Therapeutic Potential of 1,8-Dihydroanthraquinone Derivatives for Breast Cancer.

Breast cancer (BC) is the most common malignancy among women worldwide. In recent years, significant progress has been made in BC therapy. However, serious side effects resulting from the use of standard chemotherapeutic drugs, as well as the phenomenon of multidrug resistance (MDR), limit the effectiveness of approved therapies. Advanced research in the BC area is necessary to create more effective and safer forms of therapy to improve the outlook for individuals diagnosed with this aggressive neoplasm. For decades, plants and natural products with anticancer properties have been successfully utilized in treating various medical conditions. Anthraquinone derivatives are tricyclic secondary metabolites of natural origin that have been identified in plants, lichens, and fungi. They represent a few botanical families, e.g., Rhamnaceae, Rubiaceae, Fabaceae, Polygonaceae, and others. The review comprehensively covers and analyzes the most recent advances in the anticancer activity of 1,8-dihydroanthraquinone derivatives (emodin, aloe-emodin, hypericin, chrysophanol, rhein, and physcion) applied both individually, or in combination with other chemotherapeutic agents, in in vitro and in vivo BC models. The application of nanoparticles for in vitro and in vivo evidence in the context of 1,8-dihydroanthraquinone derivatives was also described.

Emodin-8-O-Glucoside-Isolation and the Screening of the Anticancer Potential against the Nervous System Tumors.

Emodin-8-O-glucoside (E-8-O-G) is a glycosylated derivative of emodin that exhibits numerous biological activities, including immunomodulatory, anti-inflammatory, antioxidant, hepatoprotective, or anticancer activities. However, there are no reports on the activity of E-8-O-G against cancers of the nervous system. Therefore, the aim of the study was to investigate the antiproliferative and cytotoxic effect of E-8-O-G in the SK-N-AS neuroblastoma, T98G human glioblastoma, and C6 mouse glioblastoma cancer cells. As a source of E-8-O-G the methanolic extract from the aerial parts of Reynoutria japonica Houtt. (Polygonaceae) was used. Thanks to the application of centrifugal partition chromatography (CPC) operated in the descending mode using a mixture of petroleum ether:ethyl acetate:methanol:water (4:5:4:5 v/v/v/v) and a subsequent purification with preparative HPLC, E-8-O-G was obtained in high purity in a sufficient quantity for the bioactivity tests. Assessment of the cancer cell viability and proliferation were performed with the MTT (3-(bromide 4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium), CTG (CellTiter-Glo®) and BrdU (5-bromo-2'-deoxyuridine) assays, respectively. E-8-O-G inhibits the viability and proliferation of SK-N-AS neuroblastoma, T98G human glioblastoma multiforme, and C6 mouse glioblastoma cells dose-dependently. E-8-O-G seems to be a promising natural antitumor compound in the therapy of nervous system tumors.

Advancements in Zebrafish Models for Breast Cancer Research: Unveiling Biomarkers, Targeted Therapies, and Personalized Medicine.

Breast cancer (BC) is the most frequently diagnosed malignancy in women worldwide. Despite the wide variety of therapeutic methods for BC, their results are not satisfying, especially in triple-negative breast cancer (TNBC) patients. One of the main challenges in efficient oncology is achieving optimal conditions to evaluate a molecular genotype and phenotype of a tumor. Therefore, new therapeutic strategies are urgently needed. Animal models are an important tool for the molecular and functional characterization of BC, and for the development of targeted BC therapies. Zebrafish, as a promising screening model organism, has been widely applied in the development of patient-derived xenografts (PDX) for the discovery of novel potential antineoplastic drugs. Moreover, the generation of BC xenografts in zebrafish embryos/larvae allows for a description of the tumor growth, cell invasion, and systemic interaction between tumor and host in vivo without immunogenic rejection of transplanted cancer cells. Interestingly, zebrafish can be genetically manipulated and their genome has been fully sequenced. Genetic studies in zebrafish have described new genes and molecular pathways involved in BC carcinogenesis. Thus, the zebrafish in vivo model is becoming an exquisite alternative for metastatic research and for discovering new active agents for BC therapy. Herein, we systematically reviewed the recent cutting-edge advances in zebrafish BC models for carcinogenesis, metastasis, and drug screening. This article aims to review the current status of the role of the zebrafish (Danio reiro) in preclinical and clinical models of biomarker identification and drug targeting, and developments in personalized medicine in BC.

