Borax Pentahydrate and Disodium Pentaborate Decahydrate Are Candidates as Anti-leukemic Drug Components by Inducing Apoptosis and Changing Bax/Bcl-2 Ratio in HL-60 Cell Line.

Acute myeloid leukemia (AML) is the most common form of acute leukemia and has the lowest 5-year survival rates. Current treatment strategies do not meet the expectations also. Therefore, there is a need to improve therapeutic approaches still. Boron, which is a natural trace element in human diet, is gaining attention with its important roles in cellular processes for the development of new anti-cancer drug candidates. For instance, bortezomib, a dipeptidyl boronic acid, has encouraging results in the treatment of multiple myeloma and mantle cell lymphoma. However, severe toxic effects and resistance development are the limitations to its application for AML treatment. Hence, the development of alternative boron-derived anti-AML agents is unmet need. Therefore, we aimed to evaluate anti-leukemic effect of two promising boron compounds, borax pentahydrate (BP) and disodium pentaborate decahydrate (DPD), and comparison of each other in terms of the capacity to trigger apoptosis on acute promyelocytic leukemia cells (HL-60). Cell viability was assessed by MTT assay. Apoptotic effects of the boron compounds on HL-60 cells were evaluated by annexin V/propidium iodide dyes and caspase 3/7 activity assay by flow cytometry. In addition, Bax/Bcl-2 and cleaved PARP levels were detected by western blotting. Although BP showed greater apoptosis-inducing capacity, we observed that both DPD (6 mM) and BP (24 mM) treatment showed anti-leukemic effect by triggering apoptotic pathway through increasing Bax/Bcl-2 ratio for the first time. Our study suggests that BP and DPD are the promising candidates for anti-AML drug development research, which may be confirmed by further wide-spectrum studies.

Combinations of polyphenols disaggregate Aß1­42 by passing through in vitro blood brain barrier developed by endothelium, astrocyte, and differentiated SH­SY5Y cells.

Disaggregation of amyloid ßeta (Aß) is considered as one of the promising therapeutic strategies for Alzheimer's disease. Polyphenols are promising molecules for the disaggregation of Aß. However, in order to find a potential therapeutic candidate, the in vitro analyses need to be performed on a model that mimics the blood­brain barrier (BBB) as much as possible. Therefore, we aimed to establish an in vitro BBB representative transwell system by using differentiated human neuroblastoma (SH­SY5Y), cerebral microvascular endothelial, and astrocyte cells to investigate transition and Aß disaggregation capacity of punicalagin (PU), ellagic acid (EA), epigallocatechin gallate (EGCG), gastrodin, and their combinations on the established system. The efficiency of the established transwell systems was evaluated by measuring the transendothelial electrical resistance (TEER) and paracellular permeability coefficients (Pe) values. The transition and Aß disaggregation capacities of the polyphenols were evaluated in the established tri­culture transwell system based on obtained TEER (50,07 Ω.cm2) and Pe (65x10­6 cm/s) values. Our results revealed that all polyphenols can successfully pass across the BBB system and disaggregate Aß. While Aß disaggregation capacities of the polyphenols were in the range of 30.52-45.01%, the percentages of their combinations were higher (75% for EGCG­PU (Com 1) and 64% for EGCG­EA (Com 2)). Consequently, this study provides the first evidence that Com 1 and Com 2 are promising polyphenol combinations in terms of Aß disaggregation. Besides, the developed tri­culture transwell system, containing differentiated SH­SY5Y cells, may provide a new tool that closely mimics the BBB for basic research and testing of candidate agents.

Synergistic Induction of Apoptosis by Quercetin and Curcumin in Chronic Myeloid Leukemia (K562) Cells: II. Signal Transduction Pathways Involved.

Flavonoids are phenolic substances with chemo-preventive and chemotherapeutic properties. They are widely found in fruits and vegetables. The polyphenols quercetin and curcumin have antioxidant, anti-inflammatory, anti-carcinogenic, and pro-apoptotic properties. They were successfully used against different human cancers, especially chronic myeloid leukemia cancer cells. We have previously investigated anti-proliferative and apoptotic effects of quercetin and curcumin combination in K562 cells. Our data showed that they had beneficial synergistic effects. Based on these findings, we aimed to clarify signaling pathways involved in synergistic combination treatment with quercetin and curcumin in these cells. Proteins were investigated by Western blotting and by confocal microscopy. Changes in several genes in 10 different pathways related to cell proliferation, apoptosis, cell cycle, inflammation, hypoxia and oxidative stress were observed. Combination of quercetin and curcumin was effective on genes that were particularly related to p53, NF-κB and TGF-α pathways. Down-regulatory (CDKN1B, AKT1, IFN-γ) and up-regulatory (BTG2, CDKN1A, FAS) effects on genes and related protein expressions may provide a multi-targeted therapy potential for chronic myeloid leukemia cancer cells without affecting healthy cells.