Hyaluronate Functionalized Multi-Wall Carbon Nanotubes Filled with Carboplatin as a Novel Drug Nanocarrier against Murine Lung Cancer Cells

Carbon nanotubes (CNTs) have emerged in recent years as a potential option for drug delivery, due to their high functionalization capacity. Biocompatibility and selectivity using tissue-specific biomolecules can optimize the specificity, pharmacokinetics and stability of the drug. In this study, we design, develop and characterize a drug nanovector (oxCNTs-HA-CPT) conjugating oxidated multi-wall carbon nanotubes (oxCNTs) with hyaluronate (HA) and carboplatin (CPT) as a treatment in a lung cancer model in vitro. Subsequently, we exposed TC–1 and NIH/3T3 cell lines to the nanovectors and measured cell uptake, cell viability, and oxidative stress induction. The characterization of oxCNTs-HA-CPT reveals that on their surface, they have HA. On the other hand, oxCNTs-HA-CPT were endocytosed in greater proportion by tumor cells than by fibroblasts, and likewise, the cytotoxic effect was significantly higher in tumor cells. These results show the therapeutic potential that nanovectors possess; however, future studies should be carried out to determine the death pathways involved, as well as their effect on in vivo models.

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Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

Melatonin Research ◽

10.32794/mr11250042 ◽

2019 ◽

Vol 2 (4) ◽

pp. 83-98 ◽

Cited By ~ 2

Author(s):

André De Lima Mota ◽

Bruna Vitorasso Jardim-Perassi ◽

Tialfi Bergamin De Castro ◽

Jucimara Colombo ◽

Nathália Martins Sonehara ◽

...

Keyword(s):

Breast Cancer ◽

Glucose Metabolism ◽

Tumor Growth ◽

Tumor Cells ◽

Carbonic Anhydrases ◽

In Vivo Models ◽

Ca Ix ◽

Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression.

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GSK-3β in Pancreatic Cancer: Spotlight on 9-ING-41, Its Therapeutic Potential and Immune Modulatory Properties

Biology ◽

10.3390/biology10070610 ◽

2021 ◽

Vol 10 (7) ◽

pp. 610

Author(s):

Robin Park ◽

Andrew L. Coveler ◽

Ludimila Cavalcante ◽

Anwaar Saeed

Keyword(s):

Pancreatic Cancer ◽

Therapeutic Potential ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

In Vivo Models ◽

Gsk 3Β ◽

Early Phase Clinical Trials

Glycogen synthase kinase-3 beta is a ubiquitously and constitutively expressed molecule with pleiotropic function. It acts as a protooncogene in the development of several solid tumors including pancreatic cancer through its involvement in various cellular processes including cell proliferation, survival, invasion and metastasis, as well as autophagy. Furthermore, the level of aberrant glycogen synthase kinase-3 beta expression in the nucleus is inversely correlated with tumor differentiation and survival in both in vitro and in vivo models of pancreatic cancer. Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.

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Plant-Derived Nano and Microvesicles for Human Health and Therapeutic Potential in Nanomedicine

Pharmaceutics ◽

10.3390/pharmaceutics13040498 ◽

2021 ◽

Vol 13 (4) ◽

pp. 498

Author(s):

Mariaevelina Alfieri ◽

Antonietta Leone ◽

Alfredo Ambrosone

Keyword(s):

Therapeutic Potential ◽

Biological Activities ◽

Plant Biotechnology ◽

Bioactive Metabolites ◽

Anticancer Activities ◽

Long Distance ◽

In Vivo Models ◽

Therapeutic Tools

Plants produce different types of nano and micro-sized vesicles. Observed for the first time in the 60s, plant nano and microvesicles (PDVs) and their biological role have been inexplicably under investigated for a long time. Proteomic and metabolomic approaches revealed that PDVs carry numerous proteins with antifungal and antimicrobial activity, as well as bioactive metabolites with high pharmaceutical interest. PDVs have also been shown to be also involved in the intercellular transfer of small non-coding RNAs such as microRNAs, suggesting fascinating mechanisms of long-distance gene regulation and horizontal transfer of regulatory RNAs and inter-kingdom communications. High loading capacity, intrinsic biological activities, biocompatibility, and easy permeabilization in cell compartments make plant-derived vesicles excellent natural or bioengineered nanotools for biomedical applications. Growing evidence indicates that PDVs may exert anti-inflammatory, anti-oxidant, and anticancer activities in different in vitro and in vivo models. In addition, clinical trials are currently in progress to test the effectiveness of plant EVs in reducing insulin resistance and in preventing side effects of chemotherapy treatments. In this review, we concisely introduce PDVs, discuss shortly their most important biological and physiological roles in plants and provide clues on the use and the bioengineering of plant nano and microvesicles to develop innovative therapeutic tools in nanomedicine, able to encompass the current drawbacks in the delivery systems in nutraceutical and pharmaceutical technology. Finally, we predict that the advent of intense research efforts on PDVs may disclose new frontiers in plant biotechnology applied to nanomedicine.

