salicylates and Leukemia

Rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase activation (mutational or nonmutational) is a key pathway for survival and proliferative advantage of leukemic cells. Salirasib (Concordia Pharmaceuticals) is an oral RAS inhibitor that causes dislocation of RAS by competing directly with farnesylated RAS in binding to its putative membrane-binding proteins. Salirasib does not inhibit farnesyl transferase enzyme.. We report on a phase I study of Salirasib in patients with relapsed/refractory hematologic malignancies. Salirasib was administered orally twice daily on days 1 to 21 of a 28-day cycle in a "3+3" dose escalation design.. Seventeen patients with relapsed/refractory leukemia were treated for a median of 4 cycles (range, 1-29). Three patients each were enrolled at a dose level of 100, 200, 400, 600, and 800 mg twice daily and 2 patients at a dose level of 900 mg twice daily. No dose-limiting toxicities were encountered. Grade 1/2 diarrhea was the only frequent nonhematologic toxicity observed in 14 of 17 (82%) patients and was resolved with oral antidiarrheal agents. Eight (47%) patients (4 with myelodysplastic syndrome, 2 with acute myeloid leukemia, 1 with chronic myelomonocytic leukemia, and 1 with chronic myeloid leukemia) had hematological improvement; 1 in 3 lineages, 1 in 2 lineages, and 6 in 1 lineage. None of the patients achieved complete remission. The responses lasted for a median of 10 weeks (range, 5-115). The study was discontinued because of financial constraints.. Salirasib was well tolerated and showed modest activity in relapsed/refractory hematological malignancies. The safety profile of Salirasib and its hematological malignancy relevant target makes it a potential drug to be used in combination therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Farnesol; Female; Genes, ras; Humans; Leukemia; Male; Middle Aged; Neoplasm Recurrence, Local; raf Kinases; Salicylates; Signal Transduction; Transcriptional Activation; Treatment Outcome

We report on our preclinical findings of a simple salicylic diamine compound (THG 1213) which has yielded exceptional results as a potential chemotherapeutic drug. THG 1213 is an easy to synthesize chiral and metal-free salan compound.. THG 1213 was tested on several leukemia, lymphoma and solid tumor cell lines in vitro. The effects have been studied by LDH release essay, FACS flow cytometry, photometric cell count, immunoblotting, and NMR spectroscopy.. THG 1213 selectively inhibits proliferation and induces apoptosis in leukemia, lymphoma and solid tumor cell lines. Necrosis or effects on healthy leucocytes could not be detected. Apoptosis is induced via the intrinsic and extrinsic pathways. The salan THG 1213 overcomes multidrug resistance in tumor cells and acts synergistically with vincristine and daunorubicin.. THG 1213 displays remarkable antitumor properties. In particular, the lack of metallic components of THG 1213 could prove to be beneficial in future clinical trials, as metal-containing drugs are known to show severe side effects.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Daunorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Humans; Leukemia; Lymphoma; Neoplasms; Phenylenediamines; Salicylates; Vincristine

We demonstrate the cytotoxic potential of the Schiff base iron complex [Fe(III)(salophene)Cl] in vitro and ex vivo and illustrate its ability to overcome multiple drug resistance in vincristine and daunorubicine resistant leukemic cells (Nalm-6). Treatment of lymphoma cells (BJAB) with [Fe(III)(salophene)Cl] led to the exclusion of unspecific necrosis, a concentration-dependent inhibition of proliferation and a specific apoptotic cell death. We further detected a significant loss of the mitochondrial membrane potential in lymphoma cells and an up- and downregulation of various apoptosis relevant genes, respectively, indicating the involvement of the intrinsic mitochondrial pathway.

