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1.
J Biomol Struct Dyn ; : 1-9, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36134605

RESUMO

Drug repurposing is a method to identify novel therapeutic agents from the existing drugs and clinical compounds. In the present comprehensive work, molecular docking, virtual screening and dynamics simulations were carried out for ten cancer types viz breast, colon, central nervous system, leukaemia, melanoma, ovarian, prostate, renal and lung (non-small and small cell) against validated eighteen kinase targets. The study aims to understand the action of chemotherapy drugs mechanism through binding interactions against selected targets via comparative docking simulations with the state-art molecular modelling suits such as MOE, Cresset-Flare, AutoDock Vina, GOLD and GLIDE. Chemotherapeutic drugs (n = 112) were shortlisted from standard drug databases with appropriate chemoinformatic filters. Based on docking studies it was revealed that leucovorin, nilotinib, ellence, thalomid and carfilzomib drugs possessed potential against other cancer targets. A library was built to enumerate novel molecules based on the scaffold and functional groups extracted from known drugs and clinical compounds. Twenty novel molecules were prioritised further based on drug-like attributes. These were cross docked against 1MQ4 Aurora-A Protein Kinase for prostate cancer and 4UYA Mitogen-activated protein kinase for renal cancer. All docking programs yielded similar results but interestingly AutoDock Vina yielded the lowest RMSD with the native ligand. To further validate the final docking results at atomistic level, molecular dynamics simulations were performed to ascertain the stability of the protein-ligand complex. The study enables repurposing of drugs and lead identification by employing a host of structure and ligand based virtual screening tools and techniques.Communicated by Ramaswamy H. Sarma.

2.
Pain Ther ; 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36098939

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) is the most common neurologic complication of chemotherapy, resulting in symptoms like pain, sensory loss, and numbness in the hands and feet that cause lots of uneasiness in patients with cancer. They often suffer from pain so severe that it interrupts the treatment, thus invalidating the entire chemotherapy-based healing process, and significantly reducing their quality of life. In this paper, we underline the role of the complement system in CIPN, highlighting the relevance of the C5a fragment and its receptor C5aR1, whose activation is thought to be involved in triggering a cascade of events that can lead to CIPN onset. Recent experimental data showed the ability of docetaxel and paclitaxel to specifically bind and activate C5aR1, thus shining light on one of the molecular mechanisms by which taxanes may activate a cascade of events leading to neuropathy. According to these new evidence, it was possible to suggest new mechanisms underlying the pathophysiology of CIPN. Hence, the C5a/C5aR1 axis may represent a new target for CIPN treatment, and the use of C5aR1 inhibitors can be proposed as a potential new therapeutic option to manage this high unmet medical need.

3.
Explor Target Antitumor Ther ; 3(4): 423-427, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36046223

RESUMO

Compared to humans, plants can synthesize an extremely diverse array of chemical compounds, including phenolic acids, flavonoids, stilbenes, lignans, terpenoids, alkaloids, and many other types of secondary metabolites that have been demonstrated to exert important bioactivities and impacts on the human health. As a result of extensive and sustained efforts, some phytochemicals like vincristine, vinblastine, and paclitaxel have already been approved as anticancer drugs today, while several others are under clinical trials. However, despite this remarkable success, studies on anticancer action of plant-derived products have been and paradoxically are still in some places, mixed up with alternative approaches and thereby considered non-credible, especially in regions where the role of traditional medicine has not been historically so prevalent as in several Asian countries. As a result, only about 10% of higher plants have been explored regarding the potential therapeutic effects of their constituents. Moreover, as one function of secondary metabolites includes the protection of plants against diverse environmental stresses, the content and composition of these phytochemicals might importantly vary between different regional habitats. Therefore, the stereotyped attitudes to plant products as something related to alternative medicine must be changed to identify new lead molecules for novel anticancer drugs. It is possible that plants still harbor an important spectrum of pharmaceutically interesting, but still unidentified, chemical compounds.

