Design, Synthesis, and Antitumor Evaluation of an Opioid Growth Factor Bioconjugate Targeting Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) presents a formidable challenge with high lethality and limited effective drug treatments. Its heightened metastatic potential further complicates the prognosis. Owing to the significant toxicity of current chemotherapeutics, compounds like [Met5]-enkephalin, known as opioid growth factor (OGF), have emerged in oncology clinical trials. OGF, an endogenous peptide interacting with the OGF receptor (OGFr), plays a crucial role in inhibiting cell proliferation across various cancer types. This in vitro study explores the potential anticancer efficacy of a newly synthesized OGF bioconjugate in synergy with the classic chemotherapeutic agent, gemcitabine (OGF-Gem). The study delves into assessing the impact of the OGF-Gem conjugate on cell proliferation inhibition, cell cycle regulation, the induction of cellular senescence, and apoptosis. Furthermore, the antimetastatic potential of the OGF-Gem conjugate was demonstrated through evaluations using blood platelets and AsPC-1 cells with a light aggregometer. In summary, this article demonstrates the cytotoxic impact of the innovative OGF-Gem conjugate on pancreatic cancer cells in both 2D and 3D models. We highlight the potential of both the OGF-Gem conjugate and OGF alone in effectively inhibiting the ex vivo pancreatic tumor cell-induced platelet aggregation (TCIPA) process, a phenomenon not observed with Gem alone. Furthermore, the confirmed hemocompatibility of OGF-Gem with platelets reinforces its promising potential. We anticipate that this conjugation strategy will open avenues for the development of potent anticancer agents.

Graphene Oxide Nanoparticles and Organoids: A Prospective Advanced Model for Pancreatic Cancer Research.

Pancreatic cancer, notorious for its grim 10% five-year survival rate, poses significant clinical challenges, largely due to late-stage diagnosis and limited therapeutic options. This review delves into the generation of organoids, including those derived from resected tissues, biopsies, pluripotent stem cells, and adult stem cells, as well as the advancements in 3D printing. It explores the complexities of the tumor microenvironment, emphasizing culture media, the integration of non-neoplastic cells, and angiogenesis. Additionally, the review examines the multifaceted properties of graphene oxide (GO), such as its mechanical, thermal, electrical, chemical, and optical attributes, and their implications in cancer diagnostics and therapeutics. GO's unique properties facilitate its interaction with tumors, allowing targeted drug delivery and enhanced imaging for early detection and treatment. The integration of GO with 3D cultured organoid systems, particularly in pancreatic cancer research, is critically analyzed, highlighting current limitations and future potential. This innovative approach has the promise to transform personalized medicine, improve drug screening efficiency, and aid biomarker discovery in this aggressive disease. Through this review, we offer a balanced perspective on the advancements and future prospects in pancreatic cancer research, harnessing the potential of organoids and GO.

Human carnosinases: A brief history, medicinal relevance, and in silico analyses.

Carnosine, an endogenous dipeptide, has been found to have a plethora of medicinal properties, such as antioxidant, antiageing, and chelating effects, but with one downside: a short half-life. Carnosinases and two hydrolytic enzymes, which remain enigmatic, are responsible for these features. Hence, here we emphasize why research is valuable for better understanding crucial concepts like ageing, neurodegradation, and cancerogenesis, given that inhibition of carnosinases might significantly prolong carnosine bioavailability and allow its further use in medicine. Herein, we explore the literature regarding carnosinases and present a short in silico analysis aimed at elucidating the possible recognition pattern between CN1 and its ligands.

Muramyl dipeptide-based analogs as potential anticancer compounds: Strategies to improve selectivity, biocompatibility, and efficiency.

