|ognizant Communication Corporation|
Featuring PRECLINICAL AND CLINICAL CANCER THERAPEUTICS
VOLUME 17, NUMBER 7
Oncology Research, Vol. 17, pp. 283-299
0965-0407/08 $90.00 + .00
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Development of Pluronic Micelle-Encapsulated Doxorubicin and Formaldehyde-Releasing Prodrugs for Localized Anticancer Chemotherapy
Michal Ugarenko,1 Chee-Kai Chan,2 Abraham Nudelman,3 Ada Rephaeli,4 Suzanne M. Cutts,1 and Don R. Phillips1
1Department of Biochemistry, La Trobe University, Victoria,
2Department of Genetics, La Trobe University, Victoria, 3086, Australia
3Chemistry Department, Bar Ilan University, Ramat Gan, 52900, Israel
4Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Beilinson Campus, Petach Tikva, 49100, Israel
The chemotherapeutic agent doxorubicin forms drug-DNA adducts that are enhanced by formaldehydereleasing prodrugs such as AN-9. One of the major limitations of doxorubicin is dose-limiting cardiotoxicity; therefore, the use of a targeting strategy that enables drug delivery and release at tumor sites is of great interest. The major aim of this study was to use the Pluronic-ultrasound delivery system to encapsulate doxorubicin and formaldehyde-releasing prodrugs within Pluronic micelles, and then use ultrasound to trigger controlled drug release from micelles. Pluronic micelles themselves were not stable upon dilution and required the use of a stabilizing agent DSPE-PEG2000 to form stable "mixed micelles." Following the separation of free doxorubicin, approximately 60% of doxorubicin remained encapsulated within mixed micelles with a retention half-life of approximately 12 h. The formaldehyde-releasing prodrugs, however, were not retained within mixed micelles, but could potentially be administered separately to doxorubicinloaded micelles to achieve tumor-localized formation of doxorubicin-DNA adducts. The use of low-frequency, high-power ultrasound (20 kHz, 100 W/cm2) released 7-10% of doxorubicin from mixed micelles. Collectively, these results indicate that the Pluronic-ultrasound system could be used to deliver and release doxorubicin with the potential of forming cytotoxic DNA adducts at tumor sites with coadministrated formaldehyde-releasing prodrugs.
Key words: Doxorubicin; Pluronics; Formaldehyde; AN-9; Ultrasound
Address correspondence to Don R. Phillips, Department of Biochemistry, La Trobe University, Victoria 3086, Australia. Tel: 61-3-94792182; Fax: 61-3-94792467; E-mail: email@example.com
Suppression of Prometastatic Phenotype of Highly Metastatic Androgen-Independent Rat Prostate Cancer MLL Cell Line by PI3K Inhibitor LY294002
Chaiwat Prawettongsopon, Sariya Asawakarn,* and Tuangporn Suthiphongchai
Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
Upregulation of the PI3K pathway has often been reported in androgen-independent prostate cancer and is implicated in cancer cell survival and proliferation in the absence of androgen. Inhibition of PI3K by LY294002 suppressed cell invasion and motility of the highly metastatic androgen-independent Dunning rat prostate cancer MLL cell line with similar IC50 values and inhibition profile. Moreover, LY294002 attenuated expression of urokinase plasminogen activator (uPA) without any significant effect on that of matrix metalloproteinase 2. These results indicated that the role of PI3K in MLL cell invasion is by regulating cell motility and uPA expression.
Key words: Androgen independent; Invasion; Metastasis; PI3K; Prostate cancer
Address correspondence to Tuangporn Suthiphongchai, Department of Biochemistry, Faculty of Science, Mahidol University, 272 Rama 6 Road, Bangkok 10400, Thailand. Tel: 662-201-5600; Fax: 662-354-7174; E-mail: firstname.lastname@example.org
*Present address: Department of Physiology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand.
Effects of Cardiotoxin III on NF-kB Function, Proliferation, and Apoptosis in Human Breast MCF-7 Cancer Cells
Chien-Chih Chiu,1,5 Kuei-Li Lin,2 Ching-Ming Chien,2 Long-Sen Chang,3,4 and Shinne-Ren Lin2,4
1Department of Biotechnology, Kaohsiung Medical University,
Kaohsiung 807, Taiwan, ROC
2Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC
3Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, ROC
4National Sun Yat-Sen University-Kaohsiung Medical University Joint Research Center, Kaohsiung, Taiwan, ROC
5Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC
Cardiotoxin III (CTX III), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has been reported to have anticancer activity. CTX III-induced apoptosis in human breast MCF-7 cancer cells was confirmed by sub-G1 formation, phosphatidylserine (PS) externalization, and poly (ADPribose) polymerase (PARP) cleavage with an IC50 of 2 mg/ml at 48 h. Effects of CTX III on proliferation and apoptosis correlated with upregulation of Bax, and downregulation of Bcl-XL, Bcl-2, and XIAP, with no appreciable alteration on the protein levels of Bid, Bim, and survivin. CTX III treatment also caused release of mitochondrial cytochrome c to the cytosol, which led to subsequent activation of capase-9. Moreover, CTX III inhibited the nuclear factor-kB (NF-kB) activation through inhibition of IkB kinase (IkK) activity. Overall, our results indicate that CTX III downregulates NF-kB in MCF-7 cells, leading to the suppression of proliferation and induction of apoptosis. These findings suggest the molecular basis for CTX III-induced apoptotic death of MCF-7 cells.
