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.

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.

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.

Deacetylation of Transcription Factors in Carcinogenesis.

Reversible Nε-lysine acetylation/deacetylation is one of the most common post-translational modifications (PTM) of histones and non-histone proteins that is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). This epigenetic process is highly involved in carcinogenesis, affecting histone and non-histone proteins' properties and their biological functions. Some of the transcription factors, including tumor suppressors and oncoproteins, undergo this modification altering different cell signaling pathways. HDACs deacetylate their targets, which leads to either the upregulation or downregulation of proteins involved in the regulation of cell cycle and apoptosis, ultimately influencing tumor growth, invasion, and drug resistance. Therefore, epigenetic modifications are of great clinical importance and may constitute a new therapeutic target in cancer treatment. This review is aimed to present the significance of HDACs in carcinogenesis through their influence on functions of transcription factors, and therefore regulation of different signaling pathways, cancer progression, and metastasis.

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.

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.

Accumulation of blood-circulating PD-L1-expressing M-MDSCs and monocytes/macrophages in pretreatment ovarian cancer patients is associated with soluble PD-L1.

BACKGROUND: Previous studies have shown clinical relevance of programmed death-ligand 1 (PD-L1) and soluble PD-L1 (sPD-L1) in human cancers. However, still contradictory results exist. Our aim was evaluation of PD-L1-expressing monocytic myeloid-derived suppressor cells (M-MDSCs), monocytes/macrophages (MO/MA), tumour cells (TC) and immune/inflammatory cells (IC) as well as investigation of the sPD-L1 in ovarian cancer (OC) patients. METHODS: The group of 74 pretreatment women were enrollment to the study. The expression of PD-L1 on M-MDSCS and MO/MA was assessed by flow cytometry. The profile of sPD-L1 was examined with ELISA. The expression of PD-L1 in mononuclear cells (MCs) was analyzed using real time PCR. PD-L1 immunohistochemical analysis was prepared on TC and IC. An in silico validation of prognostic significance of PD-L1 mRNA expression was performed based microarray datasets. RESULTS: OC patients had significantly higher frequency of MO/MA versus M-MDSC in the blood, ascites and tumour (each p < 0.0001). In contrast, PD-L1 expression was higher on M-MDSCs versus MO/MA in the blood and ascites (each p < 0.0001), but not in the tumour (p > 0.05). Significantly higher accumulation of blood-circulating M-MDSC, MO/MA, PD-L1+M-MDSC, PD-L1+MO/MA and sPD-L1 was observed in patients versus control (p < 0.001, p < 0.05, p < 0.001, p < 0.001 and p < 0.0001, respectively). Accumulation of these factors was clinicopathologic-independent (p > 0.05). The expression of PD-L1 was significantly higher on IC versus TC (p < 0.0001) and was clinicopathologic-independent (p > 0.05) except higher level of PD-L1+TC in the endometrioid versus mucinous tumours. Interestingly, blood-circulating sPD-L1 positively correlated with PD-L1+M-MDSCs (p = 0.03) and PD-L1+MO/MA (p = 0.02) in the blood but not with these cells in the ascites and tumours nor with PD-L1+TC/IC (each p > 0.05). PD-L1 and sPD-L1 were not predictors of overall survival (OS; each p > 0.05). Further validation revealed no association between PD-L1 mRNA expression and OS in large independent OC patient cohort (n = 655, p > 0.05). CONCLUSIONS: Although PD-L1 may not be a prognostic factor for OC, our study demonstrated impaired immunity manifested by up-regulation of PD-L1/sPD-L1. Furthermore, there was a positive association between PD-L1+ myeloid cells and sPD-L1 in the blood, suggesting that sPD-L1 may be a noninvasive surrogate marker for PD-L1+myeloid cells immunomonitoring in OC. Overall, these data should be under consideration during future clinical studies/trials.

Correction to: Accumulation of blood-circulating PD-L1-expressing M-MDSCs and monocytes/macrophages in pretreatment ovarian cancer patients is associated with soluble PD-L1.

