Fisetin-loaded grape-derived nanoparticles improve anticancer efficacy in MOLT-4 cells.

PURPOSE: Fisetin (FIS) is a natural flavonoid with anti-proliferative and anti-apoptotic effects on different human cancer cell lines and can be considered a therapeutic agent for ALL treatment. However, FIS has little aqueous solubility and bioavailability, limiting its therapeutic applications. Thus, novel drug delivery systems are needed to improve solubility and bioavailability of FIS. Plant-derived nanoparticles (PDNPs) could be considered a great delivery system for FIS to the target tissues. In this study, we investigated the anti-proliferative and anti-apoptotic effect of free FIS and FIS-loaded Grape-derived Nanoparticles (GDN) FIS-GDN in MOLT-4 cells. MATERIALS/METHODS: In this study, MOLT-4 cells were treated with increasing concentration of FIS and FIS-GDN and viability of cells were assessed by MTT assay. Additionally, cellular apoptosis rate and related genes expression were evaluated using flow cytometry and Real Time-PCR methods, respectively. RESULTS: FIS and FIS-GDN decreased cells viability and increased cells apoptosis dose-dependently, but not time dependently. Treatment of MOLT-4 cells with increasing concentrations of FIS and FIS-GDN considerably increased the expression of caspase 3, 8 and 9 and Bax level, and also decreased the expression of Bcl-2. Results indicated an increased apoptosis after increased concentration of FIS and FIS-GDN at 24, 48 and 72 h. CONCLUSIONS: Our data proposed that FIS and FIS-GDN can induce apoptosis and have antitumor properties in MOLT-4 cells. Furthermore, compared to FIS, FIS-GDN induced more apoptosis in these cells by increasing the solubility and efficiency of FIS. Additionally, GDNs increased FIS effectiveness in proliferation inhibition and apoptosis induction.

The role of exosomes in the molecular mechanisms of metastasis: Focusing on EMT and cancer stem cells.

Exosomes are cell-derived small membrane-encapsulated vesicles that transfer biomolecules to surrounding cells. Exosomes play fundamental roles in cell-cell communications. They can also aggravate cancer progression and metastasis. Metastasis is a complicated and multi-serial process that is regulated by various mechanisms. Epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) are important participants in cancer metastasis. Recent studies demonstrate that exosomes are associated with metastasis by modulating the EMT and the function of CSCs. Accumulating evidence shows that exosomes are implicated in regulating tumor cell metastasis by modulating signaling pathways involved in EMT and CSCs. This review aims to discuss the effect of exosomes on signaling pathways associated with EMT and CSCs, as well as possible therapeutic strategies of exosomes in cancer metastasis.

Paediatric pre-B acute lymphoblastic leukaemia-derived exosomes regulate immune function in human T cells.

Exosomes derived from solid tumour cells are involved in immune suppression, angiogenesis and metastasis; however, the role of leukaemia-derived exosomes has less been investigated. Hence, changes in immune response-related genes and human T cells apoptosis co-incubated with exosomes isolated from patients' pre-B cell acute lymphoblastic leukaemia were evaluated in this in vitro study. Vein blood sample was obtained from each newly diagnosed acute lymphoblastic leukaemia (ALL) patient prior any therapy. ALL serum exosomes were isolated by ultrafiltration and characterized using Western blotting and transmission electron microscopy. Exosomes were then co-incubated with T lymphocytes and the gene expressions, as well as functions of human T cells were quantified by qRT-PCR. Apoptosis and caspase-3 and caspase-9 protein expression were also evaluated by flowcytometry and Western blotting analysis, respectively. Exosomes isolated from ALL patients affected T lymphocytes and elevated the apoptosis. Moreover, these exosomes altered the T cells profile into regulatory type by increasing the expression of FOXP3 and Tregs-related cytokines, including TGF-B and IL-10. The expression level of Th17-related transcription factors (RoRγt) and interleukins (IL-17 and IL-23) decreased after this treatment. According to our findings, exosomes derived from ALL patients' sera carry immunosuppressive molecules, indicating the possible effect of exosomes as liquid biomarkers for cancer staging.