4.
J Nutr Biochem ; : 109147, 2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36049673

RESUMO

Gout is an inflammatory disease caused by metabolic disorder or genetic inheritance. People throughout the world are strongly dependent on ethnomedicine for the treatment of gout and some receive satisfactory curative treatment. The natural remedies as well as established drugs derived from natural sources or synthetically made exert their action by mechanisms that are closely associated with anticancer treatment mechanisms regarding inhibition of xanthine oxidase (XO), feedback inhibition of de novo purine synthesis, depolymerization and disappearance of microtubule, inhibition of NF-ĸB activation, induction of TRAIL, promotion of apoptosis, and caspase activation and proteasome inhibition. Some anti-gout and anticancer novel compounds interact with same receptors for their action e.g., colchicine and colchicine analogues. Dietary flavonoids i.e. chrysin, kaempferol, quercetin, fisetin, pelargonidin, apigenin, luteolin, myricetin, isorhamnetin, phloretinetc etc. have comparable IC50 values with established anti-gout drug and effective against both cancer and gout. Moreover, a noticeable number of newer anticancer compounds have already been isolated from plants that have been using by local traditional healers and herbal practitioners to treat gout. Therefore, the anti-gout plants might have greater potentiality to become selective candidate for screening of newer anticancer leads.

5.
Am J Transl Res ; 14(7): 4426-4442, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35958463

RESUMO

OBJECTIVES: The prognosis of gallbladder carcinoma (GBC) is poor, with a less than 5% five-year survival rate. Identifying the mechanisms underlying GBC occurrence and advancement is necessary to improve GBC patient prognosis and survival rates. The phosphatidylinositol 3-kinase (PI3K)/serine-threonine kinase (AKT) pathway is involved in cancer deterioration, tumor growth, cell proliferation, and distant metastasis. Studying the impacts of the PI3K/AKT pathway has resulted in the identification of key factors involved in GBC progression that might serve as therapeutic targets, promoting the development of new treatments. METHODS: We reviewed recent literature exploring abnormal regulation of the PI3K/AKT pathway in gallbladder cancer, with a focus on abnormal RNA levels, protein level regulation, and drug treatment advances. RESULTS: Further investigation of the regulation of small molecules and proteins by the PI3K/AKT pathway might ultimately provide new diagnostic or prognostic markers or cancer treatment targets. Recent studies have focused on RNA and proteins involved in the regulation of the cell cycle or cell movement in cancer progression via PI3K/AKT pathway, the use of anticancer drug combinations, or the anticancer effects of drugs not currently utilized for cancer treatment. CONCLUSIONS: We herein review the known available molecules that affect the PI3K/AKT pathway in patients with GBC and the mechanisms of drug action associated with this pathway.

6.
J Nanobiotechnology ; 20(1): 371, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35953863

RESUMO

Colorectal cancer is considered one of the major malignancies that threaten the lives and health of people around the world. Patients with CRC are prone to post-operative local recurrence or metastasis, and some patients are advanced at the time of diagnosis and have no chance for complete surgical resection. These factors make chemotherapy an indispensable and important tool in treating CRC. However, the complex composition of the tumor microenvironment and the interaction of cellular and interstitial components constitute a tumor tissue with high cell density, dense extracellular matrix, and high osmotic pressure, inevitably preventing chemotherapeutic drugs from entering and acting on tumor cells. As a result, a novel drug carrier system with targeted nanoparticles has been applied to tumor therapy. It can change the physicochemical properties of drugs, facilitate the crossing of drug molecules through physiological and pathological tissue barriers, and increase the local concentration of nanomedicines at lesion sites. In addition to improving drug efficacy, targeted nanoparticles also reduce side effects, enabling safer and more effective disease diagnosis and treatment and improving bioavailability. In this review, we discuss the mechanisms by which infiltrating cells and other stromal components of the tumor microenvironment comprise barriers to chemotherapy in colorectal cancer. The research and application of targeted nanoparticles in CRC treatment are also classified.