Additive pharmacological interaction between sirtuin inhibitor cambinol and paclitaxel in MCF7 luminal and MDA-MB-231 triple-negative breast cancer cells.

BACKGROUND: Breast cancer (BC) is the most common malignancy and the leading cause of cancer-related death in women worldwide. Sirtuin inhibitors (SIRTi), belonging to the histone deacetylase inhibitors group (HDIs), are potent epigenetic drugs that have been investigated for therapeutic use in different clinical disorders, including hematological malignancies and solid tumors. METHODS: The influence of cambinol (CAM; SIRTi) used individually or in combination with standard chemotherapeutic paclitaxel (PAX) on viability (MTT assay), proliferation (BrdU assay), induction of apoptosis and cell cycle arrest (FACS analysis) was determined in MCF7 luminal and MDA-MB-231 triple-negative breast cancer (TNBC) cells. The types of pharmacological drug-drug interaction between CAM and PAX were determined by an exact and rigorous pharmacodynamic method-an isobolography, to determine the presence of synergism, addition or antagonism between analyzed drugs using a variety of fixed-dose ratios. RESULTS: The combination of CAM and PAX at a fixed ratio of 1:1 exerted additive interaction in the viability of MCF7 and MDA-MB-231 BC cells. Both active agents used separately reduced viability and proliferation of BC cells as well as induced apoptosis and cell cycle arrest. These effects were much more evident in MCF7 than in MDA-MB-231 BC cells. Additionally, CAM combined with PAX increased anti-cancer activity compared to PAX used alone. CONCLUSION: CAM might be considered a potential therapeutic agent individually or in combined therapy with PAX against luminal or TNBC.

Antagonistic Pharmacological Interaction between Sirtuin Inhibitor Cambinol and Paclitaxel in Triple-Negative Breast Cancer Cell Lines: An Isobolographic Analysis.

Breast cancer (BC) is a heterogeneous disease with different intrinsic subtypes. The most aggressive subtype of BC-triple-negative breast cancer (TNBC) is characterized by high heterogeneity and metastasis rate, poor prognosis and lack of therapeutic targets due to the absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Targeted therapies have been approved for many other cancers and even other subtypes of BC, but treatment options for TNBC are still mainly limited to chemotherapy. Therefore, new, more effective treatment regimens are needed. Combined chemotherapy with two or more active agents is considered a promising anti-neoplasm tool in order to achieve better therapeutic response and reduce therapy-related adverse effects. The study demonstrated an antagonistic effect commonly used in TNBC therapy cytostatic drug-paclitaxel (PAX) and sirtuin inhibitor: cambinol (CAM) in BT-549, MDA-MB-468 and HCC1937 TNBC cell lines. The type of pharmacological interaction was determined by a precise and rigorous pharmacodynamic method-isobolographic analysis. The cytotoxic and anti-proliferative effects of CAM used alone or combined with PAX were determined utilizing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-bromo-2'-deoxyuridine (BrdU) assays, respectively. Induction of apoptosis in TNBC cell lines after PAX and CAM treatment applied individually or in combination was determined by flow cytometry (FACS) as a number of cells with active caspase-3. It has been observed that both agents used separately inhibit cell proliferation and induce apoptosis; however, applying them in combination ameliorated antiproliferative and pro-apoptotic effects in all analyzed TNBC cell lines. Our results demonstrate that CAM and PAX used in combination act antagonistically, limiting anti-cancer efficacy and showing the importance of preclinical testing.

