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Abstract In therapies, curcumin is now commonly formulated in liposomal form, administered through injections or creams. This enhances its concentration at the cellular level compared to its natural form ingestion. Due to its hydrophobic nature, curcumin is situated in the lipid part of the membrane, thereby modifying its properties and influencing processes The aim of the research was to investigate whether the toxicity of specific concentrations of curcumin, assessed through biochemical tests for the SK-N-SH and H-60 cell lines, is related to structural changes in the membranes of these cells, caused by the localization of curcumin in their hydrophobic regions. Biochemical tests were performed using spectrophotometric methods. Langmuir technique were used to evaluate the interaction of the curcumin with the studied lipids. Direct introduction of curcumin into the membranes alters their physicochemical parameters. The extent of these changes depends on the initial properties of the membrane. In the conducted research, it has been demonstrated that curcumin may exhibit toxicity to human cells. The mechanism of this toxicity is related to its localization in cell membranes, leading to their dysfunction. The sensitivity of cells to curcumin presence depends on the saturation level of their membranes; the more rigid the membrane, the lower the concentration of curcumin causes its disruption.

In therapies, curcumin is now commonly formulated in liposomal form, administered through injections or creams. This enhances its concentration at the cellular level compared to its natural form ingestion. Due to its hydrophobic nature, curcumin is situated in the lipid part of the membrane, thereby modifying its properties and influencing processes The aim of the research was to investigate whether the toxicity of specific concentrations of curcumin, assessed through biochemical tests for the SK-N-SH and H-60 cell lines, is related to structural changes in the membranes of these cells, caused by the localization of curcumin in their hydrophobic regions. Biochemical tests were performed using spectrophotometric methods. Langmuir technique were used to evaluate the interaction of the curcumin with the studied lipids. Direct introduction of curcumin into the membranes alters their physicochemical parameters. The extent of these changes depends on the initial properties of the membrane. In the conducted research, it has been demonstrated that curcumin may exhibit toxicity to human cells. The mechanism of this toxicity is related to its localization in cell membranes, leading to their dysfunction. The sensitivity of cells to curcumin presence depends on the saturation level of their membranes; the more rigid the membrane, the lower the concentration of curcumin causes its disruption. [ABSTRACT FROM AUTHOR]

Leukemic cells (LCs) arise from the hematopoietic stem/and progenitor cells (HSCs/HSPCs) and utilize cues from the bone marrow microenvironment (BMM) for their regulation in the same way as their normal HSC counterparts. Mesenchymal stromal cells (MSCs), a vital component of the BMM promote leukemogenesis by creating a protective and immune‐tolerant microenvironment that can support the survival of LCs, helping them escape chemotherapy, thereby resulting in the relapse of leukemia. Conversely, MSCs also induce apoptosis in the LCs and inhibit their proliferation by interfering with their self‐renewal potential. This review discusses the work done so far on cell‐autonomous (intrinsic) and MSCs‐mediated non‐cell‐autonomous (extrinsic) regulation of myeloid leukemia with a special focus on the need to investigate the extrinsic regulation of myeloid leukemia to understand the contrasting role of MSCs in leukemogenesis. These mechanisms could be exploited to formulate novel therapeutic strategies that specifically target the leukemic microenvironment. [ABSTRACT FROM AUTHOR]

In present study influence of allogeneic bone marrow mesenchymal stem cells (MSC) on patients’ leukemic cells is investigated. Influence on in vitro sensitivity to antileukemic drugs and spontaneous and cytarabine-induced apoptosis of leukemic cells was studied. It has`been shown that MSC reduce myeloid leukemic cells sensitivity to daunorubicine. However, MSC did not statistically significant influence on spontaneous and cytarabine-induced apoptosis of leukemic cells.

Two new monoterpenoid indole alkaloids, gelselegandines F (1) and G (2), were isolated from the aerial parts of Gelsemium elegans. Their structures were elucidated by means of spectroscopic techniques and quantum chemical calculations. The ECD calculations were conducted at the B3LYP/6-311G(d,p) level and NMR calculations were carried out using the Gauge-Including Atomic Orbitals (GIAO) method. Structurally, the two new compounds possessed rare, cage-like, monoterpenoid indole skeletons. All isolated compounds and the total alkaloids extract were tested for cytotoxicity against four different tumor cell lines. The total alkaloids extract of G. elegans exhibited significant antitumor activity with IC50 values ranging from 32.63 to 82.24 ug/mL. In order to discover anticancer leads from the active extraction, both new indole compounds (1–2) were then screened for cytotoxicity. Interestingly, compound 2 showed moderate cytotoxicity against K562 leukemia cells with an IC50 value of 57.02 uM. [ABSTRACT FROM AUTHOR]

The study of the mechanisms of resistance of tumor cells to TRAIL-induced death remains an urgent task since this cytokine is an important highly selective molecular effector of antitumor immunity. Our study showed that human leukemia cells THP-1, HL-60, and K562 increased their resistance to TRAIL-induced death in vitro as a result of induction of myeloid differentiation in them by exogenous factors in all directions of myelopoiesis, except for erythroid, by reducing the expression of DR4 and DR5 receptors on the cell surface. It was also found that ONC 201, tunicamycin, and SAHA (hydroxamic acid suberoylanilide), capable of causing an increase in the expression of DR5 in leukemic cells, suppressed their TRAIL resistance induced by differentiation factors. The results obtained are of interest for the development of drugs and strategies to improve the effectiveness of the treatment of myeloid leukemia. [ABSTRACT FROM AUTHOR]

Two new monoterpenoid indole alkaloids, gelselegandines F (1) and G (2), were isolated from the aerial parts of Gelsemium elegans. Their structures were elucidated by means of spectroscopic techniques and quantum chemical calculations. The ECD calculations were conducted at the B3LYP/6-311G(d,p) level and NMR calculations were carried out using the Gauge-Including Atomic Orbitals (GIAO) method. Structurally, the two new compounds possessed rare, cage-like, monoterpenoid indole skeletons. All isolated compounds and the total alkaloids extract were tested for cytotoxicity against four different tumor cell lines. The total alkaloids extract of G. elegans exhibited significant antitumor activity with IC50 values ranging from 32.63 to 82.24 ug/mL. In order to discover anticancer leads from the active extraction, both new indole compounds (1–2) were then screened for cytotoxicity. Interestingly, compound 2 showed moderate cytotoxicity against K562 leukemia cells with an IC50 value of 57.02 uM.