According to the WHO, cancer is the second leading cause of death in the world. This is an important global problem and a major challenge for researchers who have been trying to find an effective anticancer therapy. A large number of newly discovered compounds do not exert selective cytotoxic activity against tumorigenic cells and have too many side effects. Therefore, research on muramyl dipeptide (MDP) analogs has attracted interest due to the urgency for finding more efficient and safe treatments for oncological patients. MDP is a ligand of the cytosolic nucleotide-binding oligomerization domain 2 receptor (NOD2). This molecule is basic structural unit that is responsible for the immune activity of peptidoglycans and exhibits many features that are important for modern medicine. NOD2 is a component of the innate immune system and represents a promising target for enhancing the innate immune response as well as the immune response against cancer cells. For this reason, MDP and its analogs have been widely used for many years not only in the treatment of immunodeficiency diseases but also as adjuvants to support improved vaccine delivery, including for cancer treatment. Unfortunately, in most cases, both the MDP molecule and its synthesized analogs prove to be too pyrogenic and cause serious side effects during their use, which consequently exclude them from direct clinical application. Therefore, intensive research is underway to find analogs of the MDP molecule that will have better biocompatibility and greater effectiveness as anticancer agents and for adjuvant therapy. In this paper, we review the MDP analogs discovered in the last 10 years that show promise for antitumor therapy. The first part of the paper compiles the achievements in the field of anticancer vaccine adjuvant research, which is followed by a description of MDP analogs that exhibit promising anticancer and antiproliferative activity and their structural changes compared to the original MDP molecule.

The Pharmacological Effects of Silver Nanoparticles Functionalized with Eptifibatide on Platelets and Endothelial Cells.

Purpose: In the search for new drug delivery platforms for cardiovascular diseases and coating of medical devices, we synthesized eptifibatide-functionalized silver nanoparticles (AgNPs-EPI) and examined the pharmacological activity of AgNPs-EPI on platelets and endothelial cells in vitro and ex vivo. Methods: Spherical AgNPs linked to eptifibatide were synthesized and characterized. Cytotoxicity was measured in microvascular endothelial cells (HMEC-1), platelets and red blood cells. Platelet mitochondrial respiration was measured using the Oxygraph-2k, a high-resolution modular respirometry system. The effect of AgNPs-EPI on the aggregation of washed platelets was measured by light aggregometry and the ex vivo occlusion time was determined using a reference laboratory method. The surface amount of platelet receptors such as P-selectin and GPIIb/IIIa was measured. The influence of AgNPS-EPI on blood coagulation science was assessed. Finally, the effect of AgNPs-EPI on endothelial cells was measured by the levels of 6-keto-PGF1alpha, tPa, cGMP and vWF. Results: We describe the synthesis of AgNPs using eptifibatide as the stabilizing ligand. The molecules of this drug are directly bonded to the surface of the nanoparticles. The synthesized AgNPs-EPI did not affect the viability of platelets, endothelial cells and erythrocytes. Preincubation of platelets with AgNPs-EPI protected by mitochondrial oxidative phosphorylation capacity. AgNPs-EPI inhibited aggregation-induced P-selectin expression and GPIIb/IIIa conformational changes in platelets. AgNPs-EPI caused prolongation of the occlusion time in the presence of collagen/ADP and collagen/adrenaline. AgNPs-EPI regulated levels of 6-keto-PGF1alpha, tPa, vWf and cGMP produced in thrombin stimulated HMEC-1 cells. Conclusion: AgNPs-EPI show anti-aggregatory activity at concentrations lower than those required by the free drug acting via regulation of platelet aggregation, blood coagulation, and endothelial cell activity. Our results provide proof-of-principle evidence that AgNPs may be used as an effective delivery platform for antiplatelet drugs.

Pancreatic Cancer and Platelets Crosstalk: A Potential Biomarker and Target.

Platelets have been recognized as key players in hemostasis, thrombosis, and cancer. Preclinical and clinical researches evidenced that tumorigenesis and metastasis can be promoted by platelets through a wide variety of crosstalk between cancer cells and platelets. Pancreatic cancer is a devastating disease with high morbidity and mortality worldwide. Although the relationship between pancreatic cancer and platelets in clinical diagnosis is described, the interplay between pancreatic cancer and platelets, the underlying pathological mechanism and pathways remain a matter of intensive study. This review summaries recent researches in connections between platelets and pancreatic cancer. The existing data showed different underlying mechanisms were involved in their complex crosstalk. Typically, pancreatic tumor accelerates platelet aggregation which forms thrombosis. Furthermore, extracellular vesicles released by platelets promote communication in a neoplastic microenvironment and illustrate how these interactions drive disease progression. We also discuss the advantages of novel model organoids in pancreatic cancer research. A more in-depth understanding of tumor and platelets crosstalk which is based on organoids and translational therapies may provide potential diagnostic and therapeutic strategies for pancreatic cancer progression.

Nanodrugs as a New Approach in the Therapy of Cardiovascular Diseases and Cancer with Tumor-associated Angiogenesis.