Assessment of Pharmacological Interactions between SIRT2 Inhibitor AGK2 and Paclitaxel in Different Molecular Subtypes of Breast Cancer Cells.

Breast carcinoma (BC) is the most commonly diagnosed type of cancer in women in the world. Although the advances in the treatment of BC patients are significant, numerous side effects, severe toxicity towards normal cells as well as the multidrug resistance (MDR) phenomenon restrict the effectiveness of the therapies used. Therefore, new active compounds which decrease the MDR, extend disease-free survival, thereby ameliorating the effectiveness of the current treatment regimens, are greatly needed. Histone deacetylase inhibitors (HDIs), including sirtuin inhibitors (SIRTi), are the epigenetic antitumor agents which induce a cytotoxic effect in different types of cancer cells, including BC cells. Currently, combined forms of therapy with two or even more chemotherapeutics are promising antineoplastic tools to obtain a better response to therapy and limit adverse effects. Thus, on the one hand, much more effective chemotherapeutics, e.g., sirtuin inhibitors (SIRTi), are in demand; on the other hand, combinations of accepted cytostatics are trialed. Thus, the aim of our research was to examine the combination effects of a renowned cytotoxic drug paclitaxel (PAX) and SIRT2 inhibitor AGK2 on the proliferation and viability of the T47D, MCF7, MDA-MB-231, MDA-MB-468, BT-549 and HCC1937 BC cells. Moreover, cell cycle arrest and apoptosis induction were explored. The type of pharmacological interactions between AGK2 and PAX in different molecular subtypes of BC cells was assessed using the advanced isobolographic method. Our findings demonstrated that the tested active agents singly inhibited viability and proliferation of BC cells as well as induced cell cycle arrest and apoptosis in the cell-dependent context. Additionally, AGK2 increased the antitumor effect of PAX in most BC cell lines. We observed that, depending on the BC cell lines, the combinations of tested drugs showed synergistic, additive or antagonistic pharmacological interaction. In conclusion, our studies demonstrated that the consolidated therapy with the use of AGK2 and PAX can be considered as a potential therapeutic regimen in the personalized cure of BC patients in the future.

Vorinostat (SAHA) and Breast Cancer: An Overview.

Vorinostat (SAHA), an inhibitor of class I and II of histone deacetylases, is the first histone deacetylase inhibitor (HDI) approved for the treatment of cutaneous T-cell lymphoma in 2006. HDIs are promising anticancer agents that inhibit the proliferation of many types of cancer cells including breast carcinoma (BC). BC is a heterogeneous disease with variable biological behavior, morphological features, and response to therapy. Although significant progress in the treatment of BC has been made, high toxicity to normal cells, serious side effects, and the occurrence of multi-drug resistance limit the effective therapy of BC patients. Therefore, new active agents which improve the effectiveness of currently used regimens are highly needed. This manuscript analyzes preclinical and clinical trials data of SAHA, applied individually or in combination with other anticancer agents, considering different histological subtypes of BC.

Antagonistic Interaction between Histone Deacetylase Inhibitor: Cambinol and Cisplatin-An Isobolographic Analysis in Breast Cancer In Vitro Models.

Breast cancer (BC) is the leading cause of death in women all over the world. Currently, combined chemotherapy with two or more agents is considered a promising anti-cancer tool to achieve better therapeutic response and to reduce therapy-related side effects. In our study, we demonstrated an antagonistic effect of cytostatic agent-cisplatin (CDDP) and histone deacetylase inhibitor: cambinol (CAM) for breast cancer cell lines with different phenotypes: estrogen receptor positive (MCF7, T47D) and triple negative (MDA-MB-231, MDA-MB-468). The type of pharmacological interaction was assessed by an isobolographic analysis. Our results showed that both agents used separately induced cell apoptosis; however, applying them in combination ameliorated antiproliferative effect for all BC cell lines indicating antagonistic interaction. Cell cycle analysis showed that CAM abolished cell cycle arrest in S phase, which was induced by CDDP. Additionally, CAM increased cell proliferation compared to CDDP used alone. Our data indicate that CAM and CDDP used in combination produce antagonistic interaction, which could inhibit anti-cancer treatment efficacy, showing importance of preclinical testing.