Assuntos
Antineoplásicos , Neoplasias Colorretais , Nanopartículas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Sistemas de Liberação de Medicamentos , Humanos , Nanomedicina , Nanopartículas/química , Microambiente Tumoral
7.
Neurochem Res ; 2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-35960485

RESUMO

Chemotherapeutic agents such as methotrexate (MTX), raltitrexed (RTX), 5-fluorouracil (5-FU), hydroxyurea (HU), and retinoic acid (RA), and valproic acid (VPA), an antiepileptic drug, all can cause malformations in the developing central nervous system (CNS), such as neural tube defects (NTDs). However, the common pathogenic mechanisms remain unclear. This study aimed to explore the mechanisms of NTDs caused by MTX, RTX, 5-FU, HU, RA, and VPA (MRFHRV), based on network pharmacology and molecular biology experiments. The MRFHRV targets were integrated with disease targets, to find the potential molecules related to MRFHRV-induced NTDs. Protein-protein interaction analysis and molecular docking were performed to analyze these common targets. Utilizing the kyoto encyclopedia of genes and genomes (KEGG) signaling pathways, we analyzed and searched the possible causative pathogenic mechanisms by crucial targets and the signaling pathway. Results showed that MRFHRV induced NTDs through several key targets (including TP53, MAPK1, HSP90AA1, ESR1, GRB2, HDAC1, EGFR, PIK3CA, RXRA, and FYN) and multiple signaling pathways such as PI3K/Akt pathway, suggesting that abnormal proliferation and differentiation could be critical pathogenic contributors in NTDs induced by MRFHRV. These results were further validated by CCK8 assay in mouse embryonic stem cells and GFAP staining in embryonic brain tissue. This study indicated that chemotherapeutic and antiepileptic agents induced NTDs might through predicted targets TP53, MAPK1, GRB2, HDAC1, EGFR, PIK3CA, RXRA, and FYN and multiple signaling pathways. More caution was required for the clinical administration for women with childbearing potential and pregnant.

8.
Iran J Basic Med Sci ; 25(7): 904-912, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36033954

RESUMO

Objectives: STATs are one of the initial targets of emerging anti-cancer agents due to their regulatory roles in survival, apoptosis, drug response, and cellular metabolism in CML. Aberrant STAT3 activity promotes malignancy, and acts as a metabolic switcher in cancer cell metabolism, contributing to resistance to TKI nilotinib. To investigate the possible therapeutic effects of targeting STAT3 to overcome nilotinib resistance by evaluating various cellular responses in both sensitive and nilotinib resistant CML cells and to test the hypothesis that energy metabolism modulation could be a mechanism for re-sensitization to nilotinib in resistant cells. Materials and Methods: By using RNAi-mediated STAT3 gene silencing, cell viability and proliferation assays, apoptotic analysis, expressional regulations of STAT mRNA transcripts, STAT3 total, pTyr705, pSer727 protein expression levels, and metabolic activity as energy metabolism was determined in CML model K562 cells, in vitro. Results: Targeting STAT3 sensitized both parental and especially nilotinib resistant cells by decreasing leukemic cell survival; inducing leukemic cell apoptosis, and decreasing STAT3 mRNA and protein expression levels. Besides, cell energy phenotype was modulated by switching energy metabolism from aerobic glycolysis to mitochondrial respiration in resistant cells. RNAi-mediated STAT3 silencing accelerated the sensitization of leukemia cells to nilotinib treatment, and STAT3-dependent energy metabolism regulation could be another underlying mechanism for regaining nilotinib response. Conclusion: Targeting STAT3 is an efficient strategy for improving the development of novel CML therapeutics for regaining nilotinib response, and re-sensitization of resistant cells could be mediated by induced apoptosis and regulation in energy metabolism.