Abstract Conventional anticancer chemotherapy is limited because of severe side effects as well as a quickly evolving multidrug resistance of the tumor cells. To address this problem, we have explored a C60 fullerene-based nanosized system as a carrier for anticancer drugs for an optimized drug delivery to leukemic cells. Here, we studied the physicochemical properties and anticancer activity of C60 fullerene noncovalent complexes with the commonly used anticancer drug doxorubicin. C60-Doxorubicin complexes in a ratio 1:1 and 2:1 were characterized with UV/Vis spectrometry, dynamic light scattering, and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The obtained analytical data indicated that the 140-nm complexes were stable and could be used for biological applications. In leukemic cell lines (CCRF-CEM, Jurkat, THP1 and Molt-16), the nanocomplexes revealed ≤ 3.5 higher cytotoxic potential in comparison with the free drug in a range of nanomolar concentrations. Also, the intracellular drug’s level evidenced C60 fullerene considerable nanocarrier function. The results of this study indicated that C60 fullerene-based delivery nanocomplexes had a potential value for optimization of doxorubicin efficiency against leukemic cells.

Egletes viscosa is a plant with therapeutic value due to its antibacterial, antinociceptive and gastroprotective properties. This study aimed to purify, characterize, and evaluate the cytotoxicity of a lectin (EgviL) from the floral capitula of E. viscosa. The lectin was isolated from saline extract through precipitation with ammonium sulfate followed by Sephadex G-75 chromatography. The molecular mass and isoelectric point (pI) of EgviL were determined as well as its temperature and pH stability. Physical–chemical parameters of interaction between EgviL and carbohydrates were investigated by fluorescence quenching and 1H nuclear magnetic resonance (NMR). Cytotoxicity was investigated against human peripheral blood mononuclear cells (PBMCs) and neoplastic cells. EgviL (28.8 kDa, pI 5.4) showed hemagglutinating activity stable towards heating until 60 °C and at the pH range 5.0–7.0. This lectin is able to interact through hydrophobic and electrostatic bonds with galactose and glucose, respectively. EgviL reduced the viability of PBMCs only at the highest concentration tested (100 μg/mL) while was toxic to Jurkat E6–1 cells with IC 50 of 24.1 μg/mL,inducing apoptosis. In summary, EgviL is a galactose/glucose-binding protein with acidic character, stable to heating and with cytotoxic effect on leukemic cells. [ABSTRACT FROM AUTHOR]

Ca2+-regulating system in cancer cells is suggested to be remodulated particularly by reduced store-operated Ca2+ entry (SOCE) through plasma membrane in order to maintain moderately reduced cytosolic Ca2+ concentration and to avoid apoptosis. The endoplasmic reticulum (ER) Ca2+ pool content and the size of SOCE in leukemic wild type (L1210) and resistant to cisplatin (L1210R) cells in control, after treatment with either cisplatin (1 µg/ml) or photoexcited fulleren C60 (10-5 M) alone, or their combination were estimated with the use of Indo-1 AM. The SOCE in resistant to cisplatin L1210R cells was found to be lower than in the wild-type cells. After treatment with cisplatin the decrease of thapsigargin (TG)-sensitive ER Ca2+ pool with no significant increase of SOCE was observed in L1210 cells, while no changes were detected in L1210R cells. Photoexcitation of intracellular accumulated fullerene C60 in the visible range of spectrum (410-700 nm) was accompanied by increase of SOCE not only in sensitive, but in resistant cells as well. In resistant L1210R cells treated with photoexcited C60 essential effect of cisplatin on Ca2+ homeostasis became obvious: the size of SOCE proved to be higher than after treatment with photoexcited C60 alone. The data obtained allow suggesting­ the influence of photoexcited C60 not only on Ca2+-regulating system, but on those involved in controlling cisplatin entry into drug resistant cancer cells.

Objectives: Andrographis paniculata (A. paniculata) is a widely used herb that has potential medical properties. Andrographolide (Andro) is the major component of A. paniculata. We evaluated the anti-tumor activity of Andro using leukemic cell line cells. Methods: Leukemic cell lines U937, HL60 or H929 cells were cultured in the presence or absence of Andro and compared with the effects of Ara-C or vincristine. The anti-tumor activity was assessed by morphological observations of the cells, DNA fragmentation, MTT assay, Annexin V positive rate, caspase-3/7 activity, and cell cycle analysis. Results: After addition of Andro, the morphology of cells changed to characteristic shapes with apoptotic bodies. Furthermore, the Annexin V positive rate and caspase-3/7 activities were increased compared with untreated cells. The G1 phase of cell cycle was also similarly increased compared with cells treated with Ara-C. Conclusions: Our results show that Andro has an anti-tumor activity against leukemic cell lines, very possibly by inducing apoptosis.

Objectives: Diagnosis of central nervous system involvement in acute lymphoblastic leukemia (ALL) requires morphologic expertise; therefore, we evaluated interphase fluorescence in situ hybridization (iFISH) of cerebrospinal fluid (CSF) cytospin preparations as a potential complementary test.Methods: Twenty-three CSF cytospin specimens from 13 pediatric patients with ALL were included. iFISH probes detecting BCR-ABL1, ETV6-RUNX1, and KMT2A rearrangement and CDKN2A deletion, which were present at initial diagnosis, were used on follow-up CSF cytospin specimens and were compared with cytology.Results: Seventeen (73.9%) follow-up specimens showed concordant results between iFISH and cytology. Two (8.7%) samples with discordant results were positive by iFISH but not by cytology; one (4.3%) was positive only by cytology. In the remaining three (13.0%) specimens, too few cells were available for cytology, whereas iFISH interpretation was possible.Conclusions: iFISH of CSF cytospin preparations improves malignant cell detection in pediatric ALL. [ABSTRACT FROM AUTHOR]

Arginine deprivation has been recently suggested as a therapeutic approach against difficult to cure blood cancers. Herein, we investigated for the first time the combined effect of exogenous nitric oxide (NO) donor and recombinant human arginase (rhARG) as arginine-depleting agent on viability of several human leukemic cell lines and normal peripheral blood lymphocytes (PBL). We found that exogenous NO donor, sodium nitroprusside (SNP), at physiologically compatible dose did not counteract but augmented rhARG-mediated pro-apoptotic effect of arginine depletion in leukemic cells but not in resting lymphocytes. Thus, we hypothesize that NO deficiency resulting from arginine deprivation is not the primary cause of high leukemic cells sensitivity to the action of rhARG. The results of this study further support the notion that not arginine catabolism but other cell response mechanisms must be involved in determining cell fate upon arginine restriction. SNP or alternative NO donors can be proposed as components of metabolic anti-leukemia therapy based on arginine deprivation.