Valproic Acid and Breast Cancer: State of the Art in 2021.

Valproic acid (2-propylpentanoic acid, VPA) is a short-chain fatty acid, a member of the group of histone deacetylase inhibitors (HDIs). VPA has been successfully used in the treatment of epilepsy, bipolar disorders, and schizophrenia for over 50 years. Numerous in vitro and in vivo pre-clinical studies suggest that this well-known anticonvulsant drug significantly inhibits cancer cell proliferation by modulating multiple signaling pathways. Breast cancer (BC) is the most common malignancy affecting women worldwide. Despite significant progress in the treatment of BC, serious adverse effects, high toxicity to normal cells, and the occurrence of multi-drug resistance (MDR) still limit the effective therapy of BC patients. Thus, new agents which improve the effectiveness of currently used methods, decrease the emergence of MDR, and increase disease-free survival are highly needed. This review focuses on in vitro and in vivo experimental data on VPA, applied individually or in combination with other anti-cancer agents, in the treatment of different histological subtypes of BC.

Sensitization of MCF7 Cells with High Notch1 Activity by Cisplatin and Histone Deacetylase Inhibitors Applied Together.

Histone deacetylase inhibitors (HDIs) are promising anti-cancer agents that inhibit proliferation of many types of cancer cells including breast carcinoma (BC) cells. In the present study, we investigated the influence of the Notch1 activity level on the pharmacological interaction between cisplatin (CDDP) and two HDIs, valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA, vorinostat), in luminal-like BC cells. The type of drug-drug interaction between CDDP and HDIs was determined by isobolographic analysis. MCF7 cells were genetically modified to express differential levels of Notch1 activity. The cytotoxic effect of SAHA or VPA was higher on cells with decreased Notch1 activity and lower for cells with increased Notch1 activity than native BC cells. The isobolographic analysis demonstrated that combinations of CDDP with SAHA or VPA at a fixed ratio of 1:1 exerted additive or additive with tendency toward synergism interactions. Therefore, treatment of CDDP with HDIs could be used to optimize a combined therapy based on CDDP against Notch1-altered luminal BC. In conclusion, the combined therapy of HDIs and CDDP may be a promising therapeutic tool in the treatment of luminal-type BC with altered Notch1 activity.

Magnoflorine-Isolation and the Anticancer Potential against NCI-H1299 Lung, MDA-MB-468 Breast, T98G Glioma, and TE671 Rhabdomyosarcoma Cancer Cells.

Magnoflorine (MGN) is a quaternary aporphine alkaloid that exhibits numerous therapeutic properties, including neuropsychopharmacological, anti-anxiety, immunomodulatory, anti-inflammatory, antioxidant, or antifungal activities. The aim of the present study was an investigation of the influence of MGN on viability, proliferation, induction of apoptosis, and cell cycle arrest in NCI-H1299 lung, MDA-MB-468 breast, T98G glioma, and TE671 rhabdomyosarcoma cancer cells. MGN was isolated from the roots of Berberis cretica L. by counter-current partition chromatography (CPC). Cell viability and proliferation assessments were performed by means of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and 5-bromo-2'-deoxyuridine (BrDU) assays, respectively. The induction of apoptosis and cell cycle progression was measured using fluorescence-activated cell sorting analysis. MGN in high doses inhibits proliferation, induces apoptosis, and inhibits cell cycle in S/G2 phases in a dose-dependent manner. MGN seems to be a promising anti-cancer compound in therapy of some types of lung, breast, glioma, and rhabdomyosarcoma cancers, for which current standard therapies are limited or have severe strong side effects.

