curcumin and Leukemia--T-Cell

The burden of neoplastic diseases is widely recognized as a severe cause of mortality. The clinical inadequacy of most anticancer therapeutics urgently prompted intense drug discovery efforts toward the identification of new chemical entities endowed with a potent and safe antitumor profile. In this scenario, targeting cancer cells apoptosis machinery has emerged as a relevant strategy, useful for tackling the emergence of drug resistance. On this basis, a small library of naturally inspired hybrid molecules was obtained by combining, through a click chemistry approach, "privileged" synthons such as curcumin scaffold and 1,2,3-triazole building block. Compound

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Leukemia, T-Cell; Membrane Potential, Mitochondrial; Molecular Structure; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Structure-Activity Relationship; Triazoles; Tumor Cells, Cultured

Inhibition of arachidonic acid metabolism by curcumin has been suggested to be a key mechanism for its anti-carcinogenic action. Recently, we reported on the synthesis of curcumin analogues and their evaluation as selective COX1 inhibitors. Two compounds (HP109/HP102) were selected for evaluation of their anti-proliferative and pro-apoptotic potential in Jurkat T-cells.. Jurkat T-cells were stimulated with phorbol 12-myristate 13-acetate/phytohemagglutinin (PMA/PHA) in the absence and presence of different concentrations of curcumin or HP109/HP102. Interleukin 2 (IL2) production and IL2 promoter activity were analyzed by enzyme-linked immunosorbent assay and a luciferase reporter assay, respectively. Proliferation and cell viability were monitored by 2,3-Bis-(2-Methoxy-4-Nitro-5-Sulfophenyl)-2H-Tetrazolium-5-Carboxanilide assay, annexin -V/7-amino-actinomycin D staining and western blotting.. HP102 was about 10-times more effective in blocking IL2 synthesis compared to curcumin. Enhanced effects of HP102 were also observed in reducing the proliferation rate and cell viability. In contrast to HP102, HP109 did not exhibit enhanced effects compared to curcumin.. The curcumin analog HP102 had strongly improved the anti-proliferative and pro-apoptotic potential in Jurkat T-cells compared to curcumin.

Topics: Apoptosis; Cell Proliferation; Curcumin; Humans; Interleukin-2; Jurkat Cells; Leukemia, T-Cell; T-Lymphocytes

The cytotoxic activity of curcumin towards CCRF-CEM human T-cell leukemia cells was measured by the MTT assay. Tumor cells were more sensitive to the cytotoxic activity of curcumin or curcumin-Cu (II)compared to normal cells, and the IC(50) of curcumin towards CCRF-CEM cells was 8.68 microM, and that of curcumin-Cu (II) was 8.14 microM. The cell cycle distribution of curcumin-treated CCRF-CEM cells was analyzed by flow cytometry. DNA damage induced by oxidants such as curcumin-Cu (II) ions is considered as one of the main causes of cell inactivation. Therefore, we analyzed the effect of curcumin on DNA damage by agarose gel electrophoresis and atomic force microscopy (AFM). Gel electrophoresis analyses showed that curcumin or Cu (II) alone failed to cause DNA damage in pBR322 plasmid DNA as compared with the normal plasmid. However, DNA plasmids were mostly damaged after treatment with curcumin of different concentrations in the presence of Cu (II). Two forms were observed by means of AFM: closed circular plasmids and linear plasmids. DNA damage induced by a combination of curcumin and Cu (II) was also found by agarose gel electrophoresis, which was applied as control method to verify the results obtained by AFM.

Topics: Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Curcumin; DNA Damage; Electrophoresis, Agar Gel; Humans; Leukemia, T-Cell; Microscopy, Atomic Force; Plasmids

Adult T-cell leukemia (ATL) is a fatal malignancy of T lymphocytes caused by infection with human T-cell leukemia virus type I (HTLV-I) and remains incurable. Curcumin (diferuloylmethane), the major pigment of the spice turmeric, can be potentially effective by promoting cell apoptosis. Here we examined whether curcumin is effective in the treatment of ATL. Curcumin prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells but not of normal peripheral blood mononuclear cells. Curcumin induced cell cycle arrest by reducing the expression of cyclin D1, Cdk1 and Cdc25C and apoptosis by reducing the expression of XIAP and survivin. Most of these genes are known to be regulated by NF-kappaB, which plays a critical role in oncogenesis by HTLV-I. Curcumin suppressed constitutive active NF-kappaB of HTLV-I-infected T-cell lines and primary ATL cells by inhibiting phosphorylation of IkappaBalpha. Curcumin also inhibited Tax-induced NF-kappaB transcriptional activity. However, curcumin-induced suppression of cell growth did not correlate with Tax expression level. Curcumin inhibited the growth of HTLV-I-infected T-cell tumors implanted subcutaneously in SCID mice. Our results indicate that curcumin has tumor-suppressive activity against ATL.

Topics: Adult; Animals; Antineoplastic Agents; Apoptosis; CDC2 Protein Kinase; cdc25 Phosphatases; Cell Cycle; Cell Cycle Proteins; Cell Proliferation; Curcumin; Cyclin D1; Female; Gene Products, tax; Human T-lymphotropic virus 1; Humans; Inhibitor of Apoptosis Proteins; Leukemia-Lymphoma, Adult T-Cell; Leukemia, T-Cell; Mice; Mice, Inbred ICR; Mice, SCID; Microtubule-Associated Proteins; Neoplasm Proteins; NF-kappa B; Survivin; T-Lymphocytes; Tumor Cells, Cultured; X-Linked Inhibitor of Apoptosis Protein

Adult T cell leukemia is an aggressive and frequently fatal malignancy that expressess constitutively activated growth-signaling pathways in association with deregulated growth and resistance to apoptosis. Curcumin (diferuloylmethane) is a naturally occurring yellow pigment, isolated from the rhizomes of the plant Curcuma longa that has traditionally been used in the treatment of injury and inflammation. But the effect and mechanism of action of curcumin on T cell leukemia is not known. To investigate the antitumor activity of curcumin in T cell leukemia, we examined its effect on constitutive phosphorylation of JAK and STAT proteins, proliferation, and apoptosis in HTLV-I-transformed T cell lines. HTLV-I-transformed T cell leukemia lines, MT-2, HuT-102, and SLB-1, express constitutively phosphorylated JAK3, TYK2, STAT3, and STAT5 signaling proteins. In vitro treatment with curcumin induced a dose-dependent decrease in JAK and STAT phosphorylation resulting in the induction of growth-arrest and apoptosis in T cell leukemia. The induction of growth-arrest and apoptosis in association with the blockade of constitutively active JAK-STAT pathway suggests this be a mechanism by which curcumin induces antitumor activity in T cell leukemia.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Transformed; Cell Line, Tumor; Curcumin; Growth Inhibitors; Humans; Janus Kinase 3; JNK Mitogen-Activated Protein Kinases; Leukemia, T-Cell; MAP Kinase Signaling System; Phosphorylation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; STAT3 Transcription Factor; STAT5 Transcription Factor; TYK2 Kinase