tretinoin and tributyrin

Cell differentiation is essential for normal growth and homeostasis, and drug-induced differentiation of tumor cells into benign or normal cells is an important approach for anticancer chemotherapy. Studies of induction mechanisms for cell differentiation and discovery of differentiation-inducing factors are thus critical components of drug development. The Screening of differentiation-inducing factors, such as purified aldehyde reductase, a xenobiotic metabolite enzyme, that induces differentiation of human acute myeloid leukemia HL60 cells into monocyte/macrophage cells is described. Mechanisms of all-trans-retinoic acid (RA)-induced differentiation are also covered. RA is a potent inducer of HL60 cell differentiation and when used as a sole agent it can induce complete remission in patients with acute promyelocytic leukemia (APL). While one mechanism of the effect of RA involves RA nuclear receptors, retinoylation (a posttranslational modification of proteins by RA) may be a new nongenomic mechanism by which RA acts on cells. An early event in RA-induced differentiation may be retinoylation of RII alpha (regulatory subunits of cAMP-dependent protein kinase), in which RII alpha units are retinoylated and the retinoylated RII alpha is then translocated to the nucleus. Drugs can also be combined with RA in RA-differentiation therapy. Cytodifferation therapy by RA in APL patients exhibits limitations due to the resistance of relapsed patients to further RA treatment. This may occur through the induction of expression of various genes that reduce RA blood concentrations. Treatment with combinations of RA and other agents may be one way to reduce induction of those genes. Good candidates for such agents include cAMP-elevating agents, retinoids, steroids, and fatty acids that synergistically induce differentiation of HL60 cells. Two derivatives of falconensone A, falconensone A p-bromophenylhydrazone, which has a bromophenyl residue, and falconensone A dioxime, which possesses a hydroxy residue, were synthesized to incorporate features of RA and N-[4-hydroxyphenyl] retinamide. Both derivatives have exhibited more potent biological activity than the parent falconensone A in vitro and in vivo.

Topics: Acylation; Animals; Antineoplastic Agents; Cell Differentiation; Drug Design; Humans; Ketosteroids; Neoplasm Proteins; Neoplasms; Retinoids; Signal Transduction; Tretinoin; Triglycerides

All-trans retinoic acid (ATRA) is one of the most successful examples of differentiation agents and histone deacetylase inhibitors, such as tributyrin (TB), are known for their antitumor activity and potentiating action of drugs, such as ATRA. Nanostructured lipid carriers (NLC) represent a promising alternative to the encapsulation of lipophilic drugs such as ATRA. This study aims to develop, characterize and evaluate the cytotoxicity of ATRA-TB-loaded NLC for cancer treatment.. The influence of in situ formation of an ion pairing between ATRA and a lipophilic amine (benethamine) on the characteristics of NLC (size, zeta potential, encapsulation efficiency) was evaluated. TB, a butyric acid donor, was used as a component of the lipid matrix. In vitro activity on cell viability and distribution of cell cycle phases were evaluated for MCF-7, MDA-MB-231, HL-60 and Jurkat cell lines.. The presence of the amine significantly increased the encapsulation efficiency of ATRA in NLC. Inhibition of cell viability by TB-ATRA-loaded NLC was more pronounced than the free drug. Analysis of the distribution of cell cycle phases also showed increased activity for TB-ATRA-loaded NLC, with the clear effect of cell cycle arrest in G0/G1 phase transition. The presence of TB played an important role in the activity of the formulation.. Taken together, these findings suggest that TB-ATRA-loaded NLC represents a promising alternative to intravenous administration of ATRA in cancer treatment.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Drug Carriers; Drug Combinations; Female; Histone Deacetylase Inhibitors; HL-60 Cells; Humans; Jurkat Cells; Leukemia; Lipids; MCF-7 Cells; Nanostructures; Tretinoin; Triglycerides