9.
Biomaterials ; 288: 121704, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35948496

RESUMO

The emergence of chemotherapeutic resistance, which is closely related to the oxidative stress defense induced by the imbalance of reactive oxygen species (ROS), is one of the important reasons for the failure of anti-tumor therapy. Herein, a GSH-triggered ferroptosis/apoptosis integrated tumor therapy strategy was successfully implemented to prohibit the mitoxantrone (MTO) resistance. Owing to the overexpressed GSH in the tumor microenvironment, the tumor active targeting MTO-Cu(Ⅱ)-cRGD nanolocks could be dissociated to release Cu(Ⅰ) and MTO, which could persistently catalyze hydrogen peroxide into hydroxyl radicals (•OH) via Fenton-like reaction and generate photothermal effect, respectively. The depletion of GSH inactivated GPX4 for the accumulation of lipid peroxides (LPO) and inducing ferroptosis. With the destruction of oxidative stress defenses, the formation of chemotherapeutic resistance could be effectively prohibited. The nanolocks could eliminate the solid tumors through ferroptosis-sensitized chemotherapy under the guidance of photoacoustic imaging. The study proposed the mechanism of reversing chemotherapeutic resistance by ferroptosis, providing a feasible strategy for the treatment of drug-resistant tumors.


Assuntos
Ferroptose , Neoplasias , Apoptose , Linhagem Celular Tumoral , Humanos , Peróxido de Hidrogênio/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Espécies Reativas de Oxigênio/farmacologia , Microambiente Tumoral
10.
PeerJ ; 10: e13876, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35990899

RESUMO

Background: Cholangiocarcinoma (CCA) is a malignancy of the cholangiocytes. One of the major issues regarding treatment for CCA patients is the development of chemotherapeutic resistance. Recently, the association of intratumoral bacteria with chemotherapeutic response has been reported in many cancer types. Method: In the present study, we aimed to investigate the association between the intratumoral microbiome and its function on gemcitabine and cisplatin response in CCA tissues using 16S rRNA sequencing and 1H NMR spectroscopic analysis. Result: The results of 16S rRNA sequencing demonstrated that Gammaproteobacteria were significantly higher in both gemcitabine- and cisplatin-resistance groups compared to sensitive groups. In addition, intratumoral microbial diversity and abundance were significantly different compared between gemcitabine-resistant and sensitive groups. Furthermore, the metabolic phenotype of the low dose gemcitabine-resistant group significantly differed from that of low dose gemcitabine-sensitive group. Increased levels of acetylcholine, adenine, carnitine and inosine were observed in the low dose gemcitabine-resistant group, while the levels of acetylcholine, alpha-D-glucose and carnitine increased in the low dose cisplatin-resistant group. We further performed the intergrative microbiome-metabolome analysis and revealed a correlation between the intratumoral bacterial and metabolic profiles which reflect the chemotherapeutics resistance pattern in CCA patients. Conclusion: Our results demonstrated insights into the disruption of the microbiome and metabolome in the progression of chemotherapeutic resistance. The altered microbiome-metabolome fingerprints could be used as predictive markers for drug responses potentially resulting in the development of an appropriate chemotherapeutic drug treatment plan for individual CCA patients.

