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12 pages, 3965 KiB

Open AccessArticle

In Vitro Antitumor and Antioxidant Capacity as well as Ameliorative Effects of Fermented Kefir on Cyclophosphamide-Induced Toxicity on Cardiac and Hepatic Tissues in Rats

by Songul Cetik Yildiz, Cemil Demir, Mustafa Cengiz, Halit Irmak, Betul Peker Cengiz and Adnan Ayhanci

Biomedicines 2024, 12(6), 1199; https://doi.org/10.3390/biomedicines12061199 - 28 May 2024

Cited by 1 | Viewed by 1338

Abstract

Fermented prebiotic and probiotic products with kefir are very important to slow down and prevent the growth of tumors and to treat cancer by stimulating the immune response against tumor cells. Cyclophosphamide (CPx) is widely preferred in cancer treatment but its effectiveness in [...] Read more.

Fermented prebiotic and probiotic products with kefir are very important to slow down and prevent the growth of tumors and to treat cancer by stimulating the immune response against tumor cells. Cyclophosphamide (CPx) is widely preferred in cancer treatment but its effectiveness in high doses is restricted because of its side effects. The aim of this study was to investigate the protective effects of kefir against CPx-induced heart and liver toxicity. In an experiment, 42 Wistar albino rats were divided into six treatment groups: the control (Group 1), the group receiving 150 mg/kg CPx (Group 2), the groups receiving 5 and 10 mg/kg kefir (Groups 3 and 4) and the groups receiving 5 and 10 mg/kg kefir + CPx (Group 5 and 6). Fermented kefirs obtained on different days by traditional methods were mixed and given by gavage for 12 days, while a single dose of CPx was administered intraperitoneally (i.p.) on the 12th day of the experiment. It was observed that alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), creatinine kinase-MB (CK-MB), ischemia modified albumin (IMA) and Troponin I values, which indicate oxidative stress, increased in the CPx-administered group, and this level approached that of the control in the CPx + kefir groups. Likewise, as a result of the kefir, the rats’ CPx-induced histopathological symptoms were reduced, and their heart and liver tissue were significantly improved. In conclusion, it was observed that kefir had a cytoprotective effect against CPx-induced oxidative stress, hepatotoxicity and cardiotoxicity, bringing their biochemical parameters closer to those of the control by suppressing oxidative stress and reducing tissue damage. Full article

(This article belongs to the Special Issue Advances in Cancer Biology and Experimental Anticancer Therapies)

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15 pages, 3816 KiB

Open AccessArticle

Rotundifuran Induces Ferroptotic Cell Death and Mitochondria Permeability Transition in Lung Cancer Cells

by Myung-Ji Kang, Dong-Oh Moon, Ji-Yoon Park, Namho Kim, Su Hyeon Lee, Hyung Won Ryu, Yang Hoon Huh, Hyun-Sun Lee and Mun-Ock Kim

Biomedicines 2024, 12(3), 576; https://doi.org/10.3390/biomedicines12030576 - 5 Mar 2024

Cited by 3 | Viewed by 1498

Abstract

Rotundifuran (RF), a potent anti-inflammatory and anti-cancer compound, is a natural compound predominantly present in Vitex Rotundifolia. Herein, we investigated the effects of RF on the growth of lung cancer cells. Our findings suggested that RF inhibits cell growth, highlighting its potential [...] Read more.

Rotundifuran (RF), a potent anti-inflammatory and anti-cancer compound, is a natural compound predominantly present in Vitex Rotundifolia. Herein, we investigated the effects of RF on the growth of lung cancer cells. Our findings suggested that RF inhibits cell growth, highlighting its potential as a therapeutic agent for cancer treatment. Interestingly, we observed that cell growth inhibition was not due to apoptosis, as caspases were not activated and DNA fragmentation did not occur. Furthermore, we found that intracellular vacuoles and autophagy were induced, but RF-induced cell death was not affected when autophagy was inhibited. This prompted us to investigate other possible mechanisms underlying cell growth inhibition. Through a cDNA chip analysis, we confirmed changes in the expression of ferroptosis-related genes and observed lipid peroxidation. We further examined the effect of ferroptosis inhibitors and found that they alleviated cell growth inhibition induced by RF. We also observed the involvement of calcium signaling, ROS accumulation, and JNK signaling in the induction of ferroptosis. Our findings suggested that RF is a potent anti-cancer drug and further studies are needed to validate its clinal use. Full article

(This article belongs to the Special Issue Advances in Cancer Biology and Experimental Anticancer Therapies)