T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphomas (T-LBL) are aggressive malignancies of thymocytes. The role of thymic microenvironmental cells and stromal factors in thymocyte malignant transformation and T-ALL development remains little explored. Here, using the TEL-JAK2 transgenic (TJ2-Tg) mouse model of T-ALL/LBL, which is driven by constitutive JAK/STAT signaling and characterized by the acquisition of Notch1 mutations, we sought to identify stromal cell alterations associated with thymic leukemogenesis. Immunofluorescence analyses showed that thymic lymphomas presented epithelial areas characterized by keratin (Krt) 5 and Krt8 expression, adjacently to epithelial-free areas negative for Krt expression. Both areas contained abundant laminin (extracellular matrix) and ER-TR7+ (fibroblasts) CD31+ (endothelial) and CD11c+ (dendritic) cells. Besides Krt5, Krt-positive areas harbored medullary thymic epithelial cells (TECs) labeled by Ulex europaeus agglutinin-1. By performing flow cytometry and RNA sequencing analyses of thymic lymphomas, we observed an enrichment in medullary TEC markers in detriment of cortical TEC markers. To assess whether TECs are important for T-ALL/LBL development, we generated TJ2-Tg mice heterozygous for the FoxN1 transcription factor nude null mutation (Foxn1 +/nu). Strikingly, in TJ2-Tg; Foxn1 +/nu compound mice, both emergence of malignant cells in preleukemic thymi and overt T-ALL onset were significantly delayed. Moreover, in transplantation assays, leukemic cell expansion within the thymus of recipient Foxn1 +/nu mice was reduced as compared with control littermates. Since thymopoesis is largely normal in Foxn1 +/nu mice, these results indicate that FoxN1 haploinsufficiency in TECs has a more profound impact in thymic leukemogenesis. [ABSTRACT FROM AUTHOR]

Recent progress in nanobiotechnology has attracted interest to a biomedical application of the carbon nanostructure C 60 fullerene since it possesses a unique structure and versatile biological activity. C 60 fullerene potential application in the frame of cancer photodynamic therapy (PDT) relies on rapid development of new light sources as well as on better understanding of the fullerene interaction with cells. The aim of this study was to analyze C 60 fullerene effects on human leukemic cells (CCRF-CEM) in combination with high power single chip light-emitting diodes (LEDs) light irradiation of different wavelengths: ultraviolet (UV, 365 nm), violet (405 nm), green (515 nm) and red (632 nm). The time-dependent accumulation of fullerene C 60 in CCRF-CEM cells up to 250 ng/10 6 cells at 24 h with predominant localization within mitochondria was demonstrated with immunocytochemical staining and liquid chromatography mass spectrometry. In a cell viability assay we studied photoexcitation of the accumulated C 60 nanostructures with ultraviolet or violet LEDs and could prove that significant phototoxic effects did arise. A less pronounced C 60 fullerene phototoxic effect was observed after irradiation with green, and no effect was detected with red light. A C 60 fullerene photoactivation with violet light induced substantial ROS generation and apoptotic cell death, confirmed by caspase3/7 activation and plasma membrane phosphatidylserine externalization. Our work proved C 60 fullerene ability to induce apoptosis of leukemic cells after photoexcitation with high power single chip 405 nm LED as a light source. This underlined the potential for application of C 60 nanostructure as a photosensitizer for anticancer therapy. [ABSTRACT FROM AUTHOR]

Piperlongumine is an alkaloid compound extracted from Piper longum L. It is a chemical substance with various pharmacological effects and medicinal value, including anti-tumor, lipid metabolism regulatory, antiplatelet aggregation and analgesic properties. The present study aimed to understand whether piperlongumine induces the apoptosis and autophagy of leukemic cells, and to identify the mechanism involved. Cell viability and autophagy were detected using MTT, phenazine methyl sulfate and trypan blue exclusion assays. The apoptosis rate was calculated using flow cytometry. The protein expression levels of microtubule-associated protein 1A/1B-light chain 3, Akt and mechanistic target of rapamycin (mTOR) were measured using western blotting. The cell growth of leukemic cells was completely inhibited following treatment with piperlongumine, and marked apoptosis was also induced. Dead cells as a result of autophagy were stained using immunofluorescence and observed under a light microscope. Phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling was suppressed by treatment with piperlongumine, while p38 signaling and caspase-3 activity were induced by treatment with piperlongumine. It was concluded that piperlongumine induces apoptosis and autophagy in leukemic cells through targeting the PI3K/Akt/mTOR and p38 signaling pathways. [ABSTRACT FROM AUTHOR]

In a preliminary experiment, it was found that c-myc expression was decreased following the differentiation of THP-1 cells into monocytes/macrophages induced by phorbol 12-myristate 13 acetate (PMA) + lipopolysaccharide (LPS) + interferon (IFN)-γ. The expression of miR-let-7c-5p was then found to be elevated by cross-sectional analysis using TargetScan and PubMed and differential microarray analysis. The present study aimed to investigate the role of the miR-let-7c-5p/c-myc signaling axis in the committed differentiation of THP-1 leukemic cells into monocytes/macrophages induced by PMA + LPS + IFN-γ. Human THP-1 leukemic cells were induced to differentiate into monocytes/macrophages by PMA + LPS + IFN-γ. Following induction for 48 h, the growth density of the THP-1 cells was observed directly under an inverted microscope, cell proliferation was measured using Cell Counting Kit-8 assay and the cell cycle and the expression of differentiation-related antigens (CD11b and CD14) were measured using flow cytometry. The mRNA expression of miR-let-7c-5p and c-myc was detected using reverse transcription-quantitative PCR and the protein expression of c-myc was detected using western blot analysis. Dual luciferase reporter gene analysis was used to detect the targeted binding of miR-let-7c-5p on the 3′UTR of c-myc. The relative expression of miR-let-7c-5p and c-myc genes in THP-1 cells induced by PMA + LPS + IFN-γ was found to be up- and downregulated respectively, and expression of miR-let-7c-5p was negatively correlated with the expression of c-myc gene. Dual luciferase reporter gene assays confirmed that miR-let-7c-5p targeted the 3′UTR of c-myc and inhibited luciferase activity. Following transfection with miR-let-7c-5p mimics, the expression of c-myc was markedly downregulated and the proliferative ability of the THP-1 cells was decreased, while the expression rate of CD11b and CD14 was significantly increased. The rescue experiment revealed that the effects of miR-let-7c-5p mimics on the proliferation and differentiation of THP-1 cells were attenuated by transfection with c-myc overexpression vector. Together, the findings of the present study demonstrated that miR-let-7c-5p can target the 3′UTR region of c-myc and that the miR-let-7c-5p/c-myc signaling axis is one of the critical pathways involved in the directional differentiation of leukemic cells into monocytes/macrophages. [ABSTRACT FROM AUTHOR]