Radioiodine ablation is ineffective in patients with radioiodine nonresponsive thyroid carcinoma. We investigated the effects of all-trans retinoic acid (ATRA) combined with histone deacetylase inhibitor, tributyrin on sodium-iodide symporter (NIS) expression, radioiodine uptake, and inhibition of cell proliferation in a poorly differentiated follicular thyroid carcinoma (FTC-133) in vitro.. FTC-133 cells were cultured in the presence of ATRA and tributyrin either as a single agent or in combinations for 48 h. The expression of NIS mRNA and protein was, respectively, detected by quantitative real-time polymerase chain reaction and western blot. The radioiodine uptake was determined after incubation of FTC-133 cells with 125I-iodide. Finally, the cell proliferation test of FTC-133 was performed after treatment.. Enhanced expression of NIS mRNA and protein was observed in FTC-133 cells treated with ATRA and tributyrin, which further resulted in significant higher levels of radioiodine uptake than that of untreated control cells and cells treated with ATRA alone. Additive inhibition of the proliferation of FTC-133 cells was also observed with the combination of ATRA and tributyrin.. The combination of ATRA and tributyrin induced a synergistic effect on radioiodine uptake and inhibition of FTC-133 cells proliferation in vitro. However, further in-vivo studies and additional molecular research will be needed to determine the absolute efficiency of radioiodine therapy.

Topics: Adenocarcinoma, Follicular; Biological Transport; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Iodine Radioisotopes; Symporters; Thyroid Neoplasms; Tretinoin; Triglycerides

The pharmacokinetics of all-trans-retinoic acid (ATRA), an anti-cancer drug was highly variable due to its poor aqueous solubility. In this study, we investigated the pharmacokinetics of ATRA in male Wistar rats following intravenous administration of the ATRA loaded tributyrin emulsion. In vitro, the ATRA emulsion was proved binding to apolipoprotein(s). In vivo, the clearance of ATRA was significantly reduced by formulating into the tributyrin emulsion, leading to higher AUCs. Co-administration with 17alpha-ethynylestradiol, a compound known to upregulate the activity of low-density lipoprotein receptors in tissues, significantly increased the K(e), V, and CL of ATRA. The variation of plasma AUCs after administering the ATRA emulsion to the healthy rats was two times less than that after the ATRA solution. The IC(50) in ATRA of the ATRA emulsion for the Caco-2 carcinoma cells was 3.8 microg/mL lower than 6 microg/mL of the ATRA solution. The IC(50) of the emulsion for the HepG2 carcinoma cells was 2.8 microg/mL, while IC(50) was not achieved with the ATRA solution over the test concentration range. The finding indicated that the tributyrin emulsion could be used as a carrier for ATRA and enhances the drug effect by reducing the clearance and increasing the in vitro activity.

Topics: Animals; Antineoplastic Agents; Caco-2 Cells; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromatography, High Pressure Liquid; Drug Carriers; Emulsions; Ethinyl Estradiol; Humans; Injections, Intravenous; Lipoproteins; Male; Particle Size; Rats; Rats, Wistar; Solubility; Solutions; Tretinoin; Triglycerides

Fourteen butyrate derivatives and retinoic acid were tested with respect to the hemoglobin F-inducing activity using the K562 erythroleukemia cell line as a model system. Four novel butyrate derivatives with hemoglobin F-inducing activity have been identified. Combined treatment with the butyrate derivative tributyrin and retinoic acid in vitro led to a 7-fold increase of hemoglobin synthesis. Tributyrin and retinoic acid might be promising drugs for clinical trials to treat patients with beta-hemoglobinopathies.

Topics: Antineoplastic Agents; Fetal Hemoglobin; Humans; K562 Cells; Leukemia, Erythroblastic, Acute; Tretinoin; Triglycerides