11.
Mini Rev Med Chem ; 2022 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-35980046

RESUMO

Intestinal mucositis is characterized by inflammation and ulceration of the mucosa that affects the gastrointestinal tract and it is associated with the administration of some drugs, such as 5-fluorouracil (5-FU), a conventional chemotherapy used in clinics for cancer therapy. Inside intestinal mucosa the 5-FU acts leading to oxidative stress, stimulating the production/release of proinflammatory cytokines, local accumulation of neutrophils and consequent tissue damage. These alterations favor bacterial proliferation, triggering secondary infections and they are also responsible for undesired effects such as myelosuppression and diarrhea. These factors negatively impact the quality of life of oncological patients and explains why they commonly interrupt their treatment prematurely. Currently, there is no specific drug with the ability to completely avoid this condition, so the search for new molecules with pharmacological properties that can be used for preventing or ameliorating intestinal mucositis is important. Plumeria pudica is a plant that produces latex containing molecules with therapeutic potential. A protein fraction obtained from this latex (LPPp), which comprises a well-defined mixture of chitinases, proteinases proteinase inhibitors, was demonstrated to have antioxidant and anti-inflammatory activities, preserving tissue glutathione and malondialdehyde concentration, reducing superoxide dismutase and myeloperoxidase activity, and reducing the level of proinflammatory cytokines in different experimental models. Given this scenario, inflammation and oxidative stress are directly involved in the pathogenesis of intestinal mucositis promoted by 5-FU. So, the hypothesis in question is that LPPp could inhibit these factors to attenuate the cytotoxicity of this pathology associated to 5-FU-treatment. This article brings new insights into the potential of the laticifer proteins extracted from the latex of P. pudica and opens new perspectives for the treatment of this type of intestinal mucositis with LPPp.

12.
Curr Drug Deliv ; 2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-36017863

RESUMO

BACKGROUND: Colorectal cancer (CRC) represents one of the most daunting health problems accompanied by progressive undesirable socio-economic effects. Phytochemicals, bioactive ingredients majorly found in plants, have gained momentum for their potential against CRC occurrence and regression. However, these phytoconstituents are not exempt of biopharmaceutical drawbacks; therefore, novel strategies, especially nanotechnology, are exploited to surmount the aforementioned bottlenecks. The current paper aims to comprehensively review the phytochemical-based nanoformulations and their mechanisms in the setting of CRC. METHODS: Electronic databases including Scopus, PubMed, and Web of Science were searched with the keywords "colon cancer" or "colorectal cancer", and "plant", "phytochemical", "extract", or "herb", and "nano", "nanoformulation", "Nanoencapsulation", "nanoparticle", "nanostructure", or "nanoliposome", until January 2021. RESULTS: Of the 1230 research hits, only 69 articles were consequently analyzed. The results indicated nanoformulations of several secondary plant metabolites such as berberine, camptothecin, colchicine, apigenin, chrysin, fisetin, quercetin, curcumin, gallic acid, resveratrol, and ursolic acid have profound effects in a broad range of preclinical models of CRC. A wide variety of nanoformulations have been utilized to deliver these phytochemicals, such as nanocomposite, nanocolloids, and mesoporous silica nanoparticles, which have consequently decreased tumor angiogenesis and mitochondrial membrane potential, increased radical scavenging activity, induced cell cycle arrest at different phases of the cancer cell cycle, and induction of apoptosis process via decreased anti-apoptotic proteins (BRAF, CD44, and Bcl-2) and increased in pro-apoptotic ones (Bax, Fas, caspase 3,8, and 9), as well as modulated biopharmaceutical properties. Chitosan and PEG and their derivatives are among the most polymers exploited in the phytochemicals' nanoformulations. CONCLUSION AND PERSPECTIVE: To conclude, nanoformulated forms of natural ingredients depicted outstanding anti-CRC activity that could hold promise for help in treating CRC. However, well-designed clinical trials are needed to build up a whole picture of the health profits of nanoformulation of natural products in CRC management.

13.
Pharmaceuticals (Basel) ; 15(8)2022 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-36015177

RESUMO

Death receptor 5 (DR5) is a membrane protein that mediates exogenous apoptosis. Based on its function, it is considered to be a target for the treatment of cancers including prostate cancer. It is encouraging to note that a number of drugs targeting DR5 are now progressing to different stages of clinical trial studies. We collected 38 active compounds that could produce anti-prostate-cancer effects by modulating DR5, 28 of which were natural compounds and 10 of which were synthetic compounds. In addition, 6 clinically used chemotherapeutic agents have also been shown to promote DR5 expression and thus exert apoptosis-inducing effects in prostate cancer cells. These compounds promote the expression of DR5, thereby enhancing its function in inducing apoptosis. When these compounds were used in combination with the natural ligand of DR5, the number of apoptotic cells was significantly increased. These compounds are all promising for development as anti-prostate-cancer drugs, while most of these compounds are currently being evaluated for their anti-prostate-cancer effects at the cellular level and in animal studies. A great deal of more in-depth research is needed to evaluate whether they can be developed as drugs. We collected literature reports on small molecules against prostate cancer through modulation of DR5 to understand the current dynamics in this field and to evaluate the prospects of small molecules against prostate cancer through modulation of DR5.

