|ognizant Communication Corporation|
AN INTERNATIONAL JOURNAL
INCORPORATING ANTI-CANCER DRUG DESIGN
VOLUME 15, NUMBER 9
Oncology Research, Vol. 15, pp. 409-421
0965-0407/06 $20.00 + .00
Copyright © 2006 Cognizant Comm. Corp.
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Christian Scifo,1 Angela Milasi,2 Andrea Guarnera,1 Fulvia Sinatra,2 and Marcella Renis1
1Dipartimento di Chimica Biologica,
Chimica Medica e Biologia Molecolare, V.le A. Doria 6, Università
di Catania, 95100 Catania, Italy
2Dipartimento di Scienze Biomediche, sez. Biologia Generale, Cellulare e Genetica Molecolare, Comparto 10, Via S. Sofia 87, Università di Catania, 95100 Catania, Italy
In the Western world cancer is the second leading cause of mortality, and prostate carcinoma represents in men the second most important type of cancer-causing death. We have already shown that resveratrol (200 mM) triggers in DU145, an androgen-resistant prostate cancer cell line, a necrotic-like cell death, while propolis ethanolic extract (100 mg/ml) causes an apoptotic-like cell demise. The present research is aimed to better elucidate the molecular mechanisms activated by the two micronutrients. Vinorelbine bitartrate, a drug widely used in prostate cancer therapy, was utilized as a reference drug, because it is known to induce apoptosis. The combined treatments between the micronutrients and vinorelbine have been studied to test a possible vinorelbine dose reduction, avoiding its side effects without altering its cytotoxic action. In this investigation SEM and TEM analyses were performed to examine the morphological modifications induced; our observations confirmed necrotic cell features after treatment with resveratrol, and apoptotic modifications after propolis. We also measured cell cycle progression to study a correlation with p21 and p53, two well-known cell cycle checkpoints. The levels of HSP27 and HSP70, two chaperones also exerting antioxidant/antiapoptotic functions, were been also analyzed. Our data indicate that the two micronutrients modulate cell cycle distribution, increasing p53 levels, without the induced HSPs being able to rescue DU145 from death. The results presented suggest chemotherapy based on resveratrol and propolis, alone or in combination with vinorelbine, as a potential useful tool for prostate cancer therapy; the increase in cell cycle control and the modulation of HSPs expression reinforce this suggestion.
Key words: Human prostate cancer; DU145; Resveratrol; Propolis; Transmission electron microscopy; Immunoblotting; Cell cycle
Address correspondence to Dr. Marcella Renis, Associate Professor, Department of Biological Chemistry, Medicinal Chemistry and Molecular Biology, University of Catania, Viale Andrea Doria, 6, 95125 Catania, Italy. Tel: (39) 095 7384081; Fax: (39) 095 7384220; E-mail: firstname.lastname@example.org
Adenylate Cyclase Toxin From Bordetella pertussis Enhances Cisplatin-Induced Apoptosis to Lung Cancer Cells In Vitro
David Johansson,1 Per Bergström,2 Roger Henriksson,2 Kjell Grankvist,1 Anders Johansson,3 and Parviz Behnam-Motlagh1,2
1Department of Medical Biosciences,
Clinical Chemistry, Umeå University, S-901 85 Umeå, Sweden
2Department of Radiation Sciences, Oncology, Umeå University, S-901 85 Umeå, Sweden
3Department of Odontology, Periodontology, Umeå University, S-901 85 Umeå, Sweden
The present study examined the possibility to enhance lung cancer cell cytotoxicity and apoptosis of the anticancer drug cisplatin by exposure with adenylate cyclase (AC) toxin from Bordetella pertussis. A malignant mesothelioma cell line (P31) and a small-cell lung cancer cell line (U1690) were exposed to increasing concentrations of cisplatin and AC toxin, alone or in combination. Cytotoxicity was determined by a fluorescein-based assay and apoptosis by flow cytometry quantification of annexin V binding. Caspase-3, -8, and -9 activities were measured by enzyme activity assays. The cytotoxicity of AC toxin was time and dose dependent with an LD50 value at 72 h of 3 and 7 mg/L for P31 cells and U1690 cells, respectively. Cisplatin showed a similar time- and dose-dependent cytotoxicity, which was increased in the presence of a low toxic concentration (1 mg/L) of AC toxin. Furthermore, cisplatin caused a dose-dependent increase of annexin V binding cells of both cell lines after 24-h incubation, which was also enhanced in combination with AC toxin. AC toxin (1 mg/L) increased cisplatin-induced caspase-3, -8, and -9 activities in U1690 cells. Only minor increases of caspase-8 and -9 were noted for P31 cells. The present results, together with the knowledge that bacterial toxins decrease side effects of traditional cancer treatment, suggest a possibility to use them to enhance the therapeutic effect of cancer chemotherapy with reduced clinical adverse effects.