A herbal alkaloid Berberine (Ber), used for centuries in Ayurvedic, Chinese, Middle-Eastern, and native American folk medicines, is nowadays proved to function as a safe anticancer agent. Yet, its poor water solubility, stability, and bioavailability hinder clinical application. In this study, we have explored a nanosized carbon nanoparticle—C60 fullerene (C60)—for optimized Ber delivery into leukemic cells. Water dispersions of noncovalent C60-Ber nanocomplexes in the 1:2, 1:1, and 2:1 molar ratios were prepared. UV−Vis spectroscopy, dynamic light scattering (DLS), and atomic force microscopy (AFM) evidenced a complexation of the Ber cation with the negatively charged C60 molecule. The computer simulation showed that π-stacking dominates in Ber and C60 binding in an aqueous solution. Complexation with C60 was found to promote Ber intracellular uptake. By increasing C60 concentration, the C60-Ber nanocomplexes exhibited higher antiproliferative potential towards CCRF-CEM cells, in accordance with the following order: free Ber < 1:2 < 1:1 < 2:1 (the most toxic). The activation of caspase 3/7 and accumulation in the sub-G1 phase of CCRF-CEM cells treated with C60-Ber nanocomplexes evidenced apoptosis induction. Thus, this study indicates that the fast and easy noncovalent complexation of alkaloid Ber with C60 improved its in vitro efficiency against cancer cells.

A nanosized drug complex was explored to improve the efficiency of cancer chemotherapy, complementing it with nanodelivery and photodynamic therapy. For this, nanomolar amounts of a non-covalent nanocomplex of Doxorubicin (Dox) with carbon nanoparticle C60 fullerene (C60) were applied in 1:1 and 2:1 molar ratio, exploiting C60 both as a drug-carrier and as a photosensitizer. The fluorescence microscopy analysis of human leukemic CCRF-CEM cells, in vitro cancer model, treated with nanocomplexes showed Dox’s nuclear and C60’s extranuclear localization. It gave an opportunity to realize a double hit strategy against cancer cells based on Dox’s antiproliferative activity and C60’s photoinduced pro-oxidant activity. When cells were treated with 2:1 C60-Dox and irradiated at 405 nm the high cytotoxicity of photo-irradiated C60-Dox enabled a nanomolar concentration of Dox and C60 to efficiently kill cancer cells in vitro. The high pro-oxidant and pro-apoptotic efficiency decreased IC50 16, 9 and 7 × 103-fold, if compared with the action of Dox, non-irradiated nanocomplex, and C60’s photodynamic effect, correspondingly. Hereafter, a strong synergy of therapy arising from the combination of C60-mediated Dox delivery and C60 photoexcitation was revealed. Our data indicate that a combination of chemo- and photodynamic therapies with C60-Dox nanoformulation provides a promising synergetic approach for cancer treatment.

Metal-containing drugs have long been used in anticancer therapies. The mechansims of action of platinum-based drugs are now well-understood, which cannot be said of drugs containing other metals, such as gold or copper. To gain further insights into such mechanisms, we used a classical proteomic approach based on two-dimensional elelctrophoresis to investigate the mechanisms of action of a hydroxyquinoline-copper complex, which shows promising anticancer activities, using the leukemic cell line RAW264.7 as the biological target. Pathway analysis of the modulated proteins highlighted changes in the ubiquitin/proteasome pathway, the mitochondrion, the cell adhesion-cytoskeleton pathway, and carbon metabolism or oxido-reduction. In line with these prteomic-derived hypotheses, targeted validation experiments showed that the hydroxyquinoline-copper complex induces a massive reduction in free glutathione and a strong alteration in the actin cytoskeleton, suggesting a multi-target action of the hydroxyquinoline-copper complex on cancer cells.

The aim of the study was to investigate the effect of exosomes derived from bone marrow stromal cells (BM-SCs) on the chemoresistant characteristics of nalm-6 cells treated with etoposide (VP16). The present study isolated exosomes from BM-SC-conditioned medium by using standard differential centrifugation steps and detected the expression of 70 kilodalton heat shock proteins (HSP70) and lysosomal-associated membrane protein 3 (CD63) in exosomes by western blot analysis. Nalm-6 cells were co-cultured with exosomes in the presence of VP16. Cell viability and apoptosis were then detected using the Cell Counting Kit-8 method and Annexin-V/propidium iodide, respectively. Finally, protein levels of B-cell lymphoma 2 (BCL-2), BCL-2-like protein 4 (BAX), caspase-3, and poly ADP-ribose polymerase (PARP) were examined by western blot analysis. Exosomes were successfully isolated from the conditioned medium and confirmed by the expression of HSP70 and CD63. BM-SC-derived exosomes increased the viability of nalm-6 cells in the presence of VP16 and inhibited the apoptosis induced by VP16. Western blot analysis results showed that exosomes can block the significant reduction of BCL-2, full-length caspase-3 and full-length PARP, while preventing the increase of BAX, cleaved caspase-3 and cleaved PARP induced by VP16. Exosomes derived from BM-SCs can protect nalm-6 cells from VP16-induced apoptosis to maintain their survival and induce resistance to VP16. In addition, BCL-2/BAX, caspase-3, and PARP may be involved in the mechanism of exosome-induced drug resistance. [ABSTRACT FROM AUTHOR]

