|ognizant Communication Corporation|
Featuring PRECLINICAL AND CLINICAL CANCER THERAPEUTICS
VOLUME 18, NUMBER 10
Oncology Research, Vol. 18, pp. 461-468
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Anticancer Effect of a Novel 2-Arylidene-4,7-dimethyl indan-1-one Against Human Breast Adenocarcinoma Cell Line by G2/M Cell Cycle Arrest
R. Prasanna1 and C. C. Harish2
1Department of Chemistry, Presidency College, Chepauk, Chennai,
2Department of Virology, King Institute of Preventive Medicine, Guindy, Chennai, India
A novel compound 2-arylidene-4,7-dimethyl indan-1-one synthesized was screened for anticancer effect against the human breast adenocarcinoma cell line, MCF-7. An IC50 value of >=80 mM, nontoxic to the normal breast cell line HBL-100, showed complete inhibition of the MCF-7 cells. Analysis of mechanisms showed nuclear fragmentation and DNA laddering in gel electrophoresis. GSH and GR levels were found to be reduced after the compound treatment. Cell cycle analysis using fluorescent cytometry revealed G2/M phase arrest, which indicates the compound deserves consideration for further studies against cancer.
Key words: Anticancer activity of synthones; Synthetic anticancer drugs; Dimethyl indan-1-one; Breast cancer
Address correspondence to Dr. R. Prasanna, No 10, Ramadas St., New Perungalathur, Chennai-600063, India. Tel: 919701447730; E-mail: firstname.lastname@example.org
The Inhibitor of Growth 1 (ING1) Is Involved in Trichostatin A-Induced Apoptosis and Caspase 3 Signaling in p53-Deficient Glioblastoma Cells
Mona Tamannai,1 Sonja Farhangi,2 Matthias Truss,3 Brigitte Sinn,4 Reinhard Wurm,4 Pinaki Bose,5 Guenter Henze,1 Karl Riabowol,5 Andreas von Deimling,6 and Gesche Tallen1
1Department of Pediatric Oncology/Haematology, Charité,
Universitätsmedizin-Berlin, Berlin, Germany
2Department of Neuropathology, Charité, Universitätsmedizin-Berlin, Berlin, Germany
3Department of Pediatrics, Laboratory for Molecular Biology, Charité, Universitätsmedizin-Berlin, Berlin, Germany
4Department of Radiotherapy, Charité, Universitätsmedizin-Berlin, Berlin, Germany
5Departments of Biochemistry & Molecular Biology and Oncology, Faculty of Medicine, The University of Calgary, Calgary, Canada
6Interdisciplinary Center for Neurosciences, Department of Neuropathology, Institute for Pathology, University of Heidelberg, Heidelberg, Germany
Prognosis for patients with glioblastoma multiforme (GBM) is poor. Inhibitors of histone deacetylases (HDACi) like trichostatin A (TSA) are promising alternatives to conventional treatment. Deficient tumor suppressor functions, such as TP53 mutations and p14ARF/p16INK4a deletions, are characteristic for GBM and can cause resistance to DNA damaging agents such as cisplatin and to HDACi like TSA. The type II tumor suppressor Inhibitor of growth 1 (ING1) is involved in DNA damage response and histone modification. We have previously shown that ING1 is downregulated in GBM and involved in glioma-induced angiogenesis and in cisplatin-induced apoptosis in malignant glioma cells. Hence, the goal of our present study was to investigate whether TSA affects ING1 protein expression and also whether modulating ING1 levels affects TSA-induced apoptosis in malignant glioma cells that contain deficient p53 function and inactive p14ARF/p16INK4a signaling. If so, we asked, which apoptotic pathway might be the major mediator beyond this interaction. To test whether ING1 proteins function in TSA-induced apoptosis in GBM, we analyzed TSA effects in LN229 GBM cells, which harbor TP53 mutations and INK4a deletion, following ING1 knockdown by siRNA. Expression of ING1, acetylated core histones H3 and H4, and the proapoptotic proteins caspase 3 and Fas-associated death domain (FADD) was determined by Western blotting. Percentages of apoptotic cells were obtained by flow cytometry. TSA induced the major ING1 isoform p33ING1b and increased levels of both histone acetylation and apoptosis in LN229 cells. ING1 knockdown cells revealed marked resistance to TSA-induced apoptosis, impairment of caspase 3 activation, and suppression of FADD. The data suggest that ING1 contributes to TSA-induced apoptosis in GBM cells with deficient p53 and p14ARF/p16INK4 functions, possibly by regulating FADD/caspase 3 signaling.