Topics: Apoptosis; Biomarkers, Tumor; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Daunorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Ferric Compounds; Humans; Leukemia; Lymphoma; Membrane Potential, Mitochondrial; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Salicylates; Vincristine

Schiff base transition metal complexes are an important class of compounds with great potential for therapeutic interventions. However, data on antileukemic and antilymphoma effects of these complexes are limited. The activity of N,N'-bis(salicylidene)-1,2-phenylenediamine (salophene, 1), its iron(II/III) and manganese(II/III) complexes as well as rac-trans-N,N'-bis(salicylidene)-1,2-cyclohexanediamine (saldach, 2) and its respective iron(II/III) complexes was evaluated against U-937 non-Hodgkin's lymphoma and the HL-60, SUP-B15, and K-562 leukemia cell lines. The free ligands induced in all cell lines, if at all, only marginal, concentration-dependent growth inhibitory effects, and did not trigger Cu/Zn superoxide dismutase (Cu/Zn SOD) release or induce apoptosis. [Fe(II) (salophene)] (3) and [Fe(III) (salophene)Cl] (4) blocked cellular growth, caused a strong release of Cu/Zn SOD and induced apoptosis. In contrast, the manganese analogs [Mn(II) (salophene)] (5) and [Mn(III) (salophene)OAc] (6) inhibited cell growth, caused the programmed cell death only at higher concentrations and did not provoke release of Cu/Zn SOD in any of the four cell lines. Weaker cell death-promoting effects were observed when the salophene moiety of 3 and 4 was replaced with saldach (complexes 7 and 8), indicating the influence exerted by the ligand structure. In conclusion, Schiff base transition metal complexes induce strong inhibitory effects on human lymphoma and leukemia cells.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclohexylamines; Dose-Response Relationship, Drug; Humans; Iron; Leukemia; Ligands; Lymphoma; Manganese; Molecular Structure; Organometallic Compounds; Salicylates; Schiff Bases; Superoxide Dismutase

In the human acute myeloid leukemia cell line M07e, the growth factor interleukin-3 (IL-3) induces ROS formation, positively affecting Glut1-mediated glucose uptake and cell survival. The effect of IL-3 and exogenous hydrogen peroxide on cell viability seems to be mediated through inhibition of the cell death commitment, as shown by apoptotic markers such as caspase activities, apoptotic nuclei, and changes in the amount of proteins belonging to the Bcl-2 family. The pivotal role of ROS is confirmed using various antioxidants, such as EUK-134, ebselen, TEMPO, and hydroxylamine probe. In fact, these antioxidants, acting through different mechanisms, decrease glucose transport activity and cell proliferation activated by IL-3 or by low concentrations of hydrogen peroxide. Moreover, antioxidants foster programmed cell death commitment, as shown by the cited apoptotic parameters. EUK-134, a combined superoxide dismutase/catalase mimetic, opposes the effects of IL-3 and H(2)O(2), decreasing phosphorylation levels of signaling enzymes such as Akt, Src tyrosine kinase, and ERK. Results show that ROS production induced by IL-3 can protect leukemic cells from apoptosis, the effect being counteracted by antioxidants. This mechanism may play an important role in supporting acute myeloid leukemia treatment, thus representing a novel therapeutic strategy.

Topics: Antioxidants; Apoptosis; Caspases; Cell Line, Tumor; Cell Proliferation; Chromatin Assembly and Disassembly; Colony-Forming Units Assay; Glucose Transporter Type 1; Humans; Hydrogen Peroxide; Interleukin-3; Leukemia; Organometallic Compounds; Phosphorylation; Reactive Oxygen Species; Salicylates; Superoxide Dismutase; Transfection; Transgenes

As its name suggests, tumor necrosis factor (TNF) is known to induce cytotoxicity in a wide variety of tumor cells and cell lines. However, its use as a chemotherapeutic drug has been limited by its deleterious side effects of systemic shock and widespread inflammatory responses. Some nonsteroidal antiinflammatory drugs, such as sodium salicylate, have been shown to have a chemopreventive role in certain forms of cancer. Here, we reveal that sodium salicylate selectively enhances the apoptotic effects of TNF in human erythroleukemia cells but does not affect primary human lymphocytes or monocytes. Sodium salicylate did not affect the intracellular distribution of TNF receptors (TNFRs) but stimulated cell surface TNFR2 shedding. Erythroleukemia cells were shown to possess markedly greater basal NF-kappaB responses and elevated Fas-associated protein with death domain-like IL-1 converting enzyme (FLIP) levels. Sodium salicylate achieved its effects by reducing the elevated NF-kappaB responsiveness and FLIP levels and restoring the apoptotic response of TNF rather than the proliferative/proinflammatory effects of the cytokine in these cancer cells. Inhibition of NF-kappaB or FLIP levels in human erythroleukemia cells by pharmacological or molecular-biological means also resulted in switching the character of these cells from a TNF-responsive proliferative phenotype into an apoptotic one. These findings expose that the enhanced proliferative nature of human leukemia cells is caused by elevated NF-kappaB and FLIP responses and basal levels, reversible by sodium salicylate to allow greater apoptotic responsiveness of cytotoxic stimuli such as TNF. Such findings provide insight into the molecular mechanisms by which human leukemia cells can switch from a proliferative into an apoptotic phenotype.