Objective To observe the effects of exogenous granulocyte-macrophage colony-stimulating factor ( GM-GSF) and recombinant PcDNA3. 1-GM-CSF on the morphology and proliferation of myeloid leukemia cells K562. Methods K562 cells were randomly divided into four groups. Recombinant PcDNA3. 1- GM-CSF, exogenous GM-GSF, and PcD-NA3. 1 null plasmids were transfected into K562 cells as the recombinant plasmid group, the exogenous group and the empty plasmid group, respectively, and the non-transfected plasmid was set as the control group. The morphological changes of cells were observed under the optical microscope by using high power lens and oil lens, respectively, and the cell proliferation was measured by MTT. Results Morphological changes seen under high power lens: the control group, the empty plasmid group and exogenous group were similar in morphology, cells were stained dark blue, whereas no clear boundary was seen between the cytoplasm and nucleus; compared with these three groups, the cells of the recombinant plasmid group showed a significant difference, the cytoplasm was stained light blue, and the nuclei were pale pink along with a clear bounds between them. Kidney or horseshoe shaped nuclei could be seen in some of the cells. Morphological changes seen under oil lens: the control group, the exogenous group, and empty plasmid group were similar, the cells were stained dark blue, and granules deposition wasnt seen in the cells; as to the recombinant plasmid group, some cells were stained dark blue, while some were pale pink in which dotted formazan particles were seen. Results of cell proliferation assay: Compared with the other two groups, the inhibition rate of cell proliferation in the recombinant plasmid group showed an increase on the 3th , 5th, 7th and 9th days (P <0.05). Compared with the empty plasmid group, the inhibition rate in the exoge-neous group displayed an increase on the 3th, 5th and 7th days (PcO.05). Conclusion Both recombinant PcDNA3. 1-GM-GSF and exogenous GM-CSF could induce morphological change and lead to proliferation inhibition in K562 cells, the effects increase along with time, and the inhibitory effect of recombinant PcDNA3. 1-GM-CSF is stronger than that of the exogenous GM-CSF. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia is driven by leukemic stem cells which can be identified by cross lineage expression or arrest of differentiation compared to normal hematopoietic stem cells. Self-renewal and lack of differentiation are also features of stem cells and have been associated with the expression of embryonic genes. The aim of our study was to evaluate the expression of embryonic antigens (OCT4, NANOG, SOX2, SSEA1, SSEA3) in hematopoietic stem cell subsets (CD34+CD38- and CD34+CD38+) from normal bone marrows and in samples from acute myeloid leukemia patients. We observed an upregulation of the transcription factors OCT4 and SOX2 in leukemic cells as compared to normal cells. Conversely, SSEA1 protein was downregulated in leukemic cells. The expression of OCT4, SOX2, and SSEA3 was higher in CD34+CD38- than in CD34+CD38+ subsets in leukemic cells. There was no correlation with biological characteristics of the leukemia. We evaluated the prognostic value of marker expression in 69 patients who received an intensive treatment. The rate of complete remission was not influenced by the level of expression of markers. Overall survival was significantly better for patients with high SOX2 levels, which was unexpected because of the inverse correlation with favorable genetic subtypes. These results prompt us to evaluate the potential role of these markers in leukemogenesis and to test their relevance for better leukemic stem cell identification. [ABSTRACT FROM AUTHOR]

Dimorfolido- N-trichloroacetylphosphorylamide (HL1) and dimorfolido- N-benzoylphosphorylamide (HL2) as representatives of carbacylamidophosphates were synthesized and identified by the methods of IR, H, and P NMR spectroscopy. In vitro HL1 and HL2 at 1 mM concentration caused cell specific and time-dependent decrease of leukemic cell viability. Compounds caused the similar gradual decrease of Jurkat cells viability at 72 h (by 35%). HL1 had earlier and more profound toxic effect as compared to HL2 regardless on leukemic cell line. Viability of Molt-16 and CCRF-CEM cells under the action of HL1 was decreased at 24 h (by 32 and 45%, respectively) with no substantial further reducing up to 72 h. Toxic effect of HL2 was detected only at 72 h of incubation of Jurkat and Molt-16 cells (cell viability was decreased by 40 and 45%, respectively). It was shown that C fullerene enhanced the toxic effect of HL2 on leukemic cells. Viability of Jurkat and CCRF-CEM cells at combined action of C fullerene and HL2 was decreased at 72 h (by 20 and 24%, respectively) in comparison with the effect of HL2 taken separately. In silico study showed that HL1 and HL2 can interact with DNA and form complexes with DNA both separately and in combination with C fullerene. More stable complexes are formed when DNA interacts with HL1 or C + HL2 structure. Strong stacking interactions can be formed between HL2 and C fullerene. Differences in the types of identified bonds and ways of binding can determine distinction in cytotoxic effects of studied compounds. [ABSTRACT FROM AUTHOR]

Having found previously that leukemic cells with multidrug resistant (MDR) phenotype, but not their sensitive counterparts, exhibit collateral sensitivity to cold stress in a P-gp-dependent manner, our aim was to study the signaling pathways involved in this phenomenon in sensitive (L1210) and resistant cells (L1210R and CBMC-6). It was observed that the acquisition of MDR phenotype by leukemic cells or their transfection with the extrussion pump, P-gp, modifies the activation profile and regulation of Mitogen-Activated Protein Kinases (MAPK) in cells exposed to low temperatures. More specifically, cold stress provoked the activation of c-Jun N-terminal kinase (JNK) in sensitive cells, while attenuated JNK signaling was observed in MDR cells. This effect was also observed, although with less intensity, in P-gp-transfected cells. Using pharmacological inhibitors to determine the role of MAPK in leukemic cell survival in physiological conditions or under cold stress, a dual temperature-dependent role was observed for JNK in MDR cell survival. At 37 °C JNK is necessary for the survival of parental, resistant and P-gp-transfected cells; however, the use of inhibitors of either extracellular signal-regulated protein kinase (ERK) or JNK significantly counteracts cold-induced death of resistant and P-gp-transfected cells, supporting a role for ERK and JNK in cold-stress induced cell death. Finally, a connectivity model concerning MAPK is proposed, summarizing how cold stress and MDR-1 might trigger apoptosis in resistant cell lines. These findings on MDR cells may assist in the design of specific therapeutic strategies to complement current chemotherapy. [ABSTRACT FROM AUTHOR]