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16 pages, 3209 KiB

Open AccessArticle

A Novel Druggable Dual-Specificity tYrosine-Regulated Kinase3/Calmodulin Kinase-like Vesicle-Associated Signaling Module with Therapeutic Implications in Neuroblastoma

by Esteban J. Rozen, Kim Wigglesworth and Jason M. Shohet

Biomedicines 2024, 12(1), 197; https://doi.org/10.3390/biomedicines12010197 - 16 Jan 2024

Cited by 1 | Viewed by 1483

Abstract

High-risk neuroblastoma is a very aggressive pediatric cancer, accounting for ~15% of childhood cancer mortality. Therefore, novel therapeutic strategies for the treatment of neuroblastoma are urgently sought. Here, we focused on the potential implications of the Dual-specificity tYrosine-Regulated Kinase (DYRK) family and downstream [...] Read more.

High-risk neuroblastoma is a very aggressive pediatric cancer, accounting for ~15% of childhood cancer mortality. Therefore, novel therapeutic strategies for the treatment of neuroblastoma are urgently sought. Here, we focused on the potential implications of the Dual-specificity tYrosine-Regulated Kinase (DYRK) family and downstream signaling pathways. We used bioinformatic analysis of public datasets from neuroblastoma cohorts and cell lines to search correlations between patient survival and expression of DYRK kinases. Additionally, we performed biochemical, molecular, and cellular approaches to validate and characterize our observations, as well as an in vivo orthotopic murine model of neuroblastoma. We identified the DYRK3 kinase as a critical mediator of neuroblastoma cell proliferation and in vivo tumor growth. DYRK3 has recently emerged as a key regulator of several biomolecular condensates and has been linked to the hypoxic response of neuroblastoma cells. Our data suggest a role for DYRK3 as a regulator of the neuroblastoma-specific protein CAMKV, which is also required for neuroblastoma cell proliferation. CAMKV is a very understudied member of the Ca²⁺/calmodulin-dependent protein kinase family, originally described as a pseudokinase. We show that CAMKV is phosphorylated by DYRK3, and that inhibition of DYRK3 kinase activity induces CAMKV aggregation, probably mediated by its highly disordered C-terminal half. Importantly, we provide evidence that the DYRK3/CAMKV signaling module could play an important role for the function of the mitotic spindle during cell division. Our data strongly support the idea that inhibition of DYRK3 and/or CAMKV in neuroblastoma cells could constitute an innovative and highly specific intervention to fight against this dreadful cancer. Full article

(This article belongs to the Special Issue Advances in Cancer Biology and Experimental Anticancer Therapies)

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29 pages, 9768 KiB

Open AccessArticle

2-Aminoethyl Dihydrogen Phosphate (2-AEH2P) Associated with Cell Metabolism-Modulating Drugs Presents a Synergistic and Pro-Apoptotic Effect in an In Vitro Model of the Ascitic Ehrlich Tumor

by Monique G. Alves, Laertty G. S. Cabral, Paulo G. F. Totti, Felipe R. Azarias, Karine T. Pomini, Rose E. G. Rici, Rosa A. N. Laiso and Durvanei A. Maria

Biomedicines 2024, 12(1), 109; https://doi.org/10.3390/biomedicines12010109 - 4 Jan 2024

Viewed by 1542

Abstract

The progression and maintenance of cancer characteristics are associated with cellular components linked to the tumor and non-cellular components with pro-tumoral properties. Pharmacological association with antagonists of the cellular components of the tumor, such as anti- and pro-apoptotic drugs, represents a novel adjuvant [...] Read more.

The progression and maintenance of cancer characteristics are associated with cellular components linked to the tumor and non-cellular components with pro-tumoral properties. Pharmacological association with antagonists of the cellular components of the tumor, such as anti- and pro-apoptotic drugs, represents a novel adjuvant strategy. In this study, the antiproliferative, pro-apoptotic, and pharmacological effects of the combination of monophosphoester 2-AEH2P with Simvastatin, Coenzyme Q10, the chemotherapeutic drug paclitaxel, and colony-stimulating factor (GM-CSF) were evaluated. Tests were conducted to determine cytotoxic activity using the MTT method, cell cycle phases, and fragmented DNA by flow cytometry, mitochondrial membrane potential, expression of cell markers Bcl2, TNF-α/DR-4, Cytochrome c, caspase 3, and P53, and analysis of drug combination profiles using Synergy Finder 2.0 Software. The results showed a synergistic effect among the combinations, compared to individual treatments with the monophosphoester and other drugs. In addition, there was modulation of marker expression, indicating a pro-apoptotic and immunomodulatory effect of 2-AEH2P. Pharmacological analysis revealed that tumor cells treated with GM-CSF + 2-AEH2P exhibited a synergistic effect, while groups of tumor cells treated with paclitaxel, Coenzyme Q10, and Simvastatin showed additive effects. Furthermore, treatment with the paclitaxel + 2-AEH2P combination (12 h) resulted in a significant reduction in mitochondrial membrane potential. Pharmacological combinations for normal cells did not exhibit deleterious effects compared to mammary carcinomatosis tumor (EAT) cells. Full article

