosarcoma. In this work, we analyzed how ABCA1 and ABCB1 are regulated in osteosarcoma, and if increasing the ABCA1-dependent activation of Vγ9Vδ2 T-cells could be an effective strategy against ABCB1-expressing osteosarcoma. We used 2D-cultured doxorubicin-sensitive human U-2OS and Saos-2 cells, their doxorubicin-resistant sublines (U-2OS/DX580 and Saos-2/DX580), and 3D cultures of U-2OS and Saos-2 cells. DX580-sublines and 3D cultures had higher levels of ABCB1 and higher resistance to doxorubicin than parental cells. Surprisingly, they had reduced ABCA1 levels, IPP efflux, and Vγ9Vδ2 T-cell-induced killing. In these chemo-immune-resistant cells, the Ras/Akt/mTOR axis inhibits the ABCA1-transcription induced by Liver X Receptor α (LXRα); Ras/ERK1/2/HIF-1α axis up-regulates ABCB1. Targeting the farnesylation of Ras with self-assembling nanoparticles encapsulating zoledronic acid (NZ) simultaneously inhibited both axes. In humanized mice, NZ reduced the growth of chemo-immune-resistant osteosarcomas, increased intratumor necro-apoptosis, and ABCA1/ABCB1 ratio and Vγ9Vδ2 T-cell infiltration. We suggest that the ABCB1ABCA1 phenotype is indicative of chemo-immune-resistance. We propose aminobisphosphonates as new chemo-immune-sensitizing tools against drug-resistant osteosarcomas.
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http://dx.doi.org/10.3390/cells9030647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140509PMC
March 2020

Coencapsulation of disulfiram and doxorubicin in liposomes strongly reverses multidrug resistance in breast cancer cells.

Int J Pharm 2020 Apr 3;580:119191. Epub 2020 Mar 3.

Department of Drug Science and Technology, University of Torino, Via Giuria 9, 10125 Torino, Italy. Electronic address:

Disulfiram (DSF) is an inhibitor of P-glycoprotein (Pgp), the main obstacle limiting the success of doxorubicin (DOX), but it has poor solubility and stability. With the aim to overcome these limitations we prepared liposomes coencapsulating DSF and DOX (LipoDSF-DOX). Liposome stability, drugs release profile, effects on DOX cytotoxicity, Pgp activity and expression in breast cancer cells were evaluated. We observed that LipoDSF-DOX with a 1:3 weight ratio, with DSF in lipid bilayer and DOX in aqueous core, released DSF faster than DOX. LipoDSF-DOX increased DOX intracellular accumulation and cytotoxicity in Pgp-expressing breast cancer cells, with an efficacy superior to the mixture of free DSF and DOX, thanks to a differential kinetics of release of DSF and DOX when carried by liposomes. The mechanism of the increased DOX retention relied on the DSF-induced sulfhydraton of Pgp and followed by its ubiquitination. These events reduced Pgp expression and catalytic activity in LipoDSF-DOX-treated cells. Our results show that LipoDSF-DOX effectively reversed DOX resistance in Pgp-expressing breast cancer cells, exploiting the temporally different kinetics of release of DSF and DOX, optimized to decrease expression and activity of Pgp.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119191DOI Listing
April 2020

From single gene analysis to single cell profiling: a new era for precision medicine.

J Exp Clin Cancer Res 2020 Mar 5;39(1):48. Epub 2020 Mar 5.

Department of Precision Medicine, University of Campania "L. Vanvitelli", Naples and Biogem Scarl, Institute of Genetic Research, Laboratory of Precision and Molecular Oncology, Ariano Irpino, Italy.

Molecular profiling of DNA and RNA has provided valuable new insights into the genetic basis of non-malignant and malignant disorders, as well as an increased understanding of basic mechanisms that regulate human disease. Recent technological advances have enabled the analyses of alterations in gene-based structure or function in a comprehensive, high-throughput fashion showing that each tumor type typically exhibits distinct constellations of genetic alterations targeting one or more key cellular pathways that regulate cell growth and proliferation, evasion of the immune system, and other aspects of cancer behavior. These advances have important implications for future research and clinical practice in areas as molecular diagnostics, the implementation of gene or pathway-directed targeted therapy, and the use of such information to drive drug discovery. The 1st international and 32nd Annual Conference of Italian Association of Cell Cultures (AICC) conference wanted to offer the opportunity to match technological solutions and clinical needs in the era of precision medicine.
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http://dx.doi.org/10.1186/s13046-020-01549-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059661PMC
March 2020

Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells.

Biomolecules 2020 02 26;10(3). Epub 2020 Feb 26.

Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, 37134 Verona, Italy.