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Sphingosine 1-phosphate in inflammation

Journal of Clinical and Nursing Research ◽

10.26689/jcnr.v4i6.1610 ◽

2020 ◽

Vol 4 (6) ◽

Author(s):

Lijuan Li ◽

Lixia An ◽

Lifang Li ◽

Yongjuan Zhao

Keyword(s):

Plasma Membrane ◽

Drug Targets ◽

Therapeutic Potential ◽

Cell Types ◽

In Vivo Models ◽

Integral Role ◽

Sphingosine 1 Phosphate ◽

And Migration

Sphingolipids are formed via the metabolism of sphingomyelin, aconstituent of the plasma membrane, or by denovosynthesis. Enzymatic pathways result in the formation of several different lipid mediators, which are known to have important roles in many cellular processes, including proliferation, apoptosis and migration. Several studies now suggest that these sphingolipid mediators, including ceramide, ceramide 1-phosphate and sphingosine 1-phosphate (S1P), are likely to have an integral role in in?ammation. This can involve, for example, activation of pro-in?ammatory transcription factors in different cell types and induction of cyclooxygenase-2, leading to production of pro-in?ammatory prostaglandins. The mode of action of each sphingolipid is different. Increased ceramide production leads to the formation of ceramide-rich areas of the membrane, which may assemble signalling complexes, whereas S1P acts via high-af?nity G-protein-coupled S1P receptors on the plasma membrane. Recent studies have demonstrated that in vitro effects of sphingolipids on in?ammation can translate into in vivo models. This review will highlight the areas of research where sphingolipids are involved in in?ammation and the mechanisms of action of each mediator. In addition, the therapeutic potential of drugs that alter sphingolipid actions will be examined with reference to disease states, such as asthma and in?ammatory bowel disease, which involve important in?ammatory components. A signi?cant body of research now indicates that sphingolipids are intimately involved in the in?ammatory process and recent studies have demonstrated that these lipids, together with associated enzymes and receptors, can provide effective drug targets for the treatment of pathological in?ammation.

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Anti-Inflammatory Potential of Daturaolone from Datura innoxia Mill.: In Silico, In Vitro and In Vivo Studies

Pharmaceuticals ◽

10.3390/ph14121248 ◽

2021 ◽

Vol 14 (12) ◽

pp. 1248

Author(s):

Muhammad Waleed Baig ◽

Humaira Fatima ◽

Nosheen Akhtar ◽

Hidayat Hussain ◽

Mohammad K. Okla ◽

...

Keyword(s):

In Silico ◽

Therapeutic Potential ◽

In Vivo Studies ◽

Metabolic Reaction ◽

Datura Innoxia ◽

In Vivo Models ◽

Immobility Time ◽

Anti Inflammatory

Exploration of leads with therapeutic potential in inflammatory disorders is worth pursuing. In line with this, the isolated natural compound daturaolone from Datura innoxia Mill. was evaluated for its anti-inflammatory potential using in silico, in vitro and in vivo models. Daturaolone follows Lipinski’s drug-likeliness rule with a score of 0.33. Absorption, distribution, metabolism, excretion and toxicity prediction show strong plasma protein binding; gastrointestinal absorption (Caco-2 cells permeability = 34.6 nm/s); no blood–brain barrier penetration; CYP1A2, CYP2C19 and CYP3A4 metabolism; a major metabolic reaction, being aliphatic hydroxylation; no hERG inhibition; and non-carcinogenicity. Predicted molecular targets were mainly inflammatory mediators. Molecular docking depicted H-bonding interaction with nuclear factor kappa beta subunit (NF-κB), cyclooxygenase-2, 5-lipoxygenase, phospholipase A2, serotonin transporter, dopamine receptor D1 and 5-hydroxy tryptamine. Its cytotoxicity (IC50) value in normal lymphocytes was >20 µg/mL as compared to cancer cells (Huh7.5; 17.32 ± 1.43 µg/mL). Daturaolone significantly inhibited NF-κB and nitric oxide production with IC50 values of 1.2 ± 0.8 and 4.51 ± 0.92 µg/mL, respectively. It significantly reduced inflammatory paw edema (81.73 ± 3.16%), heat-induced pain (89.47 ± 9.01% antinociception) and stress-induced depression (68 ± 9.22 s immobility time in tail suspension test). This work suggests a possible anti-inflammatory role of daturaolone; however, detailed mechanistic studies are still necessary to corroborate and extrapolate the findings.