Topics: Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein; Cells, Cultured; Humans; Leukemia; Lymphocytes; NF-kappa B; Receptors, Tumor Necrosis Factor; Salicylates; Tumor Necrosis Factors

Divergent life or death responses of a cell can be controlled by a single cytokine (tumor necrosis factor alpha, TNF) via the signaling pathways that respond to activation of its two receptors (TNFR1 and TNFR2). Here, we show that the choice of life or death can be controlled by manipulation of TNFR signals. In human erythroleukemia patient myeloid progenitor stem cells (TF-1) as well as chronic myelogenous leukemia cells (K562), granulocyte-macrophage colony-stimulating factor primes cells for apoptosis. These death-responsive cells show prolonged TNF stimulation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, but no NF-kappaB transcriptional activity as a consequence of receptor-interacting protein degradation by caspases. Conversely, cells of a proliferative phenotype display antiapoptotic NF-kappaB responses that antagonize c-Jun N-terminal kinase and p38 mitogen-activated protein kinase stress kinase effects. These proliferative effects of TNF are apparently due to enhanced basal expression of the caspase-8/FLICE-inhibitory protein FLIP. Manipulation of the NF-kappaB, c-Jun N-terminal kinase, or p38 mitogen-activated protein kinase signals switches leukemia cells from a proliferative to an apoptotic phenotype; consequently, these highly proliferative cells die rapidly. In addition, sodium salicylate mimics the death phenotype signals and causes selective destruction of leukemia cells. These findings reveal the signaling mechanisms underlying the phenomenon of human leukemia cell life/death switching. Additionally, through knowledge of the signals that control TNF life/death switching, we have identified several therapeutic targets for selectively killing these cells.

Topics: Antineoplastic Agents; Apoptosis; Cell Division; Genes, Reporter; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; K562 Cells; Leukemia; Phenotype; Salicylates; Time Factors; Tumor Necrosis Factor-alpha

Salicylate and several structurally analogous compounds enhance merocyanine 540 (MC540)-photosensitized killing of leukemia cells (M. A. Anderson, B. Kalyanaraman, and J. B. Feix, Cancer Res., 53: 806-809, 1993). In this work, we show that salicylic acid enhances the binding of MC540 prior to illumination, as well as the light-stimulated uptake of MC540 by target L1210 murine and K562 human leukemia cells. Acetylsalicylic acid, 2,3- and 2,5-dihydroxybenzoic acids, and sodium benzoate also enhance MC540 uptake. The irradiation dose responses for loss of cell survival and enhanced MC540 uptake are well correlated, both being shifted to earlier time points in the presence of salicylate. Salicylic acid also enhanced photodynamic cell killing of A549 lung carcinoma and NIH:OVCAR-3 ovarian carcinoma cells, two cell types which are relatively resistant to MC540-mediated photosensitization. Cellular uptake of the anionic, potential-sensitive oxonol dye, bis-(1,3-dibutylbarbituric acid)-trimethine oxonol, is also increased by salicylate in a dose-dependent fashion. In contrast, cellular uptake of the cationic cyanine dye, 3,3'-dihexyloxacarbocyanine, is unaffected by salicylate. These studies suggest that increased uptake of MC540 is the basis of salicylate enhancement and that changes in plasma membrane potentials may play a mechanistic role in the potentiation of MC540 binding and cell killing.