The tumor suppressor gene is the most frequently altered gene in tumors and an increasing number of studies highlight that mutant p53 proteins can acquire oncogenic properties, referred to as gain-of-function (GOF). Reactive oxygen species (ROS) play critical roles as intracellular messengers, regulating numerous signaling pathways linked to metabolism and cell growth. Tumor cells frequently display higher ROS levels compared to healthy cells as a result of their increased metabolism as well as serving as an oncogenic agent because of its damaging and mutational properties. Several studies reported that in contrast with the wild type protein, mutant p53 isoforms fail to exert antioxidant activities and rather increase intracellular ROS, driving a pro-tumorigenic survival. These pro-oxidant oncogenic abilities of GOF mutant p53 include signaling and metabolic rewiring, as well as the modulation of critical ROS-related transcription factors and antioxidant systems, which lead ROS unbalance linked to tumor progression. The studies summarized here highlight that GOF mutant p53 isoforms might constitute major targets for selective therapeutic intervention against several types of tumors and that ROS enhancement driven by mutant p53 might represent an "Achilles heel" of cancer cells, suggesting pro-oxidant drugs as a therapeutic approach for cancer patients bearing the mutant gene.
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http://dx.doi.org/10.3390/biom10030361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175157PMC
February 2020

Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells.

Pharmaceutics 2020 Jan 24;12(2). Epub 2020 Jan 24.

Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy.

Multidrug resistance (MDR) is a critical hindrance to the success of cancer chemotherapy. The main thing responsible for MDR phenotypes are plasma-membranes associated with adenosine triphosphate (ATP) Binding Cassette (ABC) drug efflux transporters, such as the P-glycoprotein (Pgp) transporter that has the broadest spectrum of substrates. Curcumin (CURC) is a Pgp inhibitor, but it is poorly soluble and bioavailable. To overcome these limitations, we validated the efficacy and safety of CURC, loaded in biocompatible solid lipid nanoparticles (SLNs), with or without chitosan coating, with the goal of increasing the stability, homogeneous water dispersibility, and cellular uptake. Both CURC-loaded SLNs were 5-10-fold more effective than free CURC in increasing the intracellular retention and toxicity of doxorubicin in Pgp-expressing triple negative breast cancer (TNBC). The effect was due to the decrease of intracellular reactive oxygen species, consequent inhibition of the Akt/IKKα-β/NF-kB axis, and reduced transcriptional activation of the Pgp promoter by p65/p50 NF-kB. CURC-loaded SLNs also effectively rescued the sensitivity to doxorubicin against drug-resistant TNBC tumors, without signs of systemic toxicity. These results suggest that the combination therapy, based on CURC-loaded SLNs and doxorubicin, is an effective and safe approach to overcome the Pgp-mediated chemoresistance in TNBC.
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http://dx.doi.org/10.3390/pharmaceutics12020096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076516PMC
January 2020

A regulatory microRNA network controls endothelial cell phenotypic switch during sprouting angiogenesis.

Elife 2020 Jan 24;9. Epub 2020 Jan 24.

Department of Oncology, University of Turin, Candiolo, Italy.

Angiogenesis requires the temporal coordination of the proliferation and the migration of endothelial cells. Here, we investigated the regulatory role of microRNAs (miRNAs) in harmonizing angiogenesis processes in a three-dimensional in vitro model. We described a microRNA network which contributes to the observed down- and upregulation of proliferative and migratory genes, respectively. Global analysis of miRNA-target gene interactions identified two sub-network modules, the first organized in upregulated miRNAs connected with downregulated target genes and the second with opposite features. miR-424-5p and miR-29a-3p were selected for the network validation. Gain- and loss-of-function approaches targeting these microRNAs impaired angiogenesis, suggesting that these modules are instrumental to the temporal coordination of endothelial migration and proliferation. Interestingly, miR-29a-3p and its targets belong to a selective biomarker that is able to identify colorectal cancer patients who are responding to anti-angiogenic treatments. Our results provide a view of higher-order interactions in angiogenesis that has potential to provide diagnostic and therapeutic insights.
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http://dx.doi.org/10.7554/eLife.48095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299339PMC
January 2020

Design and synthesis of fluorescent ligands for the detection of cannabinoid type 2 receptor (CB2R).

Eur J Med Chem 2020 Feb 7;188:112037. Epub 2020 Jan 7.

Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, via Orabona 4, 70125, Bari, Italy. Electronic address:

The Cannabinoid 2 receptor, CB2R, belonging to the endocannabinoid system, ECS, is involved in the first steps of neurodegeneration and cancer evolution and progression and thus its modulation may be exploited in the therapeutic and diagnostic fields. However, CB2Rs distribution and signaling pathways in physiological and pathological conditions are still controversial mainly because of the lack of reliable diagnostic tools. With the aim to produce green and safe systems to detect CB2R, we designed a series of fluorescent ligands with three different green fluorescent moieties (4-dimethylaminophthalimide, 4-DMAP, 7-nitro-4-yl-aminobenzoxadiazole, NBD, and Fluorescein-thiourea, FTU) linked to the N1-position of the CB2R pharmacophore N-adamantyl-4-oxo-1,4-dihydroquinoline-3-carboxamide through polymethylene chains. Compound 28 emerged for its compromise between good pharmacodynamic properties (CB2R K = 130 nM and no affinity vs the other subtype CB1R) and optimal fluorescent spectroscopic properties. Therefore, compound 28 was studied through FACS (saturation and competitive binding studies) and fluorescence microscopy (visualization and competitive binding) in engineered cells (CB2R-HEK293 cells) and in diverse tumour cells. The fluoligand binding assays were successfully set up, and affinity values for the two reference compounds GW405833 and WIN55,212-2, comparable to the values obtained by radioligand binding assays, were obtained. Fluoligand 28 also allowed the detection of the presence and quantification of the CB2R in the same cell lines. The interactions of compound 28 within the CB2R binding site were also investigated by molecular docking simulations, and indications for the improvement of the CB2R affinity of this class of compounds were provided. Overall, the results obtained through these studies propose compound 28 as a safe and green alternative to the commonly used radioligands for in vitro investigations.
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http://dx.doi.org/10.1016/j.ejmech.2020.112037DOI Listing
February 2020

Phospholipids and cholesterol: Inducers of cancer multidrug resistance and therapeutic targets.

Drug Resist Updat 2020 03 29;49:100670. Epub 2019 Nov 29.

Department of Oncology, University of Torino, Italy; Interdepartmental Center of Research in Molecular Biotechnology, University of Torino, Italy. Electronic address:

Lipids, phospholipids and cholesterol in particular, are the predominant components of the plasma membrane, wherein multidrug efflux transporters of the ATP-binding cassette (ABC) superfamily reside as integral pump proteins. In the current review, we discuss how lipids potently modulate the expression and activity of these multidrug efflux pumps, contributing to the development of the multidrug resistance (MDR) phenotype in cancer. The molecular mechanisms underlying this modulation of the MDR phenotype are pleiotropic. First, notwithstanding the high intra-and inter-tumor variability, MDR cells display an altered composition of plasma membrane phospholipids and glycosphingolipids, and are enriched with very long saturated fatty acid chains. This feature, along with the increased levels of cholesterol, decrease membrane fluidity, alter the spatial organization of membrane nano- and micro-domains, interact with transmembrane helices of ABC transporters, hence favoring drug binding and release. Second, MDR cells exhibit a peculiar membrane lipid composition of intracellular organelles including mitochondria and endoplasmic reticulum (ER). In this respect, they contain a lower amount of oxidizable fatty acids, hence being more resistant to oxidative stress and chemotherapy-induced apoptosis. Third, drug resistant cancer cells have a higher ratio of monosatured/polyunsatured fatty acids: this lipid signature reduces the production of reactive aldehydes with cytotoxic and pro-inflammatory activity and, together with the increased activity of anti-oxidant enzymes, limits the cellular damage induced by lipid peroxidation. Finally, specific precursors of phospholipids and cholesterol including ceramides and isoprenoids, are highly produced in MDR cells; by acting as second messengers, they trigger multiple signaling cascades that induce the transcription of drug efflux transporter genes and/or promote a metabolic reprogramming which supports the MDR phenotype. High-throughput lipidomics and computational biology technologies are a great tool in analyzing the tumor lipid signature in a personalized manner and in identifying novel biomarkers of drug resistance. Moreover, beyond the induction of MDR, lipid metabolism offers a remarkable opportunity to reverse MDR by using lipid analogues and repurposing lipid-targeting drugs (e.g. statins and aminobisphosphonates) that reprogram the lipid composition of drug resistant cells, hence rendering them drug sensitive.
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http://dx.doi.org/10.1016/j.drup.2019.100670DOI Listing
March 2020

Mutant p53 induces SIRT3/MnSOD axis to moderate ROS production in melanoma cells.

Arch Biochem Biophys 2020 01 5;679:108219. Epub 2019 Dec 5.

Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Verona, Italy. Electronic address:

The TP53 tumor suppressor gene is the most frequently altered gene in tumors and mutant p53 isoforms can acquire oncogenic properties referred to as gain-of-function (GOF). In this study, we used wild-type (A375) and mutant p53 (MeWo) melanoma cell lines to assess the regulation of the mitochondrial antioxidant manganese superoxide dismutase (MnSOD) by mutant p53. The effects of mutant p53 were evaluated by qPCR, immunoblotting, enzyme activity assay, cell proliferation assay, reactive oxygen species (ROS) assay after cellular transfection. We demonstrate that mutant p53 induces MnSOD expression, which is recovered by the ROS scavenger N-acetyl-l-cysteine. This suggests MnSOD induction as a defense mechanism of melanoma cells to counterbalance the pro-oxidant conditions induced by mutant p53. We also demonstrate that mutant p53 induces the expression of Sirtuin3 (SIRT3), a major mitochondrial NAD-dependent deacetylase, stimulating MnSOD deacetylation and enzymatic activity. Indeed, the restoration of SIRT3 reverses MnSOD activity decrease by mutant p53 knock-down. Finally, MnSOD knock-down further enhances mutant p53-mediated ROS increase, counteracting mutp53-dependent cell hyperproliferation. This indicates that SIRT3 and MnSOD act to maintain ROS levels controlled to promote cell proliferation and survival, providing new therapeutic opportunities to be further considered for clinical studies in cancer patients bearing mutant TP53 gene.
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http://dx.doi.org/10.1016/j.abb.2019.108219DOI Listing
January 2020

Applicability and Limitations in the Characterization of Poly-Dispersed Engineered Nanomaterials in Cell Media by Dynamic Light Scattering (DLS).

Materials (Basel) 2019 Nov 21;12(23). Epub 2019 Nov 21.

Department of Chemistry, University of Torino, 10125 Torino, Italy.

The dispersion protocol used to administer nanomaterials (NMs) in in vitro cellular tests might affect their toxicity. For this reason, several dispersion procedures have been proposed to harmonize the toxicological methods, allowing for the comparison of the data that were obtained by different laboratories. At the same time, several techniques and methods are available to monitor the identity of the NMs in the cell media. However, while the characterization of suspensions of engineered NMs having narrow size distribution may be easily performed, the description of aggregated NMs forming polydispersions is still challenging. In the present study, sub-micrometric/nanometric TiO, SiO, and CeO were dispersed in cell media by using two different dispersion protocols, with and without albumin (0.5%) and with different sonication procedures. Dynamic Light Scattering (DLS) was used to characterize NMs in stock solutions and culture media. Pitfalls that affect DLS measurements were identified and, guidance on a critical analysis of the results provided. The NMs were then tested for their cytotoxicity (LDH leakage) toward murine macrophages (RAW 264.7) and PMA-activated human monocytes (THP-1). As markers of pro-inflammatory response, nitric oxide (NO) and cytokine IL-1β production were measured on RAW 264.7 and THP-1 cells, respectively. The pre-treatment with albumin added to a strong sonication treatment increases the stability and homogeneity of the suspensions of nanometric samples, but not of the submicrometric-samples. Nevertheless, while TiO and CeO were non-cytotoxic in any conditions, differences in cytotoxicity, NO, and IL-1β releases were found for the SiO, depending upon the protocol. Overall, the results suggest that there is no one-fits-all method valid for all NMs, since each class of NMs respond differently. The definition of validated procedures and parameters for the selection of the most appropriate method of dispersion for each class of NM appears to be a more efficacious strategy for the harmonization of the dispersion protocols.
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http://dx.doi.org/10.3390/ma12233833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926523PMC
November 2019

Combination of PDT and NOPDT with a Tailored BODIPY Derivative.

Antioxidants (Basel) 2019 Nov 7;8(11). Epub 2019 Nov 7.

Department of Drug Sciences, University of Catania, 95125 Catania, Italy.

The engineering of photosensitizers (PS) for photodynamic therapy (PDT) with nitric oxide (NO) photodonors (NOPD) is broadening the horizons for new and yet to be fully explored unconventional anticancer treatment modalities that are entirely controlled by light stimuli. In this work, we report a tailored boron-dipyrromethene (BODIPY) derivative that acts as a PS and a NOPD simultaneously upon single photon excitation with highly biocompatible green light. The photogeneration of the two key species for PDT and NOPDT, singlet oxygen (O) and NO, has been demonstrated by their direct detection, while the formation of NO is shown not to be dependent on the presence of oxygen. Biological studies carried out using A375 and SKMEL28 cancer cell lines, with the aid of suitable model compounds that are based on the same BODIPY light harvesting core, unambiguously reveal the combined action of O and NO in inducing amplified cancer cell mortality exclusively under irradiation with visible green light.
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http://dx.doi.org/10.3390/antiox8110531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912809PMC
November 2019