BACKGROUND: Cancer, along with cardiovascular diseases, is globally defined as the leading cause of death. Importantly, some risk factors are common to these diseases. The process of angiogenesis and platelet aggregation is observed in cancer development and progression. In recent years, studies have been conducted on nanodrugs for these diseases that have provided important information on the biological and physicochemical properties of nanoparticles. Their attractive features are that they are made of biocompatible, well-characterized, and easily functionalized materials. Unlike conventional drug delivery, sustained and controlled drug release can be obtained by using nanomaterials. METHODS: In this article, we review the latest research to provide comprehensive information on nanoparticle-based drugs for the treatment of cancer, cardiovascular disease associated with abnormal haemostasis, and the inhibition of tumor-associated angiogenesis. RESULTS: The results of the analysis of data based on drugs with nanoparticles confirm their improved pharmaceutical and biological properties, which give promising antiplatelet, anticoagulant, and antiangiogenic effects. Moreover, the review included in vitro, in vivo research and presented nanodrugs with chemotherapeutics approved by Food and Drug Administration. CONCLUSION: By the optimization of nanoparticle size and surface properties, nanotechnology is able to deliver drugs with enhanced bioavailability in treatment of cardiovascular disease, cancer and inhibition of cancer-related angiogenesis. Thus, nanotechnology can improve the therapeutic efficacy of the drug, but there is a need for a better understanding of the nanodrugs interaction in the human body because this is a key factor in the success of potential nanotherapeutics.

Opioid Growth Factor and its Derivatives as Potential Non-toxic Multifunctional Anticancer and Analgesic Compounds.

Despite significant research progress on the pathogenesis, molecular biology, diagnosis, treatment, and prevention of cancer, its morbidity and mortality are still high around the world. The emerging resistance of cancer cells to anticancer drugs remains still a significant problem in oncology today. Furthermore, an important challenge is the inability of anticancer drugs to selectively target tumor cells thus sparing healthy cells. One of the new potential options for efficient and safe therapy can be provided by opioid growth factor (OGF), chemically termed Met-enkephalin. It is an endogenous pentapeptide (Tyr-Gly-Gly-Phe-Met) with antitumor, analgesic, and immune-boosting properties. Clinical trials have demonstrated that OGF therapy alone, as well as in combination with standard chemotherapies, is a safe, non-toxic anticancer agent that reduces tumor size. In this paper, we review the structure-activity relationship of OGF and its analogues. We highlight also OGF derivatives with analgesic, immunomodulatory activity and the ability to penetrate the blood-brain barrier and may be used as safe agents enhancing chemotherapy efficacy and improving quality of life in cancer patients. The reviewed papers indicate that Met-enkephalin and its analogues are interesting candidates for the development of novel, non-toxic, and endowed with an analgesic activity anticancer drugs. More preclinical and clinical studies are needed to explore these opportunities.

Oxidovanadium(IV) Complex Disrupts Mitochondrial Membrane Potential and Induces Apoptosis in Pancreatic Cancer Cells.

BACKGROUND: At the present time, there is a growing interest in metal-based anticancer agents. Metal complexes exhibit many valuable clinical properties, however, due to toxicity, only a few clinically useful complexes have been discovered. It has been demonstrated that synthetic vanadium complexes exhibit many biological activities, including anti-cancer properties, however, cellular and molecular mechanisms still are not fully understood. OBJECTIVE: This investigation examined the potential effects of three newly synthesized oxidovanadium(IV) complexes with 2-amino-3-hydroxypyridine against pancreatic cancer cells. METHODS: We measured cytotoxicity by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, antiproliferative activity by bromodeoxyuridine assay and necrosis as well as late apoptosis by lactate dehydrogenase assay. Reactive oxygen species generation, apoptosis and mitochondrial membrane potential were determined by a flow cytometry technique. Cell morphology was evaluated by using a transmission electron microscope. RESULTS: The results showed that oxidovanadium(IV) complexes were cytotoxic on pancreatic cancer cells (PANC-1 and MIA PaCa2) over the concentration range of 12.5-200µM, following 48h incubation. Additionally, the cellular mechanism of cytotoxic activity of [2-NH2-3-OH(py)H]4[V2O2(pmida)2]·6H2O (V3) complex was dependent on ROS generation, induction apoptosis with simultaneous disruption of mitochondrial membrane potential. CONCLUSION: We have proven that oxidovanadium (IV) complexes show therapeutic potential in pancreatic cancer therapy. The results of our research will help to understand the cellular mechanisms of the cytotoxic activity of the vanadium complexes and will allow a more effective design structure of new vanadium-based compounds in the future.