Key words: Inhibitor of growth 1 (ING1); Glioblastoma multiforme (GBM); Apoptosis; Trichostatin A
Address correspondence to Dr. Gesche Tallen, Department of Pediatric Oncology/Haematology, Charité, Universitätsmedizin-Berlin, Campus Virchow, 13353 Berlin, Germany. Tel: 49-30-450-566032; Fax: 49-30-450-566906; E-mail: email@example.com
Intrinsic Mitochondrial Membrane Potential Change and Associated Events Mediate Apoptosis in Chemopreventive Effect of Diclofenac in Colon Cancer
Jasmeet Kaur and S. N. Sanyal
Department of Biophysics, Panjab University, Chandigarh, India
The present study explored the role of intrinsic mitochondrial membrane potential (DYM) in NSAID-induced apoptosis in the early stages of colon cancer. 1,2-Dimethylhydrazine dihydrochloride (DMH) was used to induce colon cancer and its chemoprevention was studied by diclofenac in a rat model. After 6 weeks of treatment with DMH (early stage), morphological analysis revealed a marked occurrence of preneoplastic features [i.e., mucosal plaque lesions (MPLs) in the colonic tissue]. Coadministration of diclofenac with DMH resulted in a significant reduction of these lesions, thereby proving the chemopreventive efficacy of diclofenac at the chosen anti-inflammatory dose. DMH treatment also led to a significant increase in DYM in the isolated colonocytes as assessed by JC-1 fluorescent staining, measured both by fluorescence microscopy and spectrofluorometerically. Further, there was seen a reduction in the number of cells showing low DYM and hence monomer intensity of JC-1 by DMH treatment. To study the mechanism of these alterations in DYM in the present work, we studied the protein expression of important proapoptotic proteins, cytochrome c and Bax, by Western blot analysis and immunohistochemistry. DMH treatment reduced the mitochondrial translocation of Bax whereas cytochrome c was found to be located prominently in the mitochondria. Protein expression of antiapoptotic Bcl-2 was also studied in the colonic mucosa, which was expectedly found to be overexpressed after DMH treatment. Diclofenac treatment ameliorated the elevated DYM and its associated events to exert its chemopreventive action against early stages of colon cancer.
Key words: Diclofenac; Mitochondrial membrane potential (DYM); Bax; Cytochrome c; Bcl-2; Apoptosis
Address correspondence to Dr. S. N. Sanyal, Professor, Department of Biophysics, Panjab University, Chandigarh-160 014, India. Tel: +911722534122; E-mail: firstname.lastname@example.org
Zoledronate Stimulates gdT Cells in Prostate Cancer Patients
Michio Naoe,1 Yoshio Ogawa,1 Kumiko Takeshita,1 Jun Morita,1 Takeshi Shichijo,1 Khozo Fuji,1 Takashi Fukagai,1 Sanju Iwamoto,2 and Shuji Terao3
1Division of Urology, Showa University, Tokyo, Japan
2Division of Biochemistry, Showa University, Tokyo, Japan
33Laboratory of Cell and Gene Therapy, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Hyogo, Japan
Androgen deprivation therapy is the mainstay of treatment for prostate cancer. Given its frequent failure, new therapy that reduces prostate cancer progression would be a breakthrough in treating this disease. Bisphosphonates are well-established agents for treating skeletal-related events (SREs) in prostate cancer patients with bone metastases. Exposure to bisphosphonates may not only reduce the incidence of SREs, but also have anticancer effects by modulating a patient's immunity. The purpose of this study was to examine the effect of zoledronate (ZOL) on gd T cells, serum prostate-specific antigen (PSA) levels, and velocities. The effect of ZOL, with and without IL-2, on gd T cell activation was examined in vitro. Furthermore, the activated state and the number of gd T cells and changes in serum PSA levels were examined for patients who received ZOL infusion for the prevention of SREs. We found that ZOL activated gd T cells, and the number of gd T cell was increased when IL-2 was administered with ZOL in vitro. Comparisons before and after the first ZOL infusion revealed that gd T cells in peripheral blood were activated by ZOL. Moreover, after the first ZOL treatment, reduction in serum PSA was observed in 3 of 11 patients, and reduction in PSA velocity was observed in 5 of 10 patients. Our findings indicate that ZOL stimulates gd T cells in vivo and in vitro. This study provides further insight into the ability of gd T cells to induce an antitumor immune response.