Cell cycle involvement in cancer therapy; WEE1 kinase, a potential target as therapeutic strategy.

Mitosis is the process of cell division and is regulated by checkpoints in the cell cycle. G1-S, S, and G2-M are the three main checkpoints that prevent initiation of the next phase of the cell cycle phase until previous phase has completed. DNA damage leads to activation of the G2-M checkpoint, which can trigger a downstream DNA damage response (DDR) pathway to induce cell cycle arrest while the damage is repaired. If the DNA damage cannot be repaired, the replication stress response (RSR) pathway finally leads to cell death by apoptosis, in this case called mitotic catastrophe. Many cancer treatments (chemotherapy and radiotherapy) cause DNA damages based on SSBs (single strand breaks) or DSBs (double strand breaks), which cause cell death through mitotic catastrophe. However, damaged cells can activate WEE1 kinase (as a part of the DDR and RSR pathways), which prevents apoptosis and cell death by inducing cell cycle arrest at G2 phase. Therefore, inhibition of WEE1 kinase could sensitize cancer cells to chemotherapeutic drugs. This review focuses on the role of WEE1 kinase (as a biological macromolecule which has a molecular mass of 96 kDa) in the cell cycle, and its interactions with other regulatory pathways. In addition, we discuss the potential of WEE1 inhibition as a new therapeutic approach in the treatment of various cancers, such as melanoma, breast cancer, pancreatic cancer, cervical cancer, etc.

Application of Emerging Plant-Derived Nanoparticles as a Novel Approach for Nano-Drug Delivery Systems.

Nanotechnology has enabled the delivery of small molecular drugs packaged in nanosized vesicles to the target tissues. Plant-Derived Nanoparticles (PDNPs) are vesicles with natural origin and unique properties. These nanoparticles have several advantages over synthetic exosomes and liposomes. They provide bioavailability and biodistribution of therapeutic agents when delivered into different tissues. These nanoparticles can be modified according to the specificity of their functions in target tissues. When PDNPs are internalized, they can induce stem cells proliferation, reduce colitis injury, activate intrinsic and extrinsic apoptosis pathways, and inhibit tumor growth and progression. These properties make them potential drug delivery systems in targeting diseased tissues, such as inflammatory regions and different cancers.

Exosome: From leukemia progression to a novel therapeutic approach in leukemia treatment.

Exosomes, as small vesicles, are released by tumor cells and tumor microenvironment (cells and function as key intercellular mediators and effects on different processes including tumorigenesis, angiogenesis, drug resistance, and evasion from immune system. These functions are due to exosomes' biomolecules which make them as efficient markers in early diagnosis of the disease. Also, exosomes have been recently applied in vaccination. The potential role of exosomes in immune response toward leukemic cells makes them efficient immunotherapeutic agents treating leukemia. Furthermore, variations in exosomes contents make them beneficial to be used in treating different diseases. This review introduces the role of exosomes in the development of hematological malignancies and evaluates their functional role in the treatment of these malignancies.

Berberine: A novel therapeutic strategy for cancer.

Cancer, even currently, is one of the main reasons for mortality and morbidity, worldwide. In recent years, a great deal of effort has been made to find efficient therapeutic strategies for cancer, however, particularly with regards to side effects and the possibility of complete remission. Berberine (BBR) is a nature-driven phytochemical component originated from different plant groups such as Berberis vulgaris, Berberis aquifolium, and Berberis aristata. BBR is a well-known nutraceutical because of its wide range of pharmacological activities including anti-inflammatory, antidiabetic, antibacterial, antiparasitic, antidiarrheal, antihypertensive, hypolipidemic, and fungicide. In addition, it exhibits inhibitory effects on multiple types of cancers. In this review, we have elaborated on the anticancer effects of BBR through the regulation of different molecular pathways such as: inducing apoptosis, autophagy, arresting cell cycle, and inhibiting metastasis and invasion.