Molecular and Cellular Mechanisms of Cytotoxic Activity of Vanadium Compounds against Cancer Cells.

Discovering that metals are essential for the structure and function of biomolecules has given a completely new perspective on the role of metal ions in living organisms. Nowadays, the design and synthesis of new metal-based compounds, as well as metal ion binding components, for the treatment of human diseases is one of the main aims of bioinorganic chemistry. One of the areas in vanadium-based compound research is their potential anticancer activity. In this review, we summarize recent molecular and cellular mechanisms in the cytotoxic activity of many different synthetic vanadium complexes as well as inorganic salts. Such mechanisms shall include DNA binding, oxidative stress, cell cycle regulation and programed cell death. We focus mainly on cellular studies involving many type of cancer cell lines trying to highlight some new significant advances.

Modified Nanoparticles as Potential Agents in Bone Diseases: Cancer and Implant-Related Complications.

Materials sized 1-100 nm are the nanotechnology's field of interest. Because of the unique properties such as the ability to penetrate biological barriers and a high surface to volume ratio, nanoparticles (NPs) are a powerful tool to be used in medicine and industry. This review discusses the role of nanotechnology in bone-related issues: osteosarcoma (bone cancer), the biocompatibility of the implants and implant-related infections. In cancer therapy, NPs can be used as (I) cytotoxic agents, (II) drug delivery platforms and (III) in thermotherapy. In implant-related issues, NPs can be used as (I) antimicrobial agents and (II) adjuvants to increase the biocompatibility of implant surface. Properties of NPs depend on (I) the type of NPs, (II) their size, (III) shape, (IV) concentration, (V) incubation time, (VI) functionalization and (VII) capping agent type.

Assessment of Anti-Tumor potential and safety of application of Glutathione stabilized Gold Nanoparticles conjugated with Chemotherapeutics.

Due to the high toxicity of currently used chemotherapeutics, novel methods of cancer treatment are needed. Gold nanoparticles (AuNPs) seem to be an interesting alternative due to penetration through biological membranes and systemic barriers. AuNPs as carriers of chemotherapeutics allow for reduced concentrations whilst maintaining the expected effect, and thus reducing the costs of therapy and adverse effects. We synthesized AuNPs stabilized with reduced glutathione (GSH) and conjugated with doxorubicin (DOX), gemcitabine (GEM) or cytarabine (CTA). This is the first study in which cytarabine-AuNPs were synthesized and characterized. Transmission electron microscopy (TEM), thermogravimetric analysis (TGA), nuclear magnetic resonance spectroscopy (NMR) and high-performance liquid chromatography (HPLC) were used to chemically characterize obtained nanoparticles. Antitumor activity and safety of application were assessed by MTT assay in in vitro model (human osteosarcoma cells -143B, human osteoblast- hFOB1.19, breast cancer cells - MCF7, breast epithelial cells - MCF10A, pancreatic cancer cells - PANC-1, and pancreatic cells - hTERT-HPNE cells). We have shown that cellular response varies according to the type and concentration of AuNPs. At some concentrations, we were able to show selective cytotoxicity of our AuNPs conjugates only to cancer cell lines. Synthesized nanoparticles were more cytotoxic to tumor cell lines than chemotherapeutics alone.

Therapeutic Potential of Carnosine and Its Derivatives in the Treatment of Human Diseases.

