Antiproliferative Activities of Cynaropicrin and Related Compounds against Cancer Stem Cells.

Glioblastoma (GBM) has a high mortality rate despite the availability of various cancer treatment options. Although cancer stem cells (CSCs) have been associated with poor prognosis and metastasis, and play an important role in the resistance to existing anticancer drugs and radiation; no CSC-targeting drugs are currently approved in clinical practice. Therefore, the development of antiproliferative agents against CSCs is urgently required. In this study, we evaluated the antiproliferative activities of 21 sesquiterpenoids against human GBM U-251 MG CSCs and U-251 MG non-CSCs. Particularly, the guaianolide sesquiterpene lactone cynaropicrin (1) showed strong antiproliferative activity against U-251 MG CSCs (IC50 = 20.4 µM) and U-251 MG non-CSCs (IC50 = 10.9 µM). Accordingly, we synthesized six derivatives of 1 and investigated their structure-activity relationships. Most of the guaianolide sesquiterpene lactones with the α-methylene-γ-butyrolactone moiety showed antiproliferative activities against U-251 MG cells. We conclude that the 5,7,5-ring and the α-methylene-γ-butyrolactone moiety are both important for antiproliferative activities against U-251 MG cells. The results of this study suggest that the α,ß-unsaturated carbonyl moiety, which has recently become a research hotspot in drug discovery, is the active center of 1. Therefore, we consider 1 as a potential lead for developing novel drugs targeting CSCs.

[Review of pulmonary Mycobacterium xenopi infection cases: 11 cases of our own and 18 other cases reported in Japan].

OBJECTIVE: To investigate clinical features of patients with pulmonary Mycobacterium xenopi infection treated at our hospital. SUBJECTS AND METHODS: We diagnosed 11 cases of M. xenopi infection at Tokyo National Hospital between 2000 and 2008 and recorded the drug susceptibility, patient characteristics, radiographic findings, treatments given and clinical courses. Eighteen other Japanese cases from the literature were discussed along with our findings. RESULTS AND METHODS: The cases of M. xenopi infection at our hospital consisted of 10 men and 1 woman with a mean age (+/- SD) of 55.1 +/- 19.4 years. Among the patients, 10 were smokers, 4 were heavy drinkers, and 6 had sequelae of pulmonary tuberculosis as an underlying disorder. Four patients had chronic obstructive pulmonary disease and 2 had diabetes mellitus, while there were 2 patients who had no underlying disease. All cases had radiographic opacities, predominantly found in the upper lung region, and cavernous lesions. These findings were demonstrated in both lungs in 5 patients, in the right lung only in 5 patients and in the left lung only in 1 patient. Concurrent aspergillosis was observed in 8 patients. The bacterial isolates from 7 cases were tested for drug sensitivity to levofloxacin (LVFX) and were found to be susceptible. M. xenopi disease was treated in 5 cases with INH+RFP+EB, in 2 cases with INH+RFP+Clarithromycin (CAM), and in 1 case with RFP+EB+CAM. Concurrent aspergillosis was treated with itraconazole in 2 cases. One patient underwent surgery for lung cancer. The duration of treatment was 16.4 +/- 12.8 months (range, 4-36 months). The radiographic findings were improved in 4 cases, deteriorated in 2 and unchanged in 5. M. xenopi was eradicated bacteriologically in 6 cases. The combination of radiographic and bacteriological findings indicated improvement in 3 cases, no change in 6 and deterioration in 2. DISCUSSION: The review of our cases disclosed that medical treatment alone was not sufficient in most cases for the control of clinical M. xenopi infection as reported overseas. Although we did not use LVFX for treatment, LVFX might be recommended for the treatment since all isolates tested proved to be susceptible to LVFX.

[A case of tuberculosis with multiple lung nodules, abdominal lymphadenopathy, and splenomegaly].

Abdominal tuberculous lymphadenitis is very rare. We report a case of pulmonary tuberculosis showing marked abdominal lymphadenopathy and splenomegaly. A 95-year-old man was admitted to our hospital because of abnormal chest X-ray and body weight loss in last 6 months. He had low grade fever with no abdominal pain. He did not have past history of tuberculosis. Laboratory examination showed mild renal dysfunction and mild glucose intolerance. Soluble interleukin 2 recepter was highly elevated (3800 U/ml). Tumor markers, such as carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA), and progastrin-releasing peptide (Pro GRP) were all within normal limit. Chest X-ray showed multiple nodules in bilateral lung fields. Chest computed tomography showed multiple nodules in bilateral lungs, especially in upper part of lungs, right hilar lymphadenopathy and upper mediastinal lymphadenopathy. Abdominal and pelvic enhanced computed tomography showed marked abdominal lymphadenopathy and splenomegaly (67 x 49 mm). Abdominal lymph nodes were hepatoduodenal (50 x 50 mm), splenic hilar (40 x 25 mm), upper paraaortic (30 x 60 mm), and small superior mesenteric (10 x 10 mm) lymph nodes. FDG-PET showed accumulation in the nodules of right lung field, right hilar lymph nodes, upper mediastinal lymph nodes, and abdominal lymph nodes. Bronchial lavage fluid (BAL) smear for acid-fast bacilli was positive, polymerase chain reaction for Mycobacterium tuberculosis was positive and acid-fast bacilli was cultured. Transbronchial lung biopsy specimen demonstrated non-specific intraalveolar organization and alveolitis. The patient was diagnosed as pulmonary tuberculosis, but about abdominal lymphadenopathy and splenomegaly we had to differentiate malignant lymphoma, and for definite diagnosis, laparotomy was necessary. But considering his age and general condition, we followed up carefully with anti-tuberculosis therapy. Pulmonary tuberculosis, abdominal lymphadenopathy and splenomegaly all showed marked improvement 4 months after starting anti-tuberculosis therapy with isoniazid, rifampicin, and ethambutol, so we clinically diagnosed abdominal tuberculous lymphadenitis and splenic tuberculosis.