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Metabolic breakdown of non-small cell lung cancers by mitochondrial HSPD1 targeting

10.1101/2021.03.09.434573 ◽

2021 ◽

Author(s):

Beatrice Parma ◽

Vignesh Ramesh ◽

Paradesi Naidu Gollavilli ◽

Aarif Siddiqui ◽

Luisa Pinna ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Progression ◽

Therapeutic Potential ◽

Small Cell ◽

Small Cell Lung ◽

Lung Cancers ◽

Metabolism Enzymes ◽

Shock Proteins

ABSTRACTThe identification of novel targets is of paramount importance to develop more effective drugs and improve the treatment of non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths worldwide. Since cells alter their metabolic rewiring during tumorigenesis and along cancer progression, targeting key metabolic players and metabolism-associated proteins represents a valuable approach with a high therapeutic potential. Metabolic fitness relies on the functionality of heat shock proteins (HSPs), molecular chaperones that facilitate the correct folding of metabolism enzymes and their assembly in macromolecular structures. Here, we show HSPD1 (HSP60) as a survival gene ubiquitously expressed in NSCLC and associated with poor patients’ prognosis. HSPD1 knockdown or its chemical disruption by the small molecule KHS101 induces a drastic breakdown of oxidative phosphorylation, and suppresses cell proliferation both in vitro and in vivo. By combining drug profiling with transcriptomics and through a whole-genome CRISPR/Cas9 screen, we demonstrate that HSPD1-targeted anti-cancer effects are dependent on OXPHOS and validated molecular determinants of KHS101 sensitivity, in particular, the creatine-transporter SLC6A8 and the subunit of the cytochrome c oxidase complex COX5B. These results highlight mitochondrial metabolism as an attractive target and HSPD1 as a potential theranostic marker for developing therapies to combat NCSLC.SignificanceHSPD1 elimination or disruption interferes with NSCLC metabolic activity causing a strong OXPHOS-dependent energetic breakdown, which the cancer cells fail to overcome, highlighting HSPD1 as a potential theranostic marker for improving lung cancer therapy.

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Synergy of nanodiamond-doxorubicin conjugates and PD-L1 blockade effectively turns tumor associated macrophages against tumor cells

10.21203/rs.3.rs-715564/v1 ◽

2021 ◽

Author(s):

Huazhen Xu ◽

Tongfei Li ◽

Chao Wang ◽

Yan Ma ◽

Yan Liu ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Cell ◽

Cancer Cells ◽

Tumor Cells ◽

Lung Cancer Cells ◽

Dependent Manner ◽

Tumor Associated Macrophages ◽

M1 Type

Abstract Background: Tumor-associated macrophages (TAM) are the most abundant stromal cells in the tumor microenvironment. Turning the TAM against their host tumor cells is an intriguing therapeutic strategy particularly attractive for patients with immunologically “cold” tumors. This concept was mechanistically demonstrated on in vitro human and murine lung cancer cells and their corresponding TAM models through combinatorial use of nanodiamond-doxorubicin conjugates (Nano-DOX) and a PD-L1 blocking agent BMS-1. Nano-DOX are an agent previously proved to be able to stimulate tumor cells’ immunogenicity and thereby reactivate the TAM into the anti-tumor M1 phenotype. Results: Nano-DOX were first shown to stimulate the tumor cells and the TAM to release the cytokine HMGB1 which, regardless of its source, acted through the RAGE/NF-κB pathway to induce PD-L1 in the tumor cells and PD-L1/PD-1 in the TAM. Interestingly, Nano-DOX also induced NF-κB-dependent RAGE expression in the tumor cells and thus reinforced HMGB1’s action thereon. Then, BMS-1 was shown to enhance Nano-DOX-stimulated M1-type activation of TAM both by blocking Nano-DOX-induced PD-L1 in the TAM and by blocking tumor cell PD-L1 ligation with TAM PD-1. The TAM with enhanced M1-type repolarization both killed the tumor cells and suppressed their growth. BMS-1 could also potentiate Nano-DOX’s action to suppress tumor cell growth via blocking of Nano-DOX-induced PD-L1 therein. Finally, Nano-DOX and BMS-1 achieved synergistic therapeutic efficacy against in vivo tumor grafts in a TAM-dependent manner. Conclusions: PD-L1/PD-1 upregulation mediated by autocrine and paracrine activation of the HMGB1/RAGE/NF-κB signaling is a key response of lung cancer cells and their TAM to stress, which can be induced by Nano-DOX. Blockade of Nano-DOX-induced PD-L1, both in the cancer cells and the TAM, achieves enhanced activation of TAM-mediated anti-tumor response.