An amendment to this paper has been published and can be accessed via the original article.

Gemcitabine and Selected mTOR Inhibitors in Uterine Sarcomas and Carcinosarcoma Cells- an Isobolographic Analysis.

Introduction: mTOR inhibitors are anticancer agents affecting mTOR/AKT/PI3K pathway that is one of the most important in human cancer cells. Hyperactivation of mTOR/AKT/PI3K and overexpression of this pathway members are frequently reported in uterine sarcoma and carcinosarcoma. Present study is aimed to assess the activity of the two mTOR inhibitors (rapamycin - RAP and sapanisertib - MLN) as a single agent and combined with gemcitabine (GEM, one of substances commonly used in systemic anticancer treatment) in uterine sarcoma and carcinosarcoma in vitro models. Material and methods: SK-UT-1 and SK-UT1-B (uterine carcinosarcoma), MES-SA (leiomyosarcoma) and ESS-1 (endometrial stromal sarcoma) cell lines were used. An MTT assay was performed to examine the cytotoxicity of RAP, MLN and mixtures: RAP+MLN, RAP+GEM, MLN+GEM against these cells. The interactions between tested compounds were assessed in isobolographic analysis. Results and conclusions: Carcinosarcoma cell lines (both SK-UT-1 and SK-UT-1B) do not respond to RAP and respond relatively weakly to MLN treatment. Additive and supraadditive effects were noted for combined treatment with GEM and MLN. Endometrial stromal sarcoma cell line (ESS-1) occured to be sensitive to both RAP and MLN, but the response was stronger for MLN. Additive effect of all tested drug combinations was observed for ESS-1. Leiomyosarcoma cell line (MES-SA) was found sensitive to both mTOR inhibitors. Additive effects in combinations of GEM, RAP and MLN were observed, what makes them promising for future preclinical and clinical trials. Additivity with slight tendency towards antagonism between GEM and MLN observed in MES-SA cell line is unexpected finding and might prompt the mechanistic research aimed to explain this phenomenon.

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.

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.

Additive Pharmacological Interaction between Cisplatin (CDDP) and Histone Deacetylase Inhibitors (HDIs) in MDA-MB-231 Triple Negative Breast Cancer (TNBC) Cells with Altered Notch1 Activity-An Isobolographic Analysis.

The aim of this study was to investigate the influence of the Notch1 activity level on the pharmacological interaction between cisplatin (CDDP) and two histone deacetylase inhibitors (HDIs)-valproic acid (VPA) and vorinostat (SAHA) in the triple negative breast cancer (TNBC) cells. Stable breast cancer (BC) cell lines with increased and decreased activity of Notch1 were generated using a transfection method. The type of interaction between CDDP and the HDIs was determined by isobolographic analysis of cell proliferation in MDA-MB-231 cells with differential levels of Notch1 activity in vitro. The combination of CDDP/SAHA and CDDP/VPA in the MDA-MB-231 triple negative breast cancer (TNBC) cells with increased activity of Notch1, as well as CDDP/VPA in the MDA-MB-231 cells with decreased activity of Notch1, yielded an additive interaction, whereas additivity with a tendency towards antagonism was observed for the combination of CDDP/SAHA in MDA-MB-231 cells with the decreased activity of Notch1. Our studies demonstrated that SAHA and VPA might be considered as potential therapeutic agents in combination therapy with CDDP against TNBC with altered Notch1 activity.

Blood-based analyses of cancer: Circulating myeloid-derived suppressor cells - is a new era coming?