To investigate the differentiation of NB4 and MR2 cells induced by tributyrin (TB) in combination with different doses of all-trans retinoic acid (ATRA) and to see if TB can induce apoptosis of NB4 and MR2 cells.. Cell differentiation was analyzed by NBT reduction and CD(11b), CD(14) and CD(33), apoptosis by morphology, DNA electrophoresis, flow cytometry (FCM) and TUNEL in situ hybridization, bcl-2 expression by reverse transcriptase polymerase chain reaction.. 0.2 mmol/L TB in combination with different doses of ATRA could potentiate the differentiation of NB4 cells induced by ATRA alone. No MR2 cell could be markedly induced by ATRA alone or in combination with TB. Treated with 1 mmol/L TB for 24 hours NB4 and MR2 cells exhibited a morphological characteristic of apoptosis and typical DNA ladder on gel electrophoresis. FCM analysis showed that TB could interfere with cell cycle in NB4 and MR2 cells, with a similar ratio of sub-G(1) in both cell lines. TUNEL in situ hybridization confirmed these results. Further study showed that TB could gradually down-regulated bcl-2 expression.. TB exerts synergetic effect on ATRA-induced differentiation and induces apoptosis in promyelocytic leukemic cells.

Topics: Apoptosis; Cell Differentiation; Cell Division; Dose-Response Relationship, Drug; Humans; In Situ Nick-End Labeling; Leukemia, Promyelocytic, Acute; Tretinoin; Triglycerides

To use NB4, an authentic human acute promyelocytic leukemia cell line, as well as the marrow cells from patients with acute promyelocytic leukemia (APL), containing the PML/RAR alpha fusion gene and fused protein to examine the growth inhibition and cytodifferentiation induced by all-trans retinoic acid (ATRA), butyric acid (BA) and its prodrug tributyrin (TB) either as a single agent or in combinations.. NB4 and APL cells were cultured in presence of ATRA, BA and TB respectively either as a single agent or in combinations at various concentration ratio. Cell growth was measured and myeloid differentiation was determined by morphology and the percentage of positive nitroblue tetrazolium reduction (NBT) on consecutive days over the whole process of culture.. NB4 cells can be induced by ATRA alone and synergistically induced by the combinations of BA or TB with ATRA to differentiate. The synergy was reflected by a remarkable decrease in the effective concentration of ATRA required in the combinations in comparison with it as a sole agent. The combinations also shortened the time for the cells to reach the same level of maturation as that needed for ATRA alone. The potentiation on ATRA-induced differentiation of NB4 cells seemed depending on an appropriate concentration ratio of each inducer in the combinations and the time of action. A preliminary result of in vitro induction of primarily cultured leukemic cells from APL patients by the combined inducers was promising.. The combinations of ATRA with BA or TB at an appropriate ratio may improve the clinical outcome of differentiation therapy for APL patients.

Topics: Butyric Acid; Cell Transformation, Neoplastic; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Oncogene Proteins, Fusion; Prodrugs; Stereoisomerism; Translocation, Genetic; Tretinoin; Triglycerides; Tumor Cells, Cultured

Cytodifferentiation therapy by all-trans-retinoic acid (RA) for acute promyelocytic leukemia patients is encouraging in spite of several limitations preventing better clinical outcomes. Most patients in complete remission induced by RA experience relapse and resist further treatment with RA. This resistance primarily is due to a systemic self-induced catabolism of RA, which interferes with the maintenance of effective plasma levels of RA. In this report we explored the possibility that treatment with combinations of RA and other differentiation agents may induce differentiation at lower RA concentrations, which in turn may produce diminished levels of resistance. We found that although n-butyric acid (BA), tributyrin (TB) (a prodrug of BA), or hexamethylene bisacetamide (HMBA) were inactive as sole agents they potentiated RA-induced differentiation of human acute promyelocytic NB4 cells. A measure of the effectiveness of these combinations was that the concentrations of RA in combination with BA and HMBA inducing half-maximal differentiation were 20- to 40-fold lower than those needed with RA alone. Furthermore, the concentrations of BA and HMBA in these combinations were at achievable plasma levels. Therefore, these combinations may have clinical utility for treatment of a variety of malignancies that are sensitive to RA alone.

Topics: Acetamides; Antineoplastic Agents; Butyrates; Butyric Acid; Cell Differentiation; Drug Synergism; Humans; Leukemia, Promyelocytic, Acute; Tretinoin; Triglycerides; Tumor Cells, Cultured