Anti-adult T-cell leukemia/lymphoma effects of indole-3-carbinol

<p>Abstract</p> <p>Background</p> <p>Adult T-cell leukemia/lymphoma (ATLL) is a malignancy derived from T cells infected with human T-cell leukemia virus type 1 (HTLV-1), and it is known to be resistant to standard anticancer therapies. Indole-3-carbinol (I3C), a naturally occurring component of <it>Brassica </it>vegetables such as cabbage, broccoli and Brussels sprout, is a promising chemopreventive agent as it is reported to possess antimutagenic, antitumorigenic and antiestrogenic properties in experimental studies. The aim of this study was to determine the potential anti-ATLL effects of I3C both <it>in vitro </it>and <it>in vivo</it>.</p> <p>Results</p> <p>In the <it>in vitro </it>study, I3C inhibited cell viability of HTLV-1-infected T-cell lines and ATLL cells in a dose-dependent manner. Importantly, I3C did not exert any inhibitory effect on uninfected T-cell lines and normal peripheral blood mononuclear cells. I3C prevented the G₁/S transition by reducing the expression of cyclin D1, cyclin D2, Cdk4 and Cdk6, and induced apoptosis by reducing the expression of XIAP, survivin and Bcl-2, and by upregulating the expression of Bak. The induced apoptosis was associated with activation of caspase-3, -8 and -9, and poly(ADP-ribose) polymerase cleavage. I3C also suppressed IκBα phosphorylation and JunD expression, resulting in inactivation of NF-κB and AP-1. Inoculation of HTLV-1-infected T cells in mice with severe combined immunodeficiency resulted in tumor growth. The latter was inhibited by treatment with I3C (50 mg/kg/day orally), but not the vehicle control.</p> <p>Conclusion</p> <p>Our preclinical data suggest that I3C could be potentially a useful chemotherapeutic agent for patients with ATLL.</p

結晶化ガラス顆粒の臨床応用

This reports tha development of bioactive glass ceramic particles and evaluates their use inclinical applications. 1. The subjects of the evaluation were 13 impacted teeth, 17 intramaxillary cysts (not including radicular cysts), and 7 atrophic mandibular alveolar ridges. 2. The results were classified into effective, slightly effective, ineffective, and harmful, a very high proportion, 33 or 89.3%,were judged effective or slightly effective. 3. None were evaluated to be harmful, showing the safety of the present material. Among the ineffective cases there were open wounds due to infection, leakage of the supplied material, and fistulation. In cases where inflammation had not disappeared at the supply there were cases where the particles had to be completely removed due to infection, It was determined the that this was not due to the material, but possidly due to the surgical procedures, as there were no further complications in the tretment. 4. From the results reported here, the bioactive glass ceramic material here was found to be useful in the articial bone needed after atrophic mandibular alveolar ridge surgery

Inhibition of heat shock protein-90 modulates multiple functions required for survival of human T-cell leukemia virus type I-infected T-cell lines and adult T-cell leukemia cells

The molecular chaperone Hsp90 is involved in the stabilization and conformational maturation of many signaling proteins that are deregulated in cancers. The geldanamycin derivative 17-AAG is currently tested in clinical trials and known to inhibit the function of Hsp90 and promote the proteasomal degradation of its misfolded client proteins. ATL is a fatal malignancy of T lymphocytes caused by HTLV-I infection and remains incurable. Since Hsp90 is overexpressed in HTLV-I-infected T-cell lines and primary ATL cells, we analyzed the effects of 17-AAG on cell survival, apoptosis and expression of signal transduction proteins. HTLV-I-infected T-cell lines and primary ATL cells were significantly more sensitive to 17-AAG in cell survival assays than normal PBMCs. 17-AAG induced the inhibition of cell cycle and apoptosis. These effects could be mediated by inactivation of NF-B, AP-1 and PI3K/Akt pathways, as well as reduction of expression of proteins involved in the G1-S cell cycle transition and apoptosis. Proteasome inhibition interfered with 17-AAG-mediated signaling proteins depletion. Collectively, our results indicate that 17-AAG suppresses ATL cell survival through, at least in part, destabilization of several client proteins and suggest that 17-AAG is a potentially useful chemotherapeutic agent for ATL

Fetal Thoracoamniotic Shunting in a Case of Congenital Pulmonary Airway Malformations with Hydrops Fetalis

Aim We report a case of congenital pulmonary airway malformation (CPAM) with hydrops in which the fetus underwent thoracoamniotic shunting. Case Report A 40-year-old (G1P1) woman was diagnosed with a macrocystic CPAM. Thoracoamniotic shunting was performed at 19 weeks of gestation but not well drained and was successfully performed again at 23 weeks. However, the CPAM volume ratio, abdominal circumference, and amniotic fluid index started increasing from 28 weeks and hydrops worsened. The insufficient shunting and the fetal cardiac failure had to be considered. At 32 weeks, a male infant with general edema and massive ascites was born weighing 3,362 g (+4.79 SD) with Apgar scores of 2 and 4. The infant was intubated and high-frequency oscillation and nitric oxide therapies were instituted. The resection of CPAM was performed on day 2. Nasal continuous positive airway pressure was instituted on day 16. The infant was discharged and prescribed with home oxygen therapy (HOT) on day 65. The infant was able to leave the HOT at 30 months and is currently 34 months of age in good condition. Conclusion Fetal thoracoamniotic shunting may be life-saving in CPAM complicated by hydrops and that this treatment might be sufficient to cure the child

Anti-adult T-cell leukemia effects of a novel synthetic retinoid, Am80 (Tamibarotene)

Clinical trials for treatment of adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type I (HTLV-I) using all-trans-retinoic acid (ATRA) have shown satisfactory therapeutic responses, although efficacies were limited. Recently, many synthetic retinoids have been developed and among them, a novel synthetic retinoid, Am80 (Tamibarotene) is an RARα- and RARβ-specific retinoid expected to overcome ATRA resistance. The present study examined the inhibitory effects of Am80 on HTLV-I-infected T-cell lines and ATL cells. Am80 had negligible growth inhibition of peripheral blood mononuclear cells but marked growth inhibition of both HTLV-I-infected T-cell lines and ATL cells. Am80 arrested cells in the G1 phase of the cell cycle and induced apoptosis in HTLV-I-infected T-cell lines. It inhibited also the phosphorylation of IκBα and NF-κB-DNA binding, in conjunction with reduction of expression of proteins involved in the G1/S cell cycle transition and apoptosis. Am80 also inhibited the expression of JunD, resulting in suppression of AP-1-DNA binding. Furthermore, severe combined immunodeficient mice with tumors induced by subcutaneous inoculation of HTLV-I-infected T cells, responded to Am80 treatment with partial regression of tumors and no side-effects. These findings demonstrate that Am80 is a potential inhibitor of NF-κB and AP-1, and is a potentially useful therapeutic agent against ATL. (Cancer Sci 2008; 99: 2286–2294