Progress in cancer treatment made by the beginning of the 21st century has shifted the paradigm from one-size-fits-all to tailor-made treatment. The popular vision, to study solid tumors through the relatively noninvasive sampling of blood, is one of the most thrilling and rapidly advancing fields in global cancer diagnostics. From this perspective, immune-cell analysis in cancer could play a pivotal role in oncology practice. This approach is driven both by rapid technological developments, including the analysis of circulating myeloid-derived suppressor cells (cMDSCs), and by the increasing application of (immune) therapies, the success or failure of which may depend on effective and timely measurements of relevant biomarkers. Although the implementation of these powerful noninvasive diagnostic capabilities in guiding precision cancer treatment is poised to change the ways in which we select and monitor cancer therapy, challenges remain. Here, we discuss the challenges associated with the analysis and clinical aspects of cMDSCs and assess whether the problems in implementing tumor-evolution monitoring as a global tool in personalized oncology can be overcome.

Assessment of the clinicopathological relevance of mesothelin level in plasma, peritoneal fluid, and tumor tissue of epithelial ovarian cancer patients.

Ovarian cancer remains the most lethal gynecologic malignancy. This is due to lack of effective screening, diagnosis predominance in late stage of disease, a high recurrence rate after primary therapy, and poor treatment response in platinum-resistant tumor. Thus, unique biomarkers, predictive of individual disease course, and prognosis are urgently needed. The aim of our study was to assess the clinicopathological significance of plasma, peritoneal fluid, and tumor tissue levels of mesothelin in epithelial ovarian cancer patients. Plasma and peritoneal fluid levels of mesothelin were measured by enzyme-linked immunosorbent assay. Tissue expression of MSLN was evaluated using quantitative real-time polymerase chain reaction. Preoperative plasma mesothelin levels were significantly higher in epithelial ovarian cancer patients in comparison to the patients with benign tumor and controls. There have been noticed significant differences in the plasma mesothelin levels based on International Federation of Gynecology and Obstetrics stage, grade, and histology type. No significant changes were observed between Kurman and Shih type I versus type II epithelial ovarian cancer. Interestingly, peritoneal fluid mesothelin levels revealed significant differences based on both grade and Kurman and Shih-type epithelial ovarian cancer. There were no relevant changes in the mesothelin level in peritoneal fluid between different stages and histology types compared to benign tumor. MSLN expression level in tumor tissue was significantly higher based on stage, grade, and Kurman and Shih-type epithelial ovarian cancer than in the benign masses. In addition, data showed significant higher MSLN expression in endometrioid tumors compared to benign masses and serous tumors. Plasma, peritoneal fluid, and tumor tissue levels of mesothelin positively correlated with level of CA125. Low mesothelin concentrations in plasma were also associated with prolonged patient survival. More importantly, we revealed that plasma mesothelin level was correlated with both peritoneal fluid mesothelin level and tumor MSLN expression. This study highlights that plasma mesothelin level may be a useful noninvasive biomarker surrogate for local tumor mesothelin status in monitoring of epithelial ovarian cancer patients.

Exploring the therapeutic efficacy of crocetin in oncology: an evidence-based review.

With cancer being a leading cause of death globally, there is an urgent need to improve therapeutic strategies and identify effective chemotherapeutics. This study aims to highlight the potential of crocetin, a natural product derived from certain plants, as an anticancer agent. It was  conducted an extensive review of the existing literature to gather and analyze the most recent data on the chemical properties of crocetin and its observed effects in various in vitro and in vivo studies. The study  particularly focused on studies that examined crocetin's impact on cell cycle dynamics, apoptosis, caspases and antioxidant enzyme levels, tumor angiogenesis, inflammation, and overall tumor growth. Crocetin exhibited diverse anti-tumorigenic activities including inhibition of tumor cell proliferation, apoptosis induction, angiogenesis suppression, and potentiation of chemotherapy. Multiple cellular and molecular pathways such as the PI3K/Akt, MAPK and NF-κB were modulated by it. Crocetin demonstrates promising anti-cancer properties and offers potential as an adjunctive or alternative therapy in oncology. More large-scale, rigorously designed clinical trials are needed to establish therapeutic protocols and ascertain the comprehensive benefits and safety profile of crocetin in diverse cancer types.

p53 isoform expression promotes a stemness phenotype and inhibits doxorubicin sensitivity in breast cancer.