Key words: Prostate cancer; Zoledronate; gd T cells
Address correspondence to Michio Naoe, Department of Urology, Showa University, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo, Japan. Tel: +81-3-3784-8560; Fax: +81-3-3784-1400; E-mail: email@example.com
Accelerated Partial Breast Irradiation: Use of Four-Dimensional CT for Target Localization and Assessment of Intrafractional Motion
Zhi-Wei Liao, Xun-Xing Guan, Feng-Yan Li, Zhen-Yu He, Ming Xue, Xiao-Yan Huang, and Li-xin Chen
Department of Radiation Oncology, Cancer Center, State key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou, P.R. China
The aim of this study was to use four-dimensional CT (4DCT) in the planning of 3D conformational external beam radiation therapy (3DCRT) for patients with early stage breast cancer. A total of nine Chinese women who received breast conservation treatment were included in this study. Target localization and movement (range of motion) during normal respiration were assessed using ultrasound and 4DCT. Plans based on 3DCT and 4DCT scans were developed in accordance to RTOG0319 guidelines and dose delivery comparisons were made between these plans. The mean ranges of motion of the excision cavity volume as determined using 4DCT were 1.03 ± 0.51, 2.08 ± 0.92, and 1.27 ± 0.58 mm in the right-left, anterior-posterior, and superior-interior directions, respectively. There were no significant differences between the mean and maximum PTV-E doses or the volume receiving 95% of the prescribed dose (V95). 4D plan prescribed dose levels were significantly lower (p < 0.05) than 3D plan levels for all of the following: ipsilateral breast V100, ipsilateral lung V30, and contralateral lung V5. Maximum contralateral breast and thyroid doses were also significantly lower with the 4D plan (p < 0.05). This study highlights the usefulness of 4DCT for the planning of 3DCRT in breast cancer patients. Our findings suggest that the use of 4DCT can lead to improvements in target definition and decreases in normal tissues irradiation.
Key words: Breast neoplasm; Accelerated partial breast irradiation; Ultrasound; Four-dimensional computed tomography
Address correspondence to Xun-Xing Guan, Department of Radiation Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, P.R. China. Tel: (+86)-20-87343543; Fax: (+6)-20-87343392; E-mail: firstname.lastname@example.org
Allelic Loss of the ING Gene Family Loci Is a Frequent Event in Ameloblastoma
Silvia S. Borkosky,1 Mehmet Gunduz,1,2 Levent Beder,2 Hidetsugu Tsujigiwa,3 Ryo Tamamura,1 Esra Gunduz,1,4 Naoki Katase,1 Andrea P. Rodriguez,1 Akira Sasaki,5 Noriyuki Nagai,1 and Hitoshi Nagatsuka1
1Department of Oral Pathology and Medicine, Graduate School
of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University,
2Department of Otolaryngology Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan
3Department of Virology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
4Department of Molecular Genetics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
5Department of Oral and Maxillofacial Surgery and Biopathology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
Ameloblastoma is the most frequently encountered odontogenic tumor, characterized by a locally invasive behavior, frequent recurrences, and, although rare, metastatic capacity. Loss or inactivation of tumor suppressor genes (TSGs) allows cells to acquire neoplastic growth. The ING family proteins are tumor suppressors that physically and functionally interact with p53 to perform important roles in apoptosis, DNA repair, cell cycle regulation, and senescence. TP53 genetic alterations were reported to infrequently occur in ameloblastoma. Considering that other TSGs related to TP53 could be altered in this tumor, we focused our study on the ING family genes. We analyzed the loss of heterozygosity (LOH) status of the ING family (ING1-ING5) chromosomal loci in a group of ameloblastomas by microsatellite analysis, and correlated the ING LOH status with clinicopathological characteristics. By using specific microsatellite markers, high frequency of LOH was found at the loci of each ING gene family member (33.3-72.2%). A significant relationship was shown between LOH of D2S140 (ING5 locus) and solid tumor type (p = 0.02). LOH of ING3MS (ING3 locus) was also high in solid type tumors, showing a near significant association. In addition, a notable tendency toward higher LOH for half of the markers was observed in recurrent cases. LOH of ING family genes appears as a common genetic alteration in solid ameloblastoma. The current study provides interesting novel information regarding the potential prognostic significance of the allelic loss of the ING gene family loci in ameloblastoma tumorigenesis.
Key words: Ameloblastoma; ING family; Tumor suppressor genes; Allelic loss; Microsatellite
Address correspondence to Hitoshi Nagatsuka, D.D.S., Ph.D., Department
of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry
and Pharmaceutical Sciences, Okayama University, 2-5-1, Shikata-Cho, Okayama
700-8525, Japan. Tel: +81 86 235-6651 or +81 86 235-6652; Fax: +81 86 235-6654;