Despite significant progress in the pathogenesis, diagnosis, treatment, and prevention of cancer and neurodegenerative diseases, their occurrence and mortality are still high around the world. The resistance of cancer cells to the drugs remains a significant problem in oncology today, while in the case of neuro-degenerative diseases, therapies reversing the process are still yet to be found. Furthermore, it is important to seek new chemotherapeutics reversing side effects of currently used drugs or helping them perform their function to inhibit progression of the disease. Carnosine, a dipeptide constisting of ß-alanine and l-histidine, has a variety of functions to mention: antioxidant, antiglycation, and reducing the toxicity of metal ions. It has therefore been proposed to act as a therapeutic agent for many pathological states. The aim of this paper was to find if carnosine and its derivatives can be helpful in treating various diseases. Literature search presented in this review includes review and original papers found in SciFinder, PubMed, and Google Scholar. Searches were based on substantial keywords concerning therapeutic usage of carnosine and its derivatives in several diseases including neurodegenerative disorders and cancer. In this paper, we review articles and find that carnosine and its derivatives are potential therapeutic agents in many diseases including cancer, neurodegenerative diseases, diabetes, and schizophrenia. Carnosine and its derivatives can be used in treating neurodegenerative diseases, cancer, diabetes, or schizophrenia, although their usage is limited. Therefore, there's an urge to synthesize and analyze new substances, overcoming the limitation of carnosine itself.

Synthesis and Cholinesterase Inhibitory Activity of N-Phosphorylated/ N-Tiophosphorylated Tacrine.

BACKGROUND: Alzheimer's disease (AD) is progressive and irreversible neurodegenerative disorder. Current pharmacotherapy is not able to stop progression of the disease and can only improve cognitive functions. Therefore, new drugs are being sought that will slow down the development of the disease. OBJECTIVE: Novel phosphorus and thiophosphorus tacrine derivatives 7-14 were designed, synthesized and their biological activity and molecular modeling was investigated as a new potential anti- Alzheimer's disease (AD) agents. METHODS: 9-Chlorotacrine was treated with propane-1,3-diamine in the presence of sodium iodide to yield N1-(1,2,3,4-tetrahydroacridin-9-yl)propane-1,3-diamine 6. Finally, it was treated with corresponding acid ester or thioester to give phosphorus or thiophosphorus tacrine derivative 7-14. All of the obtained final structures were characterized by 1H NMR, 13C NMR, 31P NMR and MS. RESULTS: The results of the docking studies showed that the newly designed phosphorus and thiophosphorus tacrine analogs, theoretically possess AChE and BChE-binding ability. Kinetic study showed that 8 and 12 in the series proved to be more potent electric eel AChE (eeAChE) and human (hAChE) inhibitors than tacrine, where 8 inhibited eeAChE three times more than the referenced drug. The highest BChE inhibition revealed 11 and 13. The most active compounds against eeAChE, hAChE and BChE showed mixed type of inhibition. CONCLUSION: All new synthesized compound exhibited lower toxicity against neuroblastoma.cell line (SH-SY5Y) in comparison with tacrine. Two analogues in the series, 7 and 9, demonstrated lack of cytotoxicity against hepatocellular cells (hepG2).

Shape-Depended Biological Properties of Ag3PO4 Microparticles: Evaluation of Antimicrobial Properties and Cytotoxicity in In Vitro Model-Safety Assessment of Potential Clinical Usage.

Implant-related infections are an emerging clinical and economic problem. Therefore, we decided to assess potential clinical usefulness and safety of silver orthophosphate microparticles (SOMPs) regarding their shape. We synthesized and then assessed antimicrobial properties and potential cytotoxicity of six shapes of SOMPs (tetrapod, cubes, spheres, tetrahedrons, branched, and rhombic dodecahedron). We found that SOMPs had a high antimicrobial effect; they were more efficient against fungi than bacteria. SOMPs exerted an antimicrobial effect in concentrations not toxic to mammalian cells: human fetal osteoblast (hFOB1.19), osteosarcoma (Saos-2), mouse preosteoblasts (MC3T3-E1), skin fibroblast (HDF), and mouse myoblast (C2C12). At higher concentration SOMPs, induced shape- and concentration-dependent cytotoxicity (according to MTT and BrdU assays). Tetrapod SOMPs had the smallest effect, whereas cubical SOMPs, the highest on cell viability. hFOB1.19 were the most resistant cells and C2C12, the most susceptible ones. We have proven that the induction of oxidative stress and inflammation is involved in the cytotoxic mechanism of SOMPs. After treatment with microparticles, we observed changes in levels of reactive oxygen species, first-line defense antioxidants-superoxide dismutase (SOD1, SOD3), and glutathione peroxidase (GPX4), metalloproteinase (MMP1, MMP3), and NF-κB protein. Neither cell cycle distribution nor ultrastructure was altered as determined by flow cytometry and transmission electron microscopy, respectively. In conclusion, silver orthophosphate may be a safe and effective antimicrobial agent on the implant surface. Spherical-shaped SOMPs are the most promising for biomedical application.