Key words: Adenylate cyclase toxin; Apoptosis; Cisplatin; Cytotoxicity; Mesothelioma; Small-cell lung cancer
Address correspondence to Parviz Behnam-Motlagh, Department of Medical Biosciences, Clinical Chemistry, Building 6 M, 2nd Floor, S-901 85 Umeå, Sweden. Tel: +46 90 785 29 81; Fax: +46 90 785 28 29; E-mail: email@example.com
Does Survival Increase in Metastatic Breast Cancer With Recently Available Anticancer Drugs?
C. Abrial,1,2 M. Leheurteur,1 A. Cabrespine,1,2 M. A. Mouret-Reynier,1 X. Durando,1,2 J. P. Ferriere,1 F. Kwiatkowski,1 F. Penault-Llorca,1 H. Cure,1,2 and P. Chollet1,2
1Centre Jean Perrin, 58 rue Montalembert,
63011 Clermont Ferrand Cedex1, France
2INSERM U484, rue Montalembert, 63005 Clermont Ferrand Cedex, France
Metastatic breast cancer (MBC) is incurable in
most cases. While multiple treatments are available, the median survival
is still approximately 2 years.
We planned to assess the apparent impact of taxanes and aromatase inhibitors (letrozole, anastrozole, and exemestane) on the survival of 857 MBC patients for more than 30 years. Patients classed into decades by metastatic disease onset date did not survive significantly longer in recent years. This does not exclude some marked improvements with time: 1) in the same period, the disease-free interval for M0 patients increased progressively and significantly with time; 2) the overall relapse ratio in M0 patients was 20% lower in the 1990-2000 decade compared with 1980-1990; 3) since 1995, treatment for metastasis has been significantly lighter with periods of chemotherapy separated by hormonotherapy or observation in the case of negative receptors. Analyzing individual therapies, availability of taxanes since 1994 did not result in a significant increase of the overall survival. Conversely, receiving hormonotherapy was an important prognostic factor of the overall survival. Three groups were classified according to hormone therapy: group 1 - tamoxifen, group 2 - aromatase inhibitors, group 3 - a combination of tamoxifen then aromatase inhibitors. The combination of tamoxifen then aromatase inhibitors favored a survival improvement from metastasis appearance to death compared with aromatase inhibitors alone and with tamoxifen alone. The sequential treatment of tamoxifen then aromatase inhibitors is presently discussed as a possible standard when used as adjuvant treatment. This sequential effect could also constitute a valuable concept for metastatic patients.
Key words: Breast cancer; Overall survival; Tamoxifen; Anastrozole; Letrozole; Exemestane
Address correspondence to Catherine Abrial, Centre Jean Perrin, Bureau de Recherche Clinique, 58, rue Montalembert, BP 392, 63011 Clermont-Ferrand Cedex 1, France. Tel: 33-4-73-27-80-05; Fax: 33-4-73-27-80-29; E-mail: Recherche.CLINIQUE@cjp.fr
Immunohistochemical Detection of Apoptotic Markers in Gastric Cancer
Laura Smith,1 Helen K. Berrieman,1 Sara L. O'Kane,1 Anne Campbell,2 Anthony Maraveyas,1 and Lynn Cawkwell1
1The Cancer Biology Proteomics Group,
Postgraduate Medical Institute of the University of Hull in association
with the Hull-York Medical School, University of Hull, Hull, UK
2Histopathology, Hull Royal Infirmary, Hull, UK
Apoptosis proteins may play a role in prognosis and therapy response; however, they have not been fully investigated in gastric cancer. We aimed to assess the expression of proteins in the Bcl-2 family. Immunohistochemistry was employed to examine the expression of the antiapoptotic proteins Bcl-2 and Bcl-XL and the proapoptotic proteins Bad, Bak, Bax, Bid, Bim, and p53 in 21 cases of gastric cancer. Immunopositivity was observed in 12/21 (57%) cases for p53, 16/21 (76%) cases for Bcl-XL, and 5/21 (23%) cases for Bcl-2. For the proapoptotic members of the Bcl family, loss of protein expression was observed: Bid (14/21 cases; 66%), Bad (13/21 cases; 61%), Bax (12/21 cases; 57%), Bak (9/21 cases; 42%), and Bim (4/21 cases; 19%). This study identified apoptosis proteins that exhibit heterogeneous expression between primary gastric carcinomas.