Topics: Animals; Benzoates; Benzoic Acid; Cell Survival; Drug Screening Assays, Antitumor; Drug Synergism; Fluorescence; Humans; Leukemia; Leukemia L1210; Mice; Neoplasms; Photochemotherapy; Photosensitizing Agents; Pyrimidinones; Salicylates; Salicylic Acid

A population-based case-control interview study of 486 adult leukemia cases and 502 healthy controls was carried out in Shanghai, People's Republic of China during 1987-89 to evaluate the etiologic role of prior medical conditions, medications, and diagnostic X-rays. Risks were examined separately for 236 cases with acute non-lymphocytic leukemia (ANLL), 79 with chronic myeloid leukemia (CML), 81 with acute lymphocytic leukemia (ALL), and 21 with chronic lymphocytic leukemia (CLL). Little difference was found between cases and controls for prior history of diabetes, hypertension, allergic conditions, most medications, and diagnostic X-rays. A few significant associations were observed for appendectomy, tuberculosis, and for several other chronic disorders with specific leukemia cell types, but the odds ratio estimates for most of these ranged from two to three and, with the exception of the two specified above, were based generally on five or fewer exposed controls. In contrast to an association with childhood leukemia in Shanghai, prior use of chloramphenicol was not linked with ANLL or other forms of adult leukemia. Further research is needed to clarify the relation of specific medical conditions and exposures with particular subtypes of leukemia, and to examine reasons for the low incidence of CLL in China and other Asian populations.

Topics: Adolescent; Adult; Age Factors; Aged; Appendectomy; Case-Control Studies; China; Disease; Female; Humans; Hyperthyroidism; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Middle Aged; Population Surveillance; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Salicylates; Tuberculosis

Merocyanine 540 (MC540) is a photosensitizing dye of potential use in the purging of cancer cells from autologous bone marrow explants. Treatment of marrow with MC540, followed by illumination with visible light, selectively kills neoplastic cells while sparing a sufficient number of stem cells to allow marrow engraftment. The photodynamic action of MC540 is thought to be mediated by reactive oxygen species, particularly singlet oxygen. We have previously shown that salicylic acid (SA) scavenges MC540-generated singlet oxygen. In this work, we sought to abrogate MC540-mediated cell killing of murine L1210 and human K562 leukemia cells with salicylate. Paradoxically, the presence of salicylate during illumination in the presence of MC540 appreciably enhanced cell killing. Enhancement was dependent on salicylate concentration in the range 0.1 to 10 mM, with 1.0 mM SA potentiating the MC540-mediated reduction in survival of L1210 and K562 cells by factors of 2.7 and 1.9, respectively. Neither preincubation with SA followed by washing prior to illumination nor addition of SA following illumination altered MC540-mediated cell killing, indicating that potentiation was dependent on the presence of SA during illumination. Illumination in the presence of salicylate alone did not diminish cell viability. In addition to SA, a number of structurally related compounds including dihydroxybenzoic acids, aspirin, and sodium benzoate also enhanced MC540-mediated cell killing. Potentiation of leukemic cell killing by salicylate could provide a basis for enhancing the clinical efficacy of MC540-mediated phototherapy.

Topics: Animals; Cell Survival; Drug Synergism; Gentisates; Humans; Hydroxides; Hydroxybenzoates; Hydroxyl Radical; Leukemia; Leukemia L1210; Oxygen; Photochemotherapy; Photosensitizing Agents; Pyrimidinones; Salicylates; Salicylic Acid

The practical importance of BSR and blood cell changes for the early recognition should not be overestimated. But every symptomless person with raised BSR should be examined very carefully, especially for occult hepatic diseases (active hepatitis, liver cirrhosis), for anaemias, leukaemias, malignant lymphomas and other malignant diseases. The practical use of the diagnosis of blood cell changes is the possible recognition of anaemias, leukaemias and malignant lymphomas.

Topics: Adrenal Cortex Hormones; Anemia; Blood Cell Count; Blood Sedimentation; Eosinophilia; Humans; Hyperlipidemias; Leukemia; Liver Diseases; Lymphoma; Multiple Myeloma; Parasitic Diseases; Salicylates

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelet Disorders; Blood Protein Disorders; Humans; Kidney Failure, Chronic; Leukemia; Liver Diseases; Salicylates; Thrombocythemia, Essential; Uremia