Impact of gold nanoparticles shape on their cytotoxicity against human osteoblast and osteosarcoma in in vitro model. Evaluation of the safety of use and anti-cancer potential.

Due to development of nanotechnology and gold nanoparticles (AuNPs) increasing use in different areas of medicine, especially in oncology, better understanding of their potential cytotoxicity is necessary to protect patients safety. Shape and size of AuNPs is an important modulator of their cytotoxicity. Therefore, we investigated the cytotoxicity of AuNPs rods (≈39 nm length, 18 nm width), AuNPs stars (≈ 215 nm) and AuNPs spheres (≈ 6.3 nm) against human fetal osteoblast (hFOB 1.19), osteosarcoma (143B, MG63) and pancreatic duct cell (hTERT-HPNE) lines by MTT and neutral-red uptake assay. Moreover, influence of AuNPs on level of proapoptotic protein (Bax) and anti-apoptotic protein (Bcl-2) was measured by western blot. Cellular uptake of nanoparticles and ultrastructure changes were examined by transmission electron microscopy (TEM). In the present study we have proven that AuNPs stars are the most cytotoxic against human cells. We observed that cancer cells are more susceptible to AuNPs cytotoxic effect. Furthermore, AuNPs rods and AuNPs stars caused increased expression of Bax and decreased expression of Bcl-2 protein in osteosarcoma cells. We found that AuNPs penetrated through the cell membrane and caused ultrastructural changes. Our results clearly demonstrated that the cytotoxicity of AuNPs was shape-dependent. AuNPs stars with the highest anti-cancer potential were also the most cytotoxic type of tested NPs, whereas AuNPs spheres which appears to be the safest one had small anti-cancer potential.

New Oxidovanadium(IV) Coordination Complex Containing 2-Methylnitrilotriacetate Ligands Induces Cell Cycle Arrest and Autophagy in Human Pancreatic Ductal Adenocarcinoma Cell Lines.

Pancreatic cancer is characterized by one of the lowest five-year survival rates. In search for new treatments, some studies explored several metal complexes as potential anticancer drugs. Therefore, we investigated three newly synthesized oxidovanadium(IV) complexes with 2-methylnitrilotriacetate (bcma3-), N-(2-carbamoylethyl)iminodiacetate (ceida3-) and N-(phosphonomethyl)-iminodiacetate (pmida4-) ligands as potential anticancer compounds using pancreatic cancer cell lines. We measured: Cytotoxicity using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), neutral red (NR) and lactate dehydrogenase (LDH) assay; antiproliferative activity by bromodeoxyuridine BrdU assay; reactive oxygen species (ROS) generation and cell cycle analysis by flow cytometry; protein level by Western blot and cellular morphology by confocal laser scanning microscopy. The results showed that these oxidovanadium(IV) complexes were cytotoxic on pancreatic cancer cells (PANC-1 and MIA PaCa2), but not on non-tumor human immortalized pancreas duct epithelial cells (hTERT-HPNE) over the concentration range of 10⁻25 µM, following 48 h incubation. Furthermore, molecular mechanisms of cytotoxicity of [4-NH2-2-Me(Q)H][VO(bcma)(H2O)]2H2O (T1) were dependent on antiproliterative activity, increased ROS generation, cell cycle arrest in G2/M phase with simultaneous triggering of the p53/p21 pathway, binucleation, and induction of autophagy. Our study indicates that oxidovanadium(IV) coordination complexes containing 2-methylnitrilotriacetate ligand are good candidates for preclinical development of novel anticancer drugs targeting pancreatic cancer.

Role of Oxidative and Nitro-Oxidative Damage in Silver Nanoparticles Cytotoxic Effect against Human Pancreatic Ductal Adenocarcinoma Cells.