Synergistic or Additive Pharmacological Interactions between Magnoflorine and Cisplatin in Human Cancer Cells of Different Histological Origin.

Magnoflorine is an aporphine alkaloid present in plant species belonging to the Berberidaceae, Magnoliaceae, Menispermaceae, or Papaveraceae botanical families. The interest of magnoflorine has increased recently due to its multiplicity of pharmacological properties. The aim of this study was the analysis of combined anti-proliferative effect of magnoflorine and cisplatin and the assessment of drug-drug pharmacological interaction between these agents using isobolographic method in MDA-MB-468 human breast, NCIH1299 lung, TE671 rhabdomyosarcoma, or T98G glioblastoma cancer cell lines. Magnoflorine in combination with cisplatin at a fixed ratio of 1:1 augmented their anticancer action and yielded synergistic or additive pharmacological interactions by means of isobolographic method, therefore combined therapy using these two active agents can be a promising chemotherapy regimen in the treatment of some types of breast, lung, rhabdomyosarcoma, and glioblastoma cancers.

Advances in Chemistry and Bioactivity of Magnoflorine and Magnoflorine-Containing Extracts.

The review collects together some recent information on the identity and pharmacological properties of magnoflorine, a quaternary aporphine alkaloid, that is widely distributed within the representatives of several botanical families like Berberidaceae, Magnoliaceae, Papaveraceae, or Menispermaceae. Several findings published in the scientific publications mention its application in the treatment of a wide spectrum of diseases including inflammatory ones, allergies, hypertension, osteoporosis, bacterial, viral and fungal infections, and some civilization diseases like cancer, obesity, diabetes, dementia, or depression. The pharmacokinetics and perspectives on its introduction to therapeutic strategies will also be discussed.

Histone deacetylase inhibitors reinforce the phenotypical markers of breast epithelial or mesenchymal cancer cells but inhibit their migratory properties.

INTRODUCTION: Histone deacetylase inhibitors (HDIs) are a group of compounds that exhibit anticancer activity, but their significance and usefulness in breast cancer (BC) treatment are still controversial. The ability of cancer cells to invade and migrate is augmented by the acquisition of a mesenchymal phenotype - a process known as epithelial-to-mesenchymal transition (EMT). Changes in the expression level of different cadherins, so-called cadherin switches, have been used to monitor the EMT process in development and tumor progression, in particular migration and invasion potential. The aim of this study was to analyze the influence of two HDIs - valproic acid (VPA) and vorinostat (SAHA) - on the migration potential of different BC cell types, as well as on EMT, or its reverse process - mesenchymal-to-epithelial transition, progression by means of shift in epithelial and mesenchymal marker expression. METHODS: HDI treatment-induced expression of E- and N-cadherin at the mRNA and protein levels was evaluated by qPCR, Western blotting and immunostaining methods, respectively. BC cell proliferation and migration were assessed by BrdU, xCELLigence system and wound-healing assay. RESULTS: VPA and SAHA inhibited the proliferation and migration in a dose- and time-dependent manner, regardless of the BC cell type. Unawares, BC cells having a more mesenchymal phenotype (MDA-MB-468) were found to overexpress N-cadherin, whereas BC lines having an epithelial phenotype (T47D, MCF7) responded to HDI treatment by a significant increase of E-cadherin expression. DISCUSSION: We suggest that HDAC inhibition results in a more relaxed chromatin concomitant to an increase in the expression of already expressing genes. CONCLUSION: By using multiple cancer cell lines, we conclude that HDI induction or reversal of EMT is not a universal mechanism, yet inhibition of cell migration is, and thus EMT should not be considered as the only measurement for tumor aggressiveness.

MMP-9 and MMP-2 regulation in patients undergoing non-oncological and non-vascular elective surgery independent of the use of propofol or sevoflurane.