14.
J Control Release ; 349: 783-795, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35908622

RESUMO

Skin melanoma is one of the most common cancer types in the United States and worldwide, and its incidence continues to grow. Primary skin melanoma can be removed surgically when feasible and if detected at an early stage. Anti-cancer drugs can be applied topically to treat skin cancer lesions and used as an adjunct to surgery to prevent the recurrence of tumor growth. We developed a topical formulation composed of Navitoclax (NAVI), a BCL-2 inhibitor that results in apoptosis, and an ionic liquid of choline octanoate (COA) to treat early-stage melanoma. NAVI is a small hydrophobic molecule that solubilizes at 20% (w/v) when dissolved in 50% COA. Although NAVI is a highly effective chemotherapeutic, it is equally thrombocytopenic. We found that COA-mediated topical delivery of NAVI enhanced its penetration into the skin and held the drug in the deeper skin layers for an extended period. Topical delivery of NAVI produced a higher cancer-cell killing efficacy than orally administrated NAVI. In vivo experiments in a mouse model of human melanoma-induced skin cancer confirmed the formulation's effectiveness via an apoptotic mechanism without any significant skin irritation or systemic absorption of NAVI. Overall, this topical approach may provide a safe and effective option for better managing skin cancer in the clinic.


Assuntos
Antineoplásicos , Líquidos Iônicos , Melanoma , Neoplasias Cutâneas , Administração Cutânea , Animais , Caprilatos/farmacologia , Caprilatos/uso terapêutico , Colina , Coenzima A/farmacologia , Coenzima A/uso terapêutico , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2 , Pele , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia
15.
Antioxidants (Basel) ; 11(7)2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35883869

RESUMO

A nanosized food-grade quercetin-loaded nanoemulsion (QNE) system comprising capmul MCM NF (oil) and cremophor RH 40 (surfactant) was developed using a high-speed homogenization technique. The developed QNE was studied for its significant neuroprotective (anti-Parkinsonism) and cytotoxicity (anticancer) effects against Caenorhabditis elegans (C. elegans) strains and human cancer cells, respectively. HR-TEM studies revealed that the QNE was spherical with a mean globule size of ~50 nm. Selected area electron diffraction (SAED) studies results demonstrated that QNE was amorphous. In vivo results show that QNE potentially reduced the α-Syn aggregation, increased mitochondrial and fat content, and improved the lifespan in transgenic C. elegans strain NL5901. QNE significantly downregulated the reactive oxygen species (ROS) levels in wild-type C. elegans strain N2. In vitro results of the MTT assay show that QNE significantly exhibited chemotherapeutic effects in all treated human cancer cells in an order of cytotoxicity: HeLa cells > A549 cells > MIA PaCa-2 cells, based on the IC50 values at 24 h. Conclusively, the QNE showed improved solubility, targetability, and neuroprotective effects against the PD-induced C. elegans model, and also cytotoxicity against human cancer cells and could be potentially used as an anti-Parkinson's or anticancer agent.