(This article belongs to the Special Issue Advances in Cancer Biology and Experimental Anticancer Therapies)

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22 pages, 7809 KiB

Open AccessArticle

Anti-Cancer Potential of Transiently Transfected HER2-Specific Human Mixed CAR-T and NK Cell Populations in Experimental Models: Initial Studies on Fucosylated Chondroitin Sulfate Usage for Safer Treatment

by Irina O. Chikileva, Alexandra V. Bruter, Nadezhda A. Persiyantseva, Maria A. Zamkova, Raimonda Ya. Vlasenko, Yuliya I. Dolzhikova, Irina Zh. Shubina, Fedor V. Donenko, Olga V. Lebedinskaya, Darina V. Sokolova, Vadim S. Pokrovsky, Polina O. Fedorova, Nadezhda E. Ustyuzhanina, Natalia Yu. Anisimova, Nikolay E. Nifantiev and Mikhail V. Kiselevskiy

Biomedicines 2023, 11(9), 2563; https://doi.org/10.3390/biomedicines11092563 - 18 Sep 2023

Cited by 2 | Viewed by 1935

Abstract

Human epidermal growth factor receptor 2 (HER2) is overexpressed in numerous cancer cell types. Therapeutic antibodies and chimeric antigen receptors (CARs) against HER2 were developed to treat human tumors. The major limitation of anti-HER2 CAR-T lymphocyte therapy is attributable to the low HER2 [...] Read more.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in numerous cancer cell types. Therapeutic antibodies and chimeric antigen receptors (CARs) against HER2 were developed to treat human tumors. The major limitation of anti-HER2 CAR-T lymphocyte therapy is attributable to the low HER2 expression in a wide range of normal tissues. Thus, side effects are caused by CAR lymphocyte “on-target off-tumor” reactions. We aimed to develop safer HER2-targeting CAR-based therapy. CAR constructs against HER2 tumor-associated antigen (TAA) for transient expression were delivered into target T and natural killer (NK) cells by an effective and safe non-viral transfection method via nucleofection, excluding the risk of mutations associated with viral transduction. Different in vitro end-point and real-time assays of the CAR lymphocyte antitumor cytotoxicity and in vivo human HER2-positive tumor xenograft mice model proved potent cytotoxic activity of the generated CAR-T-NK cells. Our data suggest transient expression of anti-HER2 CARs in plasmid vectors by human lymphocytes as a safer treatment for HER2-positive human cancers. We also conducted preliminary investigations to elucidate if fucosylated chondroitin sulfate may be used as a possible agent to decrease excessive cytokine production without negative impact on the CAR lymphocyte antitumor effect. Full article

(This article belongs to the Special Issue Advances in Cancer Biology and Experimental Anticancer Therapies)

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11 pages, 2692 KiB

Open AccessArticle

High-Resolution Magic-Angle-Spinning NMR in Revealing Hepatoblastoma Hallmarks

by Ljubica Tasic, Nataša Avramović, Milka Jadranin, Melissa Quintero, Danijela Stanisic, Lucas G. Martins, Tássia Brena Barroso Carneiro Costa, Estela Novak, Vicente Odone, Maria Rivas, Talita Aguiar, Dirce Maria Carraro, Isabela Werneck da Cunha, Cecilia Maria Lima da Costa, Mariana Maschietto and Ana Krepischi

Biomedicines 2022, 10(12), 3091; https://doi.org/10.3390/biomedicines10123091 - 1 Dec 2022

Cited by 4 | Viewed by 1905

Abstract

Cancer is one of the leading causes of death in children and adolescents worldwide; among the types of liver cancer, hepatoblastoma (HBL) is the most common in childhood. Although it affects only two to three individuals in a million, it is mostly asymptomatic [...] Read more.