Pancreatic ductal adenocarcinoma is one of the most aggressive human malignancies, where the 5-year survival rate is less than 4% worldwide. Successful treatment of pancreatic cancer is a challenge for today's oncology. Several studies showed that increased levels of oxidative stress may cause cancer cells damage and death. Therefore, we hypothesized that oxidative as well as nitro-oxidative stress is one of the mechanisms inducing pancreatic cancer programmed cell death. We decided to use silver nanoparticles (AgNPs) (2.6 and 18 nm) as a key factor triggering the reactive oxygen species (ROS) and reactive nitrogen species (RNS) in pancreatic ductal adenocarcinoma cells (PANC-1). Previously, we have found that AgNPs induced PANC-1 cells death. Furthermore, it is known that AgNPs may induce an accumulation of ROS and alteration of antioxidant systems in different type of tumors, and they are indicated as promising agents for cancer therapy. Then, the aim of our study was to evaluate the implication of oxidative and nitro-oxidative stress in this cytotoxic effect of AgNPs against PANC-1 cells. We determined AgNP-induced increase of ROS level in PANC-1 cells and pancreatic noncancer cell (hTERT-HPNE) for comparison purposes. We found that the increase was lower in noncancer cells. Reduction of mitochondrial membrane potential and changes in the cell cycle were also observed. Additionally, we determined the increase in RNS level: nitric oxide (NO) and nitric dioxide (NO2) in PANC-1 cells, together with increase in family of nitric oxide synthases (iNOS, eNOS, and nNOS) at protein and mRNA level. Disturbance of antioxidant enzymes: superoxide dismutase (SOD1, SOD2, and SOD3), glutathione peroxidase (GPX-4) and catalase (CAT) were proved at protein and mRNA level. Moreover, we showed cells ultrastructural changes, characteristic for oxidative damage. Summarizing, oxidative and nitro-oxidative stress and mitochondrial disruption are implicated in AgNPs-mediated death in human pancreatic ductal adenocarcinoma cells.

Silver nanoparticles of different sizes induce a mixed type of programmed cell death in human pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma, with the high resistance to chemotherapeutic agents, remains the fourth leading cause of cancer-death in the world. Due to the wide range of biological activity and unique properties, silver nanoparticles (AgNPs) are indicated as agents with potential to overcome barriers involved in chemotherapy failure. Therefore, in our study we decided to assess the ability of AgNPs to kill pancreatic cancer cells, and then to identify the molecular mechanism underlying this effect. Moreover, we evaluated the cytotoxicity of AgNPs against non-tumor cell of the same tissue (hTERT-HPNE cells) for comparison. Our results indicated that AgNPs with size of 2.6 and 18 nm decreased viability, proliferation and caused death of pancreatic cancer cells in a size- and concentration-dependent manner. Ultrastructural analysis identified that cellular uptake of AgNPs resulted in apoptosis, autophagy, necroptosis and mitotic catastrophe. These alterations were associated with increased pro-apoptotic protein Bax and decreased level of anti-apoptotic protein Bcl-2. Moreover, AgNPs significantly elevated the level of tumor suppressor p53 protein as well as necroptosis- and autophagy-related proteins: RIP-1, RIP-3, MLKL and LC3-II, respectively. In addition, we found that PANC-1 cells were more vulnerable to AgNPs-induced cytotoxicity compared to pancreatic non-tumor cells. In conclusion, AgNPs by inducing mixed type of programmed cell death in PANC-1 cells, could provide a new therapeutic strategy to overcome chemoresistance in one of the deadliest human cancer.

Metal nanoparticles in dermatology and cosmetology: Interactions with human skin cells.

Nanotechnology is a rapidly developing branch of science, which studies control of phenomena and materials sized below 100 nm. Nanotechnology is applicable in many areas of life and medicine including skin care and personal hygiene. The nanoparticles (NPs) of metals and metal oxides are increasingly used in dermatology and cosmetology, especially in prevention and treatment of bacterial and fungal infections, in protection against the harmful effects of the sun and in preparations reducing the visibility of scars by accelerating the repair processes of skin cells. NPs may also be used for skin care and dermatological treatments to improve the quality of life of patients. Nanodermatology and nanocosmetology offer effective, safe, fast-acting product formulations, thus minimizing the side effects of the products used so far. The unique properties of NPs: high surface area relative to the size as well as the ability to penetrate biological membranes and barriers greatly reduces systemic dose thus potential side effects and toxicity. Recent studies show very promising clinical potential of NPs to serve as controlled release and delivery systems for drugs/active substances. In addition, NPs can be used in diagnostic imaging of skin diseases. However, NPs may also carry a risk of cytotoxicity and side effects. The present review focuses on the use of metal and metal oxide NPs in dermatology and cosmetology and their interactions with skin cells.