16.
Cells ; 11(14)2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35883606

RESUMO

Immunotherapy is an attractive therapeutic strategy for the treatment of osteosarcoma (OS). The unique features of γδ T cells have made them popular for cancer immunotherapy. Here, we expanded γδ T cells using human peripheral blood mononuclear cells (PBMCs) and investigated their therapeutic potential against OS cells. PBMCs from healthy donors were cultured for 10 days with CON medium (unstimulated control); EX media, CON with recombinant human interleukin-2 (rhIL-2) and zoledronate; and EX28 media, CON with rhIL-2, zoledronate, and CD3/CD28 activator. The expanded γδ T cells were isolated by magnetic cell separation or fluorescence-activated cell sorting, cultured with two OS cell lines (KHOS/NP and MG-63) at various cell ratios with or without doxorubicin or ifosfamide, and analyzed for cytotoxicity and cytokine secretion. The number of CD3+γδTCR+Vγ9+ triple-positive γδ T cells and concentrations of IFN-γ and TNF-α were highest in the rhIL-2 (100 IU) and zoledronate (1 µM) supplemented culture conditions. The CD3/CD28 agonist did not show any additional effects on γδ T cell expansion. The expanded γδ T cells exhibited potent in vitro cytotoxicity against OS in a ratio- and time-dependent manner. The γδ T cells may enhance the effect of chemotherapeutic agents against OS and may be a new treatment strategy, including chemo-immunotherapy, for OS.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Receptores de Antígenos de Linfócitos T gama-delta , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/terapia , Antígenos CD28/metabolismo , Difosfonatos/metabolismo , Difosfonatos/farmacologia , Humanos , Imidazóis/metabolismo , Imidazóis/farmacologia , Leucócitos Mononucleares/metabolismo , Osteossarcoma/metabolismo , Osteossarcoma/terapia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/uso terapêutico , Linfócitos T/metabolismo , Linfócitos T/transplante , Ácido Zoledrônico/farmacologia
17.
Photodiagnosis Photodyn Ther ; 39: 102991, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35779857

RESUMO

Nanodrug delivery systems are novel strategies for tumor treatment since delivery of chemotherapy drugs such as paclitaxel (PTX) is associated with substantial challenges due to its poor aqueous solubility. In addition, sonodynamic therapy (SDT) is a promising approach that can increase the uptake, accumulation, and dispersion of desirable amounts of the drugs by activating sonosensitizer and enhancing cell membrane permeability. Herein, gold-paclitaxel nanoparticles (Au-PTX NPs) were synthesized and characterized to evaluate the cytotoxicity toward C540 cancer cells in comparison of free PTX, AuNPs, and AuNPs+free PTX in the absence and presence of ultrasound radiation. Evidence shows that AuNPs have a median diameter size of 95.0 ± 15.4, while the size of Au-PTX NPs is roughly 219.7 ±  40.4 nm. Negative zeta-potential results indicate high stability and good dispersion of nanoparticles. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay results revealed that Au-PTX NPs increased the cytotoxicity compared to other treatment groups that ensure the great potential of AuNPs as a promising nano-carrier for PTX drug delivery. Moreover, the viability of C540 cells treated by Au-PTX NPs under ultrasound radiation was decreased significantly by generating more reactive oxygen species (ROS) upon STD, with representing synergism effects confirming the role of gold nanoparticles as an excellent sonosensitizer and the role of SDT as an adjunctive treatment method with chemotherapy.


Assuntos
Melanoma , Nanopartículas Metálicas , Nanopartículas , Fotoquimioterapia , Linhagem Celular Tumoral , Ouro/química , Humanos , Melanoma/tratamento farmacológico , Nanopartículas Metálicas/química , Nanopartículas/química , Paclitaxel/química , Paclitaxel/farmacologia , Fotoquimioterapia/métodos
18.
Front Oncol ; 12: 928204, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35814472