Cancer is one of the leading causes of death in children and adolescents worldwide; among the types of liver cancer, hepatoblastoma (HBL) is the most common in childhood. Although it affects only two to three individuals in a million, it is mostly asymptomatic at diagnosis, so by the time it is detected it has already advanced. There are specific recommendations regarding HBL treatment, and ongoing studies to stratify the risks of HBL, understand the pathology, and predict prognostics and survival rates. Although magnetic resonance imaging spectroscopy is frequently used in diagnostics of HBL, high-resolution magic-angle-spinning (HR-MAS) NMR spectroscopy of HBL tissues is scarce. Using this technique, we studied the alterations among tissue metabolites of ex vivo samples from (a) HBL and non-cancer liver tissues (NCL), (b) HBL and adjacent non-tumor samples, and (c) two regions of the same HBL samples, one more centralized and the other at the edge of the tumor. It was possible to identify metabolites in HBL, then metabolites from the HBL center and the border samples, and link them to altered metabolisms in tumor tissues, highlighting their potential as biochemical markers. Metabolites closely related to liver metabolisms such as some phospholipids, triacylglycerides, fatty acids, glucose, and amino acids showed differences between the tissues. Full article

(This article belongs to the Special Issue Advances in Cancer Biology and Experimental Anticancer Therapies)

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Review

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36 pages, 1627 KiB

Open AccessReview

Current Non-Metal Nanoparticle-Based Therapeutic Approaches for Glioblastoma Treatment

by Agata M. Gawel, Anna Betkowska, Ewa Gajda, Marlena Godlewska and Damian Gawel

Biomedicines 2024, 12(8), 1822; https://doi.org/10.3390/biomedicines12081822 - 11 Aug 2024

Cited by 1 | Viewed by 1479

Abstract

The increase in the variety of nano-based tools offers new possibilities to approach the therapy of poorly treatable tumors, which includes glioblastoma multiforme (GBM; a primary brain tumor). The available nanocomplexes exhibit great potential as vehicles for the targeted delivery of anti-GBM compounds, [...] Read more.

The increase in the variety of nano-based tools offers new possibilities to approach the therapy of poorly treatable tumors, which includes glioblastoma multiforme (GBM; a primary brain tumor). The available nanocomplexes exhibit great potential as vehicles for the targeted delivery of anti-GBM compounds, including chemotherapeutics, nucleic acids, and inhibitors. The main advantages of nanoparticles (NPs) include improved drug stability, increased penetration of the blood–brain barrier, and better precision of tumor targeting. Importantly, alongside their drug-delivery ability, NPs may also present theranostic properties, including applications for targeted imaging or photothermal therapy of malignant brain cells. The available NPs can be classified into two categories according to their core, which can be metal or non-metal based. Among non-metal NPs, the most studied in regard to GBM treatment are exosomes, liposomes, cubosomes, polymeric NPs, micelles, dendrimers, nanogels, carbon nanotubes, and silica- and selenium-based NPs. They are characterized by satisfactory stability and biocompatibility, limited toxicity, and high accumulation in the targeted tumor tissue. Moreover, they can be easily functionalized for the improved delivery of their cargo to GBM cells. Therefore, the non-metal NPs discussed here, offer a promising approach to improving the treatment outcomes of aggressive GBM tumors. Full article

(This article belongs to the Special Issue Advances in Cancer Biology and Experimental Anticancer Therapies)

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23 pages, 1312 KiB

Open AccessReview

Ribosome-Directed Therapies in Cancer

by Gazmend Temaj, Silvia Chichiarelli, Margherita Eufemi, Fabio Altieri, Rifat Hadziselimovic, Ammad Ahmad Farooqi, Ilhan Yaylim and Luciano Saso

Biomedicines 2022, 10(9), 2088; https://doi.org/10.3390/biomedicines10092088 - 26 Aug 2022

Cited by 14 | Viewed by 4397

Abstract

The human ribosomes are the cellular machines that participate in protein synthesis, which is deeply affected during cancer transformation by different oncoproteins and is shown to provide cancer cell proliferation and therefore biomass. Cancer diseases are associated with an increase in ribosome biogenesis [...] Read more.

The human ribosomes are the cellular machines that participate in protein synthesis, which is deeply affected during cancer transformation by different oncoproteins and is shown to provide cancer cell proliferation and therefore biomass. Cancer diseases are associated with an increase in ribosome biogenesis and mutation of ribosomal proteins. The ribosome represents an attractive anti-cancer therapy target and several strategies are used to identify specific drugs. Here we review the role of different drugs that may decrease ribosome biogenesis and cancer cell proliferation. Full article

(This article belongs to the Special Issue Advances in Cancer Biology and Experimental Anticancer Therapies)

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