In breast cancer, dysregulated TP53 expression signatures are a better predictor of chemotherapy response and survival outcomes than TP53 mutations. Our previous studies have shown that high levels of Δ40p53 are associated with worse disease-free survival and disruption of p53-induced DNA damage response in breast cancers. Here, we further investigated the in vitro and in vivo implications of Δ40p53 expression in breast cancer. We have shown that genes associated with cell differentiation are downregulated while those associated with stem cell regulation are upregulated in invasive ductal carcinomas expressing high levels of Δ40p53. In contrast to p53, endogenous ∆40p53 co-localised with the stem cell markers Sox2, Oct4, and Nanog in MCF-7 and ZR75-1 cell lines. ∆40p53 and Sox2 co-localisation was also detected in breast cancer specimens. Further, in cells expressing a high ∆40p53:p53 ratio, increased expression of stem cell markers, greater mammosphere and colony formation capacities, and downregulation of miR-145 and miR-200 (p53-target microRNAs that repress stemness) were observed compared to the control subline. In vivo, a high ∆40p53:p53 ratio led to increased tumour growth, Ki67 and Sox2 expression, and blood microvessel areas in the vehicle-treated mice. High expression of ∆40p53 also reduced tumour sensitivity to doxorubicin compared to control tumours. Enhanced therapeutic efficacy of doxorubicin was observed when transiently targeting Δ40p53 or when treating cells with OTSSP167 with concomitant chemotherapy. Taken together, high Δ40p53 levels induce tumour growth and may promote chemoresistance by inducing a stemness phenotype in breast cancer; thus, targeting Δ40p53 in tumours that have a high Δ40p53:p53 ratio could enhance the efficacy of standard-of-care therapies such as doxorubicin.

Kaiso Protein Expression Correlates with Overall Survival in TNBC Patients.

Triple-negative breast cancers (TNBCs) are histologically heterogenic invasive carcinomas of no specific type that lack distinctive histological characteristics. The prognosis for women with TNBC is poor. Regardless of the applied treatments, recurrences and deaths are observed 3-5 years after the diagnosis. Thus, new diagnostic markers and targets for personalized treatment are needed. The subject of our study-the Kaiso transcription factor has been found to correlate with the invasion and progression of breast cancer. The publicly available TCGA breast cancer cohort containing Illumina HiSeq RNAseq and clinical data was explored in the study. Additionally, Kaiso protein expression was assessed in formalin-fixed and paraffin-embedded tissue archive specimens using the tissue microarray technique. In this retrospective study, Kaiso protein expression (nuclear localization) was compared with several clinical factors in the cohort of 103 patients with TNBC with long follow-up time. In univariate and multivariate analysis, high Kaiso protein but not mRNA expression was correlated with better overall survival and disease-free survival, as well as with premenopausal age. The use of radiotherapy was correlated with better disease-free survival (DFS) and overall survival (OS). However, given the heterogeneity of TNBC and context-dependent molecular diversity of Kaiso signaling in cancer progression, these results must be taken with caution and require further studies.

Gentiopicroside-An Insight into Its Pharmacological Significance and Future Perspectives.

Gentiopicroside (GPS) is a leading component of several plant species from the Gentianaceae botanical family. As a compound with plenty of biological activities and a component of herbal drugs, GPS has an important role in the regulation of physiological processes in humans. The results of recently published scientific studies underline a meaningful role of this molecule as an active factor in metabolic pathways and mechanisms, which may have an influence in the treatment of different diseases, including digestive tract disorders, malignant changes, neurological disorders, microbial infections, bone formation disorders, inflammatory conditions, and others. This review aims to collect previously published reports on the biological properties of GPS as a single compound that were confirmed by in vitro and in vivo studies, and to draw attention to the newly discovered role of this bitter-tasting secoiridoid. Thanks to these properties, the research on this substance could be revisited.

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.