RESUMO

Objective: Many studies have drawn their attention to the immunotherapy of bladder urothelial carcinoma in terms of immunologic mechanisms of human body. These include immunogenicity of the tumor cells and involvement of long non-coding RNA (lncRNA). We constructed a necroptosis-related long noncoding RNA (nrlncRNA) risk factor model to predict BLCA outcomes and calculate correlations with chemosensitivity and immune infiltration. Methods: Transcriptomic data from BLCA specimens were accessed from The Cancer Genome Atlas, and nrlncRNAs were identified by performing co-expression analysis. Univariate analysis was performed to identify differentially expressed nrlncRNA pairs. We constructed least absolute contraction and selector operation regression models and drew receiver operating characteristic curves for 1-, 3-, and 5-year survival rates. Akaike information criterion (AIC) values for survival over 1 year were determined as cutoff values in high- and low-risk subgroups. We reassessed the differences between subgroups in terms of survival, clinicopathological characteristics, chemotherapy efficacy, tumor-infiltrating immune cells, and markers of immunosuppression. Results: We identified a total of 260 necroptosis-related lncRNA pairs, of which we incorporated 13 into the prognostic model. Areas under the curve of 1-, 3-, and 5- year survival time were 0.763, 0.836, and 0.842, respectively. We confirmed the excellent predictive performance of the risk model. Based on AIC values, we confirmed that the high-risk group was susceptible to unfavorable outcomes. The risk scores correlated with survival were age, clinical stage, grade, and tumor node metastases. The risk model was an independent predictor and demonstrated higher predictive power. The risk model can also be utilized to determine immune cell infiltration status, expression levels of immune checkpoint genes, and the sensitivity to cisplatin, doxorubicin, and methotrexate. Conclusion: We constructed a novel necroptosis-related signature that predicts BLCA outcomes and performs satisfactorily in the immune landscape and chemotherapeutic responses.

19.
Cancers (Basel) ; 14(14)2022 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-35884410

RESUMO

A major challenge in the clinical management of prostate cancer (PC) is to inhibit tumor growth and prevent metastatic spreading. In recent years, considerable efforts have been made to discover new compounds useful for PC therapy, and promising advances in this field were reached. Drugs currently used in PC therapy frequently induce resistance and PC progresses toward metastatic castration-resistant forms (mCRPC), making it virtually incurable. Curcumin, a commercially available nutritional supplement, represents an attractive therapeutic agent for mCRPC patients. In the present study, we compared the effects of chemotherapeutic drugs such as docetaxel, paclitaxel, and cisplatin, to curcumin, on two PC cell lines displaying a different metastatic potential: DU145 (moderate metastatic potential) and PC-3 (high metastatic potential). Our results revealed a dose-dependent reduction of DU145 and PC-3 cell viability upon treatment with curcumin similar to chemotherapeutic agents (paclitaxel, cisplatin, and docetaxel). Furthermore, we explored the EGFR-mediated signaling effects on ERK activation in DU145 and PC-3 cells. Our results showed that DU145 and PC-3 cells overexpress EGFR, and the treatment with chemotherapeutic agents or curcumin reduced EGFR expression levels and ERK activation. Finally, chemotherapeutic agents and curcumin reduced the size of DU145 and PC-3 spheroids and have the potential to induce apoptosis and also in Matrigel. In conclusion, despite different studies being carried out to identify the potential synergistic curcumin combinations with chemopreventive/therapeutic efficacy for inhibiting PC growth, the results show the ability of curcumin used alone, or in combinatorial approaches, to impair the size and the viability of PC-derived spheroids.

20.
Int J Mol Sci ; 23(14)2022 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-35887320

RESUMO

Supplementing chemotherapy and radiotherapy with selenium has been shown to have benefits against various cancers. This approach has also been shown to alleviate the side effects associated with standard cancer therapies and improve the quality of life in patients. In addition, selenium levels in patients have been correlated with various cancers and have served as a diagnostic marker to track the efficiency of treatments or to determine whether these selenium levels cause or are a result of the disease. This concise review presents a survey of the selenium-based literature, with a focus on hematological malignancies, to demonstrate the significant impact of selenium in different cancers. The anti-cancer mechanisms and signaling pathways regulated by selenium, which impart its efficacious properties, are discussed. An outlook into the relationship between selenium and cancer is highlighted to guide future cancer therapy development.


Assuntos
Neoplasias Hematológicas , Neoplasias , Selênio , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Neoplasias/tratamento farmacológico , Qualidade de Vida , Selênio/metabolismo
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