BACKGROUND: There is debate regarding whether inhaled sevoflurane or intravenous propofol used during anesthesia achieves the best outcome. Propofol has been shown to affect expression of matrix metalloproteinases (MMPs). MMPs are enzymes that play a role in extracellular matrix remodeling, with activity balance disturbances during surgery. The goal of this study was to compare MMP-2/9 concentrations, activity, and tissue inhibitors of metalloproteinases (TIMPs) 1/2 concentrations in blood of who had undergone 2 types of anesthesia: based on volatile sevoflurane and intravenous propofol during non-oncological, non-vascular surgery. METHODS: 39 patients were enrolled into analysis, 20 anesthetized with total intravenous anesthesia with propofol (P), 19 with volatile induction/maintenance of anesthesia with sevoflurane (S). Plasma samples collected before and 24 h after surgery were analyzed for MMP-2/9, and TIMP-1/2 concentrations using ELISAs. Additionally, MMP-2/9 activities were assessed by gelatin zymography. RESULTS: Study revealed increased MMP-9 concentration (ELISA) (P:p = 0.011; S:p = 0.001) and activity (zymography) (P:p = 0.004; S:p = 0.008) in both groups 24 h after surgery. We noticed decreased (both groups) MMP-2 concentration (P:p = 0.044; S:p = 0.027) with MMP-2 activity increase (P:p = 0.002; S:p = 0.006) 24 h after surgery. We observed decreased TIMP-1 plasma concentrations (P:p = 0.002; S:p = 0.000) 24 h after procedures, while TIMP-2 plasma levels remain unchanged (P:p = 0.097; S:p = 0.172). There were no differences between concentration and activity of MMPs and TIMPs in regard to anesthetic used. Meperidine administration correlated with lower MMP-9 activity (R=-0.430; p = 0.006). CONCLUSIONS: Concluding, neither sevoflurane nor propofol used as anesthetics modulate MMP-2 and MMP-9 concentrations and activities during non-oncological, non-vascular elective surgery. Meperidine seems to decrease MMP-9 activity.

Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells.

Histone deacetylase inhibitors (HDIs) are a group of potent epigenetic drugs which have been investigated for their therapeutic potential in various clinical disorders, including hematological malignancies and solid tumors. Currently, several HDIs are already in clinical use and many more are on clinical trials. HDIs have shown efficacy to inhibit initiation and progression of cancer cells. Nevertheless, both pro-invasive and anti-invasive activities of HDIs have been reported, questioning their impact in carcinogenesis. The aim of this review is to compile and discuss the most recent findings on the effect of HDIs on the epithelial-mesenchymal transition (EMT) process in human cancers. We have summarized the impact of HDIs on epithelial (E-cadherin, ß-catenin) and mesenchymal (N-cadherin, vimentin) markers, EMT activators (TWIST, SNAIL, SLUG, SMAD, ZEB), as well as morphology, migration and invasion potential of cancer cells. We further discuss the use of HDIs as monotherapy or in combination with existing or novel anti-neoplastic drugs in relation to changes in EMT.

MicroRNAs-role in lung cancer.

Regulation of gene expression is essential for normal physiological functions; thus deregulation of gene expression is common in disease conditions. One level of regulation of gene expression is performed by noncoding RNAs, among which microRNAs (miRNA) are the best studied. Abnormal expression of these molecular players can lead to pathogenic processes such as heart disease, immune system abnormalities, and carcinogenesis, to name but a few. Of a length of 18-25 nucleotides miRNAs are involved in binding partial complementary sequences within the 3'-UTR (3'-untranslated region) of the target mRNAs. Depending on the type of neoplastic transformation, miRNAs can act both as oncogenes (oncomirs) or as tumor suppressors. Because of the great importance of miRNAs, most researches focus on either their role as biomarkers or their potential as therapeutic targets. Herein, we present the review of microRNA biology, function, and tumorigenic potential with emphasis on their role in lung cancer.