Fullerene C as a representative of carbon nanocompounds is suggested to be promising agent for application in photodynamic therapy due to its unique physicochemical properties. The goal of this study was to estimate the accumulation of fullerene C in leukemic cells and to investigate its phototoxic effect on parental and resistant to cisplatin leukemic cells. Stable homogeneous water colloid solution of pristine C with average 50-nm diameter of nanoparticles was used in experiments. Fluorescent labeled C was synthesized by covalent conjugation of C with rhodamine B isothiocyanate. The results of confocal microscopy showed that leukemic Jurkat cells could effectively uptake fullerene C from the medium. Light-emitting diode lamp (100 mW cm, λ = 420-700 nm) was used for excitation of accumulated C. A time-dependent decrease of viability was detected when leukemic Jurkat cells were exposed to combined treatment with C and visible light. The cytotoxic effect of photoexcited C was comparable with that induced by HO, as both agents caused 50% decrease of cell viability at 24 h at concentrations about 50 μM. Using immunoblot analysis, protein phosphotyrosine levels in cells were estimated. Combined action of C and visible light was followed by decrease of cellular proteins phosphorylation on tyrosine residues though less intensive as compared with that induced by HO or protein tyrosine kinase inhibitor staurosporine. All tested agents reduced phosphorylation of 55, 70, and 90 kDa proteins while total suppression of 26 kDa protein phosphorylation was specific only for photoexcited C. The cytotoxic effect of C in combination with visible light irradiation was demonstrated also on leukemic L1210 cells both sensitive and resistant to cisplatin. It was shown that relative value of mitochondrial membrane potential measured with tetramethylrhodamine ethyl ester perchlorate (TMRE) probe was lower in resistant cells in comparison with sensitive cells and the drop of mitochondrial potential corresponded to further decrease of resistant cell viability after C photoexcitation. The data obtained allow to suggest that C-mediated photodynamic treatment is a candidate for restoration of drug-resistant leukemic cell sensitivity to induction of mitochondrial way of apoptosis. [ABSTRACT FROM AUTHOR]

The present study investigated possible mechanisms on the apoptosis induction of human leukemic cells by fucoidan, a sulfated polysaccharide found in marine algae. Fucoidan treatment of cells resulted in inhibition of growth and induction of apoptosis, as measured by 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyl-tetrazolium (MTT) assay, fluorescence microscopy, DNA fragmentation, and flow cytometry analysis. The increase in apoptosis was associated with the proteolytic activation of caspases, Bid cleavage, insertion of pro-apoptotic Bax into the mitochondria, release of cytochrome c from mitochondria to cytosol, and loss of mitochondria membrane potential (MMP) in U937 cells. However, apoptosis induced by fucoidan was attenuated by caspase inhibitors, indicating that fucoidan-induced apoptosis was dependent on the activation of caspases. Furthermore, fucoidan treatment effectively activated the p38 mitogen-activated protein kinase (MAPK) and p38 MAPK inhibitor, SB203580, and significantly reduced fucoidan-induced apoptosis through inhibition of Bax translocation and caspases activation, suggesting that the activation of p38 MAPK may play a key role in fucoidan-induced apoptosis. In addition, the authors found fucoidan-induced significantly attenuated in Bcl-2 overexpressing U937 cells, and pretreatment with fucoidan and HA 14-1, a small-molecule Bcl-2 inhibitor, markedly increased fucoidan-mediated apoptosis in Bcl-2 overexpressing U937 cells. Our findings imply that we may attribute some of the biological functions of p38 MAPK and Bcl-2 to their ability to inhibit fucoidan-induced apoptosis.

Some types of tumor cells are unable to synthesize arginine from its precursors. They exhibit growth inhibition and decreased viability in vitro and in vivo under enzymatic arginine deprivation. However, prolonged arginine starvation in human may cause vasoconstriction and thrombosis due to the deficit of arginine derivative, nitric oxide (NO), as vasodilator and disaggregant. This problem can be overcome via supplementation with exogenous NO-donors in vivo, which, in turn, may produce either, pro-apoptotic or anti-apoptotic specific effects on cancer cells under arginine restriction. In this study we elucidated the effect of exogenous NO donor, sodium nitroprusside (SNP) on the viability of human Jurkat leukemic cells under arginine deprivation in vitro. We observed that arginine deprivation suppressed cell proliferation and led to a rapid decrease in cell viability concomitant with progression of apoptosis. According to SNP IC50 determination and apoptosis assays, NO-donor at physiological concentration did not promote survival of tumor cells in arginine-free medium. Moreover, SNP cytotoxicity for Jurkat cells was increased upon arginine withdrawal, suggesting that application of NO donor in vivo may potentially enhance the therapeutic effect of arginine deprivation.

The polyphenol nordihydroguaiaretic acid ( NDGA) has antineoplastic properties, hence it is critical to understand its action at the molecular level. Here, we establish that NDGA inhibits glucose uptake and cell viability in leukemic HL-60 and U-937 cell lines. We monitored hexose uptake using radio-labeled 2-deoxyglucose (2 DG) and found that the inhibition by NDGA followed a noncompetitive mechanism. In addition, NDGA blocked hexose transport in human red blood cells and displaced prebound cytochalasin B from erythrocyte ghosts, suggesting a direct interaction with the glucose transporter GLUT1. We propose a model for the mechanism of action of NDGA on glucose uptake. Our study shows for the first time that NDGA can act as inhibitor of the glucose transporter GLUT1. [ABSTRACT FROM AUTHOR]

A series of curcumin pyrazole derivatives ( 3a-e) were synthesized. The chemical structures were determined by H and C NMR spectroscopic techniques and their purity was confirmed by LC-MS and melting point determination. The compounds were screened for anticancer effects on different cancer cell lines by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay. The analogs demonstrated growth inhibitory effect on MCF-7, HeLa, and K562 cell lines with significant IC values. Compound 3b exhibited a high degree of cytotoxicity against cancer cells and minimum growth inhibitory effects against normal cells HEK293T and hence further, cell cycle analysis and mitochondrial membrane potential studies (JC-1 assay) were conducted by utilizing flow cytometry against K562 cells. This compound effectively arrested cell cycle progression at SubG1 phase and cells exhibited decreased membrane potential in a concentration-dependent manner with fluorescence shifting from red to green. Our findings suggest that compound 3b could be a promising anticancer agent since it effectively inhibited cell proliferation and can be selected for further in vitro and in vivo investigations. [ABSTRACT FROM AUTHOR]