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Influence of Carbon Nanotubes and Its Derivatives on Tumor Cells In Vitro and Biochemical Parameters, Cellular Blood Composition In Vivo

Nanoscale Research Letters ◽

10.1186/s11671-018-2689-9 ◽

2018 ◽

Vol 13 (1) ◽

Cited By ~ 5

Author(s):

Olena M. Perepelytsina ◽

Andriy P. Ugnivenko ◽

Alexey V. Dobrydnev ◽

Olga N. Bakalinska ◽

Andrii I. Marynin ◽

...

Keyword(s):

Carbon Nanotubes ◽

Tumor Cells ◽

Biochemical Parameters ◽

Blood Composition

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Breast Tumor Cells Highly Resistant to Drugs Are Controlled Only by the Immune Response Induced in an Immunocompetent Mouse Model

Integrative Cancer Therapies ◽

10.1177/1534735419848047 ◽

2019 ◽

Vol 18 ◽

pp. 153473541984804 ◽

Cited By ~ 7

Author(s):

Paola Lasso ◽

Mónica Llano Murcia ◽

Tito Alejandro Sandoval ◽

Claudia Urueña ◽

Alfonso Barreto ◽

...

Keyword(s):

Breast Cancer ◽

Immune Response ◽

Tumor Cells ◽

High Capacity ◽

Cancer Cell Line ◽

Tumor Model ◽

Main Element ◽

In Vivo Models

Background: The tumor cells responsible for metastasis are highly resistant to chemotherapy and have characteristics of stem cells, with a high capacity for self-regeneration and the use of detoxifying mechanisms that participate in drug resistance. In vivo models of highly resistant cells allow us to evaluate the real impact of the immune response in the control of cancer. Materials and Methods: A tumor population derived from the 4T1 breast cancer cell line that was stable in vitro and highly aggressive in vivo was obtained, characterized, and determined to exhibit cancer stem cell (CSC) phenotypes (CD44+, CD24+, ALDH+, Oct4+, Nanog+, Sox2+, and high self-renewal capacity). Orthotopic transplantation of these cells allowed us to evaluate their in vivo susceptibility to chemo and immune responses induced after vaccination. Results: The immune response induced after vaccination with tumor cells treated with doxorubicin decreased the formation of tumors and macrometastasis in this model, which allowed us to confirm the immune response relevance in the control of highly chemotherapy-resistant ALDH+ CSCs in an aggressive tumor model in immunocompetent animals. Conclusions: The antitumor immune response was the main element capable of controlling tumor progression as well as metastasis in a highly chemotherapy-resistant aggressive breast cancer model.

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Functional Studies on Viable Circulating Tumor Cells

Clinical Chemistry ◽

10.1373/clinchem.2015.242537 ◽

2016 ◽

Vol 62 (2) ◽

pp. 328-334 ◽

Cited By ~ 53

Author(s):

Klaus Pantel ◽

Catherine Alix-Panabières

Keyword(s):

Cancer Patients ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Diagnostics ◽

Published Data ◽

Liquid Biopsies ◽

In Vivo Models ◽

Functional Studies

AbstractBACKGROUNDResearch on circulating tumor cells (CTCs) as new biomarkers has received great attention over the past decade. In particular, the capture and analysis of CTCs as “liquid biopsies” provides the possibility to avoid invasive tissue biopsies, with obvious implications in cancer diagnostics.CONTENTThe focus of this review is to describe and discuss how functional studies on viable CTCs can enlarge the spectrum of applications of liquid biopsies, with emphasis on breast, prostate, colon, and lung cancer as the major tumor entities in industrialized countries. The low number of CTCs in the peripheral blood of most cancer patients makes challenging the in vitro culture of CTCs. Epithelial tumor cells are difficult to culture, even when starting with millions of tumor cells. Recently, several groups have achieved important advances in the in vitro and in vivo expansion of CTCs from cancer patients at very advanced stages with higher amounts of CTCs. Here, we present current technologies to enrich and detect viable human CTCs, including positive and negative enrichment strategies that are based on antigen expression and physical properties of CTCs. We also discuss published data about functional studies on CTCs that use in vitro and in vivo models.SUMMARYFunctional analyses on CTCs offer the possibility to identify the biological properties of metastatic cells, including the identification of metastasis-initiating cells. Moreover, CTC-derived cell lines and xenografts might reveal new therapeutic targets and can be used for drug screening.

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