Apricoxib upregulates 15-PGDH and PGT in tobacco-related epithelial malignancies.

BACKGROUND: Despite focused research in conventional therapies and considerable advances in the understanding of the molecular carcinogenesis of head and neck squamous cell carcinoma (HNSCC), the 5-year survival rate for patients with advanced disease remains ∼15-20%. The major causes of HNSCC-related deaths are cervical node and distant metastasis. E-cadherin has a key role in epithelial intercellular adhesion and its downregulation is a hallmark of epithelial-mesenchymal transition (EMT), which is associated with invasion, metastasis, and poor prognosis. Epithelial-mesenchymal transition is the major mechanism responsible for mediating invasiveness and metastasis of epithelial cancers. Recently, we reported the role of E-cadherin transcriptional repressors in the inflammation-induced promotion of EMT in HNSCC, which is mediated by COX-2. These findings suggest that therapies targeting the cyclooxygenase pathway may diminish the propensity for tumour metastasis in HNSCC by blocking the PGE2-mediated induction of E-cadherin transcriptional repressors. METHODS: Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration. RESULTS: Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration. Treatment of HNSCC cells with apricoxib also causes greater upregulation of E-cadherin and Muc1 expression and downregulation of vimentin, as compared with celecoxib treatment. This has significant implications for targeted chemoprevention and anti-cancer therapy because E-cadherin expression has been implicated as a marker of sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor and other therapies. We show for the first time the molecular mechanisms underlying the efficacy of apricoxib in HNSCC cells. CONCLUSION: In addition to reversing EMT via inhibition of COX-2, apricoxib upregulates 15-prostaglandin dehydrogenase and the prostaglandin transporter, thereby reducing the levels of active PGE2 by both suppressing its synthesis and increasing its catabolism. These findings have significant implications for metastasis and tumour progression in HNSCC.

Infectious complications and immunodeficiency in patients with human T-cell lymphotropic virus I-associated adult T-cell leukemia/lymphoma.

BACKGROUND: Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T-cells occurring in patients infected with the human T-cell lymphotropic virus-I. These patients frequently develop a variety of infections throughout their disease course. METHODS: Charts and autopsy reports were reviewed for 41 patients with ATL with follow-up varying from 2 to 120 months. Infectious episodes were identified and documented. Analyses of humoral and cell-mediated immunity were performed. Cell-mediated immunity was assessed in vivo with the Merieux multitest skin test panel. Humoral immunity was assessed by quantitative immunoglobulin levels, by determining human antimouse antibody after murine monoclonal antibody infusion and by an in vitro immunoglobulin biosynthesis coculture system. RESULTS: A total of 112 infectious episodes were documented. Fifty-seven serious infections were identified. The incidence of total infections was 1.40/patient-year and for serious infections was 0.71/patient-year. The mean serum IgG and IgA levels were within normal range, the mean IgM level was at the lower limit of normal. Peripheral blood mononuclear cells from all patients studied failed to make meaningful amounts of IgG, M, or A when activated. Peripheral blood mononuclear cells of all of the 13 patients studied suppressed production of immunoglobulin by cocultured normal PBMC. Twenty-three of the 27 patients tested were anergic. CONCLUSIONS: ATL is a profoundly immunosuppressing malignancy. This is manifested by an extremely high incidence of infectious episodes/patient-year. The incidence of infection appears to be greater than for mycosis fungoides, Hodgkin's lymphoma and non-Hodgkin's lymphoma.

B-chronic lymphocytic leukemia cells contain both endogenous kappa immunoglobulin mRNA and critical immunoglobulin gene activation transcription factors.

B-cell chronic lymphocytic leukemia (B-CLL) is a hematologic malignancy characterized by the proliferation and accumulation of mature-looking B lymphocytes. Patients with B-CLL exhibit a number of immune defects including: auto-antibodies, depressed cell-mediated immunity and hypogammaglobulinemia (HG). We investigated the control of Ig production in the malignant CLL B-cell at a transcriptional and translation level. We isolated fresh leukemic B-cells from CLL patients and analyzed for the presence of nuclear factors OCT-1, OCT-2, and NF-KB. Malignant B-cells were purified to greater than 90% B-cells, and total cellular RNA and nuclear proteins were isolated from these cells. Mobility shift assays were probed with 32P-labeled oligonucleotides specific to the immunoglobulin (Ig) enhancer and promotor regions. We detected endogenous OCT-1, OCT-2, and NF-KB in all patients tested (n = 5). We then evaluated whether activation of CLL B cells could augment kappa-mRNA levels. CLL cells (n = 3) exposed to phorbol ester and A23187 were harvested at 0, 2, 4, 8, and 48 min and examined for kappa-mRNA by Northern blot. All CLL patients (n = 3) had easily detectable levels of endogenous kappa-mRNA. However, only one patient had an obvious increase in kappa-mRNA post-induction with TPA/A23187. There was no concomitant increase in this patient's OCT-1, OCT-2, or NF-KB level. This finding prompted us to survey other B-CLL patients (n = 6) for Ig nuclear transcriptional factors pre- and post-induction. In summary, CLL B cells express Ig transcriptional factor OCT-1, OCT-2, and NF-KB constitutively. The endogenous level of NF-KB may account for the basal kappa-mRNA detected in B-CLL cells. However, the inability to augment NF-KB levels may, in part, explain the low levels of Ig synthesis in CLL B-cells.

Immunoregulatory cell dysfunction in chronic B-cell leukemias.

Chronic B-cell malignancies are routinely characterized as B-cell clonal diseases that have signs and symptoms primarily related to the continuing expansion of these cells. This review discusses chronic lymphocytic leukemia, multiple myeloma and hairy cell leukemia from the perspective of secondary abnormalities in non-malignant cells. Thus, our main purpose is to elaborate on the alterations/abnormalities of the immunoregulatory (IR) cells in these diseases and focus on the qualitative and quantitative aspects of T-cells, natural killer (NK) cells and monocytes. The relevance of the IR-cell changes to the basic disease process and their complications are emphasized.