curcumin and Thymus-Neoplasms

Curcumin (CUR) is a kind of polyphenolic compound and widely used in the treatment of diseases. However, the involvement of CUR in thymic carcinoma remains unknown. The object of our research is to clarify the role of CUR and related regulatory mechanism in thymic carcinoma cells. After treatment with CUR for 24 hr, cell viability, apoptosis, migration, and invasion of TC1889 cells were measured. Real-time polymerase chain reaction was executed to examine the expression of microRNA-27a (miR-27a) in thymic carcinoma tissues and TC1889 cells. After miR-27a mimic transfection, whether miR-27a is involved in CUR-modulated cell behaviors was measured. Finally, western blot was utilized to detect mTOR and Notch 1 pathways-linked proteins. CUR restrained cell viability and increased cell apoptosis of TC1889 cells. In addition, cell migration and invasion were restrained by CUR. Meanwhile, miR-27a expression was positively regulated in thymic carcinoma tissues and downregulated by CUR in TC1889 cells. Overexpressed miR-27a reversed the CUR-induced reduction of growth, migration, and invasion in TC1889 cells. Furthermore, CUR blocked mTOR and Notch 1 pathways via downregulating miR-27a. We demonstrated that CUR blocked mTOR and Notch 1 pathways via downregulating miR-27a, thereby suppressing cell growth, migration, and invasion of thymic carcinoma cells.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Curcumin; Down-Regulation; Humans; Middle Aged; Thymus Neoplasms; Transfection

Adoptive T-cell therapy involves the ex vivo expansion and subsequent transfusion of tumor-specific T lymphocytes to eliminate tumors. Using immune modulators to block immunosuppressive factors in the tumor microenvironment has emerged as a promising strategy to enhance T-cell-mediated tumor regression. Curcumin, a major component of turmeric, has been shown to possess antitumor and immunomodulatory effects by regulating a diverse range of molecular targets. Thus, we hypothesize that these beneficial effects of curcumin may improve the therapeutic efficacy of adoptive therapy. Here, we have shown that curcumin enhances cytotoxicity of CD8(+) T cells toward tumors via alteration of the tumor microenvironment when combined with adoptive therapy. We found that T-cell accumulation and function were increased in combined treatment due to the blockade of different immunosuppressors, including TGF-β, indoleamine 2,3-dioxygenase, and regulatory T cells. Furthermore, bioluminescent imaging with a granzyme B promoter-conjugated optical reporter also reflected improved cytotoxicity of antigen-specific CD8(+) T cells in tumor-bearing mice during treatment. These findings suggest that combination of multitargeting drugs, such as curcumin, with adoptive therapy may have potential for clinical application. In addition, using a granzyme B-specific imaging reporter to assess T-cell function may also be applied for the development and therapeutic evaluation of new immunotherapy in preclinical studies.

Topics: Animals; Antineoplastic Agents; Blotting, Western; CD8-Positive T-Lymphocytes; Combined Modality Therapy; Curcumin; Flow Cytometry; Fluorescent Antibody Technique; Granzymes; Immune Tolerance; Immunomodulation; Immunotherapy, Adoptive; Indoleamine-Pyrrole 2,3,-Dioxygenase; Luminescent Measurements; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Imaging; RNA, Messenger; T-Lymphocytes; T-Lymphocytes, Regulatory; Thymus Neoplasms; Transforming Growth Factor beta; Tumor Cells, Cultured

Previous reports from our laboratory have shown that in Swiss female mice exposed to an acute dose (3 Gy) of whole body irradiation (WBI), induced thymic lymphoma (TL) resulted after three to four weeks of exposure. The present study was aimed to further evaluate dependency on gender and effect of age of mice at the time of irradiation on TL incidence. A significant decrease in body weight gain was observed in female mice exposed to WBI, which was found to be correlated with the increase in weight and size of thymus, compared to their respective controls. An increase in TL incidence was observed with the increased postirradiation time, which was 47, 80, and 93% after 90, 120, and 150 days of WBI, respectively, in female mice. In irradiated female mice, the TL incidence was significantly higher and the growth of tumor in terms of weight and size was more aggressive than in males of the same age. Moreover, mice with higher age groups at the time of irradiation showed substantial decrease in TL incidence and its aggressiveness; and these effects were more conspicuous in males than in females. In mice irradiated at the age group of three to four weeks, the TL incidence was 83 and 72% in female and male, respectively, which was decreased to 74% in female and 14% in male in the age group of 12-13 weeks. It was further observed that the postirradiation feeding of animals with antioxidants resulted in a significant decrease in TL incidence, and the prevention in TL incidence was more in animals fed with curcumin (55%) than with ascorbic acid and eugenol (20%). These results have provided significant new findings on the phenomenon of radiation-induced TL incidence related to gender and age at the time of irradiation and its prevention by postirradiation antioxidant feeding to mice.

Topics: Aging; Animals; Antioxidants; Ascorbic Acid; Body Weight; Curcumin; Eugenol; Female; Gamma Rays; Lymphoma; Male; Mice; Neoplasms, Radiation-Induced; Organ Size; Sex Factors; Thymus Gland; Thymus Neoplasms; Whole-Body Irradiation

Curcumin is a dietary compound with diverse anti-inflammatory and anticarcinogenic effects in several experimental models. A mechanism by which curcumin exerts these actions might be the direct modification of protein thiols, thereby altering the activity of the affected proteins. An early event in inflammatory signaling cascades is the recruitment of the interleukin-1 (IL-1) receptor-associated kinase (IRAK) to the IL-1 receptor (IL-1RI) upon stimulation with IL-1. IRAK recruitment was shown recently to be inhibited by agents that modify thiols of IRAK. We asked, therefore, whether IRAK is also a target for curcumin. Curcumin indeed blocked IRAK thiols in a murine T-cell line stably overexpressing IRAK (EL-4(IRAK)), which resulted in the inhibition of IRAK recruitment to the IL-1RI and phosphorylation of IRAK and IL-1RI-associated proteins. Inhibitory effects were not reversible by thiol-reducing agents. Thus, modification by curcumin did not occur by oxidation but rather by alkylation, as is typical for electrophilic compounds reacting as Michael addition acceptors. The block in one of the earliest events in the IL-1 signaling cascade can explain the often observed inhibition of IL-1-mediated signaling steps by curcumin further downstream. Hence, thiol modification might be a crucial step in the anti-inflammatory functions of curcumin.

Topics: Animals; Cell Line, Tumor; Curcumin; Interleukin-1; Interleukin-1 Receptor-Associated Kinases; Mice; Oxidation-Reduction; Protein Kinase Inhibitors; Protein Kinases; Receptors, Interleukin-1; Signal Transduction; Thymoma; Thymus Neoplasms