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are pivotal components of the leukemic microenvironment. BM-MSCs have been previously reported to promote the proliferation of leukemic cells. To further understand the molecular mechanisms of BM-MSC-induced proliferation of leukemic cells, the present study co-cultured acute lymphoblastic leukemia (ALL) Reh cells with BM-MSCs. The current study used methods including shRNA, flow cytometry, MTT, reverse transcription-quantitative polymerase chain reaction, ELISA and western blotting. The data of the present study demonstrated that BM-MSCs promote the proliferation of Reh cells and the NR2F2 mRNA and protein levels were elevated in BM-MSCs following co-culture. Additionally, it was demonstrated that shRNA knockdown of NR2F2 inhibited BM-MSC-induced proliferation of Reh cells. Furthermore, following downregulation of NR2F2, vascular endothelial growth factor A (VEGFA) secretion by BM-MSCs was reduced. The present study demonstrated that NR2F2 mediates BM-MSC-induced proliferation of Reh cells, partially via regulation of VEGFA. Disrupting micro-environmental support by targeting NR2F2 may be a potential therapeutic strategy for ALL. [ABSTRACT FROM AUTHOR]

Alisertib, a potent and selective Aurora kinase A inhibitor, has been demonstrated to exert potent anti-cancer effects in pre-clinical and clinical studies. However, mechanisms of action of alisertib, including the molecular pathways involved in alisertib-induced apoptosis and autophagy of leukemic cells, have remained elusive. The aim of the present study was to investigate the effects of alisertib on cell growth, apoptosis and autophagy and to delineate the possible molecular mechanisms in leukemic cells. Acid phosphatase, MTT and Annexin V/propidium iodide staining assays as well as immunostaining for light chain 3B showed that treatment of the REH leukemia cell line with alisertib exerted potent growth inhibitory effects, and induced apoptosis and autophagy in a dose-dependent manner. Western blot analysis indicated that these effects may be attributed to the suppression of the activity of the Akt/mammalian target of rapamycin/5'-AMP-dependent kinase/p38 mitogen-activated protein kinase signaling pathways in REH cells. The present study confirmed that alisertib may represent a promising autophagy-inducing drug for the treatment of leukemia and shed light on its molecular mechanism of action. [ABSTRACT FROM AUTHOR]

Doxycycline, a tetracycline-based antibiotic, has been reported to attenuate melanoma cell migration through inhibiting the focal adhesion kinase (FAK) signaling pathway. However, it remains to be elucidated whether doxycycline exerts this effect on leukemia cell migration. The present study aimed to examine the role of doxycycline in leukemia cell migration. The invasion capacities of the human leukemia cell lines KG1a (acute myelogenous leukemia) and K562 (chronic myelogenous leukemia) were evaluated using Matrigel® matrix-coated Transwell® chamber assays; leukemic cell lines treated with doxycycline (1 µg/ml) or anti-β1-integrin antibodies were added to the upper chamber, while untreated cells were included as controls. Reverse transcription quantitative polymerase chain reaction was performed in order to further understand the influence of doxycycline treatment on the expression of FAK and gelatinases in the KG1a and K562 leukemic cell lines. In addition, FAK protein expression and phosphorylation were determined using western blot analysis in order to investigate the mechanism by which doxycycline inhibited leukemic cell migration. The results revealed that doxycycline treatment significantly attenuated the migration of KG1a and K562 cells, which was demonstrated to be associated with inhibition of the expression and phosphorylation of FAK. In addition, doxycycline treatment inhibited matrix metalloproteinase (MMP)-2 and MMP-9 expression. Furthermore, incubation with blocking anti-β1-integrin antibodies had an analogous inhibitory effect on leukemic cell migration to that of doxycycline. In conclusion, the results of the present study suggested that doxycycline attenuated leukemic cell migration through inhibiting the FAK signaling pathway. Therefore, doxycycline may have potential for use as a novel strategy for the treatment of leukemia. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), either alone or in combination with other anti-cancer agents, is a promising new strategy for the treatment of cancer. However, aberrant PI3K/Akt/mTOR survival signaling may confer TRAIL resistance by altering the balance between pro- and anti-apoptotic proteins. In the present study, we showed that the Akt/mTOR inhibitor RAD001 (everolimus) induced cell death in a dose-dependent manner and enhanced TRAIL-induced apoptosis in human leukemic Jurkat T cells, which show PI3K/Akt/mTOR pathway activation and basal expression levels of death receptor (DR) 5 (TRAIL-R2). Investigation of the effect of RAD001 treatment on the expression of TRAIL receptors (TRAIL-Rs) in Jurkat T cells showed that RAD001 significantly upregulated DR5 by up to 51.22%, but not other TRAIL-Rs such as DR4 (TRAIL-R1), decoy receptor (DcR) 1 (TRAIL-R3), and DcR2 (TRAIL-R4). Pretreatment with DR5:Fc chimera abrogated the RAD001-induced increase of TRAIL cytotoxicity, indicating that the upregulation of DR5 by RAD001 plays a role in enhancing the susceptibility of Jurkat T cells to TRAIL. Our results indicate that combination treatment with RAD001 and TRAIL may be a novel therapeutic strategy in leukemia. [ABSTRACT FROM AUTHOR]

Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors.

Background: Cellfood™ (CF) is a nutritional supplement containing deuterium sulphate, minerals, amino acids, and enzymes, with well documented antioxidant properties. Its organic and inorganic components are extracted from the red algae Lithothamnion calcareum, whose mineral extract has shown growth-inhibitory effect both on in vitro and in vivo models. The purpose of this study was to evaluate the antiproliferative effects of CF on leukemic cells. In fact, according to its capacity to modulate O2 availability and to improve mitochondrial respiratory metabolism, we wondered if CF could affect cancer cell metabolism making cells susceptible to apoptosis. Methods: Three leukemic cell lines, Jurkat, U937, and K562, were treated with CF 5 μl/ml up to 72 hours. Cell viability, apoptosis (i.e. caspase-3 activity and DNA fragmentation), hypoxia inducible factor 1 alpha (HIF-1α) concentration, glucose transporter 1 (GLUT-1) expression, lactate dehydrogenase (LDH) activity and lactate release in the culture medium were detected and compared with untreated cells. Results: CF significantly inhibited leukemic cell viability by promoting cell apoptosis, as revealed by caspase-3 activation and DNA laddering. In particular, CF treated cells showed lower HIF-1α levels and lower GLUT-1 expression as compared to untreated cells. At the same time, CF was able to reduce LDH activity and, consequently, the amount of lactate released in the extracellular environment. Conclusions: We supplied evidence for an antiproliferative effect of CF on leukemia cell lines by inducing cell death through an apoptotic mechanism and by altering cancer cell metabolism through HIF-1α and GLUT-1 regulation. Thanks to its antioxidative and proapoptotic properties, CF might be a good candidate for cancer prevention. [ABSTRACT FROM AUTHOR]