Key words: Cardiotoxin III; MCF-7 cells; NF-kB; Apoptosis
Address correspondence to Dr. Shinne-Ren Lin, Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan 807, ROC. Fax: 886-7-3123443; E-mail: email@example.com
Genetic Polymorphism in UDP-Glucuronosyltransferase 2B7 and Colorectal Cancer Risk
E. M. J. van der Logt,1 R. H. M. te Morsche,1 N. Groenendaal,1 H. M. J. Roelofs,1 M. de Metz,2 J. W. van der Stappen,2 F. M. Nagengast,1 and W. H. M. Peters1
1Department of Gastroenterology, Radboud University Nijmegen
Medical Center, Nijmegen, Netherlands
2Department of Clinical Chemistry, Canisius Wilhelmina Hospital, Nijmegen, Netherlands
Colorectal cancer (CRC) is one of the most common malignancies in the Western world. CRC is strongly associated with lifestyle factors. Susceptibility to CRC may be partly due to deficient detoxification capacity in the gastrointestinal tract. Genetic polymorphisms in detoxification enzymes result in variations in detoxification activities, which might influence the levels of carcinogens in the gastrointestinal tract, influencing the risk for CRC. To determine whether a genetic polymorphism in the detoxification enzyme UDP-glucuronosyltransferase 2B7 (UGT2B7) predisposes to CRC, 411 Caucasian patients with sporadic CRC and 600 Caucasian controls recruited from the same geographic area were genotyped for the functional UGT2B7 H268Y polymorphism. DNA was isolated and tested by a dual-color real-time polymerase chain reaction assay. Overall, no differences in genotype distributions between patients with CRC and controls were observed. When analyzed with respect to tumor location, a shift from the UGT2B7*1*2 into the UGT2B7*2*2 genotype was seen in patients with proximal CRC (OR 1.80, 95% CI 1.11-2.89). In the male patient subpopulation an even stronger association was observed (*1*1 + *1*2 vs. *2*2: OR 2.17, 95% CI 1.11-4.04; *1*2 vs. *2*2: OR 2.19, 95% CI 1.10-4.37). No associations with respect to tumor stage were seen. In conclusion, the frequency of the UGT2B7*2*2 genotype is higher in CRC patients with proximal location of the tumor, especially in males, which suggests that this genotype is associated with an increased risk for proximal CRC.
Key words: Colorectal cancer; Genetic polymorphism; UDP-glucuronosyltransferase 2B7
Address correspondence to Dr. W. H. M. Peters, Department of Gastroenterology, Radboud University Nijmegen Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: +31-24-3616316; E-mail: firstname.lastname@example.org
Relationship Between FDG Uptake and Expressions of Glucose Transporter Type 1, Type 3, and Hexokinase-II in Reed-Sternberg Cells of Hodgkin Lymphoma
Hye Kyung Shim,1 Won Woo Lee,1,3 So Yeon Park,1 Haeryoung Kim,2 and Sang Eun Kim1,3
1Department of Nuclear Medicine, Seoul National University
Bundang Hospital, Seoul National University College of Medicine, Seoul,
2Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea
3Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Korea
Reed-Sternberg (R-S) cells are the main tumor cells of Hodgkin lymphoma (HL). HL has been reported to demonstrate a high level of [18F]2-fluoro-2-deoxy-D-glucose (FDG) uptake, but the determinant of FDG uptake for HL has not been well elucidated. Thus, we investigated the relationship of FDG uptake and the expressions of glucose transporter type 1 (Glut-1), glucose transporter type 3 (Glut-3), and hexokinase II (HK-II) in R-S cells of HL. There were 25 tissue-proven HL patients from January 2003 to July 2007 in our hospital. Of the 25 HL patients, 4 cases obtained by surgical excision were included in the present study. The immunostaining for Glut-1, Glut-3, and HK-II was conducted in the excised masses. The maximum standardized uptake values (maxSUVs) were compared to the expressions of Glut-1, Glut-3, and HK-II. Three HL patients (mixed cellularity = 2 and nodular sclerosis = 1) demonstrated moderate-strong expressions of Glut-1 in almost all R-S cells, and of these three HL patients, two underwent FDG-PET, which revealed a high level of maxSUVs (7.7, 6.5) in the corresponding HL lesions. One HL patient (lymphocyte depletion) showed weak Glut-1 expressions in only 10% of R-S cells, but no FDG-PET study was available. The expressions of Glut-3 and HK-II were various in all four HL patients, and no specific correlations with FDG uptake were found. In conclusion, high expressions of Glut-1 in R-S cells may play a crucial role for the high FDG uptake in Hodgkin lymphoma.
Key words: Hodgkin lymphoma; FDG-PET; Glucose transporter; Hexokinase
Address correspondence to Won Woo Lee, M.D., Associate Professor,
Department of Nuclear Medicine, Seoul National University Bundang Hospital,
166 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-707, Korea. Tel:
82-31-787-7672; Fax: 82-31-787-4018; E-mail: email@example.com