Key words: Apoptosis; Immunohistochemistry; Gastric cancer; Stomach
Address correspondence to Dr. Lynn Cawkwell, Ph.D., R&D Building, Castle Hill Hospital, Hull, HU16 5JQ, UK. Tel: (+44) 1482 875875, ext. 3617; Fax: (+44) 1482 622398; E-mail: L.Cawkwell@hull.ac.uk
VEGF Expression in the Colorectal Adenoma-Carcinoma Sequence
Loukas Kaklamanis,1 Miltiades Trichas,2 Kyriakos Amarantidis,3 Niko Spathari,1,4 Anastasia Micheli,4 Anastasios Karayiannakis,5 Ekaterini Chatzaki,6 Vasilis Georgoulias,7 and Stelios Kakolyris3
1Department of Pathology, Onassis Center
for Cardiovascular Diseases, Athens, Greece
2Department of Radiation Oncology, 401 General Army Hospital, Athens, Greece
3Department of Clinical Oncology, University General Hospital of Alexandroupolis, Greece
4Department of Internal Medicine, University General Hospital of Alexandroupolis, Greece
5Department of Surgery, University General Hospital of Alexandroupolis, Greece
6Pharmacology, University General Hospital of Alexandroupolis, Greece
7Department of Clinical Oncology, University General Hospital of Heraklion, Crete, Greece
Angiogenesis is essential for tumor growth and metastasis. It is controlled by multiple factors, one of the most important being vascular endothelial growth factor (VEGF). VEGF and p53 expression were evaluated in 16 hyperplastic polyps, 35 solitary tubular and tubulovillous adenomas, and 47 cases of sporadic colorectal carcinomas arising on the basis of preexisting adenomas, using immunohistochemistry. In parallel, angiogenesis was assessed by the Chalkley score (CS) method. VEGF positivity was detected in 19/47 carcinoma cases (40%). In the respective adenomatous part of the tumor, VEGF positivity was detected in 11/47 cases (23%). Carcinomas arising from VEGF-positive adenomas were mostly VEGF positive (10/11, 91%), whereas in 28/36 (78%) carcinomas arising from VEGF-negative adenomas VEGF expression was not detected. CS was higher in VEGF-positive compared with VEGF-negative carcinomas (9.1 ± 1.8 and 7.8 ± 2.3, respectively, p < 0.05), whereas there was no statistically significant difference between the CS in the VEGF-negative and VEGF-positive adenomatous part of the tumor (3.3 ± 1.8 and 4.3 ± 2.3, respectively). Nuclear p53 positivity was detected in 26/47 (55%) cases in the cancerous part and in 14/47 (29%) cases in the adenomatous part of the tissue, and no significant correlation with VEGF expression was observed. We conclude that VEGF associates with angiogenesis in colorectal cancer, and its pattern of expression in adenomas is maintained in the arising carcinomas. Further investigation is warranted to clarify whether these findings could be used as indicators of prognosis in screening programs or in patients with limited stage disease where the usefulness of adjuvant therapies with either cytotoxic drugs or inhibitors of angiogenesis is still unclear.
Key words: Vascular endothelial growth factor (VEGF); Immunohistochemistry; Colorectal cancer
Address correspondence to Associate Professor
Stylianos Kakolyris, University General Hospital of Alexandroupolis, Department
of Clinical Oncology, Dragana 68100, Alexandroupolis, Greece. Tel: +30-25510-74053;
Fax: +30-25510-74093; E-mail: firstname.lastname@example.org