Abstract: Multidrug resistance (MDR) remains a significant problem for effective cancer chemotherapy. In spite of considerable advances in drug discovery, most of the cancer cases still stay incurable because of resistance to chemotherapy. We synthesized a novel, Mn (II) complex (chelate), viz., manganese N-(2-hydroxy acetophenone) glycinate (MnNG) that exhibits considerable efficacy to overcome drug resistant cancer. The antiproliferative activity of MnNG was studied on doxorubicin resistant and sensitive human T lymphoblastic leukemia cells (CEM/ADR 5000 and CCRF/CEM). MnNG induced apoptosis significantly in CEM/ADR 5000 cells probably through generation of reactive oxygen species. Moreover, intraperitoneal (i.p.) application of MnNG at non-toxic doses caused significant increase in the life-span of Swiss albino mice bearing sensitive and doxorubicin resistant subline of Ehrlich ascites carcinoma cells. [Copyright &y& Elsevier]

Resveratrol acts as a chemopreventive agent for cancer and as a potential antiobesity and antidiabetic compound, by leading to reduced body fat and improved glucose homeostasis. The exact mechanisms involved in improving hyperglycemic state are not known, but most of the glucose uptake into mammalian cells is facilitated by the GLUT hexose transporters. Resveratrol is structurally similar to isoflavones such as genistein, which inhibit the glucose uptake facilitated by the GLUT1 hexose transporter. Here we examined the direct effects of resveratrol on glucose uptake and accumulation in HL-60 and U-937 leukemic cell lines, which express mainly GLUT1, under conditions that discriminate transport from the intracellular substrate phosphorylation/ accumulation. Resveratrol blocks GLUT1-mediated hexose uptake and thereby affects substrate accumulation on these cells. Consequently, we characterized the mechanism involved in inhibition of glucose uptake in human red cells. Resveratrol inhibits glucose exit in human red cells, and the displacement of previously bound cytochalasin B revealed the direct interaction of resveratrol with GLUT1. Resveratrol behaves as a competitive blocker of glucose uptake under zero-trans exit and exchange kinetic assays, but it becomes a mixed noncompetitive blocker when zero-trans entry transport was assayed, suggesting that the binding site for resveratrol lies on the endofacial face of the transporter. We propose that resveratrol interacts directly with the human GLUT1 hexose transporter by binding to an endofacial site and that this interaction inhibits the transport of hexoses across the plasma membrane. This inhibition is distinct from the effect of resveratrol on the intracellular phosphorylation/accumulation of glucose. [ABSTRACT FROM AUTHOR]

The present study investigated possible mechanisms on the apoptosis induction of human leukemic cells by fucoidan, a sulfated polysaccharide found in marine algae. Fucoidan treatment of cells resulted in inhibition of growth and induction of apoptosis, as measured by 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyl-tetrazolium (MTT) assay, fluorescence microscopy, DNA fragmentation, and flow cytometry analysis. The increase in apoptosis was associated with the proteolytic activation of caspases, Bid cleavage, insertion of pro-apoptotic Bax into the mitochondria, release of cytochrome c from mitochondria to cytosol, and loss of mitochondria membrane potential (MMP) in U937 cells. However, apoptosis induced by fucoidan was attenuated by caspase inhibitors, indicating that fucoidan-induced apoptosis was dependent on the activation of caspases. Furthermore, fucoidan treatment effectively activated the p38 mitogen-activated protein kinase (MAPK) and p38 MAPK inhibitor, SB203580, and significantly reduced fucoidan-induced apoptosis through inhibition of Bax translocation and caspases activation, suggesting that the activation of p38 MAPK may play a key role in fucoidan-induced apoptosis. In addition, the authors found fucoidan-induced significantly attenuated in Bcl-2 overexpressing U937 cells, and pretreatment with fucoidan and HA 14-1, a small-molecule Bcl-2 inhibitor, markedly increased fucoidan-mediated apoptosis in Bcl-2 overexpressing U937 cells. Our findings imply that we may attribute some of the biological functions of p38 MAPK and Bcl-2 to their ability to inhibit fucoidan-induced apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: The antiproliferative activity of lectins Canavalia ensiformis (ConA) and Canavalia brasiliensis (ConBr) were studied using human leukemia MOLT-4 and HL-60 cell lines. It was revealed that both ConA and ConBr were markedly cytotoxic to cells using MTT and NAC assays. The IC50 values were approximately 3 and 20μg/mL for ConA and ConBr, respectively, for both MOLT-4 and HL-60 cells. However, in normal human peripheral blood lymphocytes, the lectins were not cytotoxic, even when tested at concentrations as high as 200μg/ml. Using comet assay, the lectins produced a rate of DNA damage exceeding 80% in MOLT-4 and HL-60 cells. Fluorescence analysis revealed the morphology characteristic of apoptosis, with low concentrations of apoptotic bodies and fragmented DNA (5μg/ml). Flow cytometric analysis demonstrated an accumulation of cells in the sub-G1 cell cycle that is characteristic of DNA fragmentation, and a decrease in membrane integrity at high concentrations. Lastly, we evaluated the alterations in mitochondrial potential that reduced after treatment with lectins. Our results indicate that ConA and ConBr inhibited cell proliferation selectively in tumor cells and that apoptosis was the main death mechanism. Therefore, lectins can be considered a class of molecules with a high antitumor activity potential. [Copyright &y& Elsevier]

Abstract: The effects of combined administration of doxorubicin (DOX) and vincristine (VCR), with 5-aminolevulinic acid photodynamic treatment (ALA-PDT), were analyzed in sensitive murine leukemic cell lines (LBR-) and DOX and VCR chemoresistant LBR-D160 and LBR-V160 cell lines. Low doses of DOX and VCR increased anti-cancer effect of ALA-PDT in LBR-cells. Decrease in cell survival was higher when the combination VCR+ALA-PDT was used compared to DOX+ALA-PDT. Resistant cell lines LBR-D160 and LBR-V160 were sensitive to ALA-PDT; however, no changes occured when combining therapies. Thus, ALA-PDT can overcome drug resistance and is a good candidate for using treating multidrug resistant (MDR) cells. [Copyright &y& Elsevier]