Oncology Research 19(6) Abstracts

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Oncology Research, Vol. 19, pp. 245–257, 2011
0965-0407/11 $90.00 + .00
DOI: 10.3727/096504011X13021877989711
E-ISSN 1555-3906
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Tea Polyphenols Induce Apoptosis Through Mitochondrial Pathway and by Inhibiting Nuclear Factor-κB and Akt Activation in Human Cervical Cancer Cells

Madhulika Singh, Richa Singh, Kulpreet Bhui, Shilpa Tyagi, Zafar Mahmood, and Yogeshwer Shukla

Proteomics Laboratory, Indian Institute of Toxicology Research (CSIR), Lucknow, India

Phytochemicals present in tea, particularly polyphenols, have anticancer properties against several cancer types. However, studies elucidating the role and the mechanism(s) of action of tea polyphenols in cervical cancer are sparse. In this study, we investigated the mechanism of antiproliferative and apoptotic actions exerted by tea polyphenols on human papilloma virus-18-positive HeLa cervical cancer cells. Treatment of green tea polyphenol (−)-epigallocatechin gallate (EGCG) and black tea polyphenol theaflavins (TF) in HeLa cells showed a marked concentration- and time-dependent inhibition of proliferation and induced sub-G1 phase in a dose-dependent manner after 24 h. There was an attenuation of mitochondrial membrane potential with the increase of reactive oxygen species generation, p53 expression, Bax/Bcl-2 ratio, cytochrome-c release, and cleavage of procaspase-3 and -9 and poly(ADP-ribose)-polymerase, indicating the participation of a mitochondria related mechanism. In addition, EGCG as well as TF inhibited activation of Akt and nuclear factor-κB (NF-κB) via blocking phosphorylation and subsequent degradation of inhibitor of κBα and κBβ subunits, thereby downregulating cyclooxygenase-2. Additionally, the protein level of cyclin D1, a transcriptional target of NF-κB, was also reduced significantly. Thus, we can conclude that tea polyphenols inhibit the growth of cervical cancer cells by inducing apoptosis and regulating NF-κB and Akt.

Key words: Tea polyphenols; Cervical cancer; Apoptosis; Nuclear factor-κB (NF-κB); Akt; Cyclooxygenase-2

Address correspondence to Yogeshwer Shukla, Proteomics Laboratory, Indian Institute of Toxicology Research (CSIR), MG Marg, P.O. Box-80, Lucknow-226001, India. Tel: (+91) 522-2963827; Fax: (+91) 522-2628227; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 259–263, 2011
0965-0407/11 $90.00 + .00
DOI: 10.3727/096504011X13021877989748
E-ISSN 1555-3906
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Melatonin and β-Glucan Alone or in Combination Inhibit the Growth of Dunning Prostatic Adenocarcinoma

Levent Kabasakal,* Göksel Şener,* Jale Balkan,† Semra Doğru-Abbasoğlu,‡ Meral Keyer-Uysal,* and Müjdat Uysal‡

*Department of Pharmacology, Faculty of Pharmacy, Marmara University, Istanbul, Turkey
†Department of Biochemistry, Medical Faculty, Yeditepe University, Istanbul, Turkey
‡Department of Biochemistry, Medical Faculty of Istanbul, Istanbul University, Istanbul, Turkey

In this study, the effects of melatonin or β-glucan treatments on tumor growth, pro-oxidant, and antioxidant status in tumor tissue were investigated in Dunning 3327 MatLyLu prostatic adenocarcinoma model. Prostate cancer (PCa) was induced by single intradermal injection of 2 × 104 MatLyLu cells into the right hind leg of Copenhagen rats. Melatonin (10 mg/kg/daily; IP) or β-glucan (50 mg/kg/daily; orally) treatments applied alone and together continued for 39 days. Melatonin or β-glucan treatments alone or together inhibited tumor growth and decreased malondialdehyde (MDA) levels in tumor tissues of Dunning rats. However, there were no significant differences in tumor volumes and MDA levels among treatment groups. Melatonin and melatonin + β-glucan treatments elevated glutathione (GSH) levels and superoxide dismutase, glutathione peroxidase, and glutathione transferase activities in tumor tissues. However, β-glucan treatment did not influence GSH levels and antioxidant enzyme activities in tumor tissue of Dunning rats. These results indicate that melatonin and β-glucan treatments alone or together inhibit tumor progression and oxidative stress in tumor tissues of rats with Dunning PCa.

Key words: Antioxidant enzymes; β-Glucan; Lipid peroxidation; MatLyLu Dunning prostatic adenocarcinoma; Melatonin

Address correspondence to Müjdat Uysal, M.D., Department of Biochemistry, Medical Faculty of Istanbul, Istanbul University, 34093, Çapa, Istanbul, Turkey. Tel: +90 212 4142188; Fax: +90 212 6215642; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 265–274, 2011
0965-0407/11 $90.00 + .00
DOI: 10.3727/096504011X13021877989793
E-ISSN 1555-3906
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Evaluation of an 18F-Labeled Oligonucleotide Probe Targeting p21WAF1 Transcriptional Changes in Human Tumor Cells

I. Koslowsky,* S. Shahhosseini,† R. Mirzayans,‡ D. Murray,‡ and J. Mercer†

*Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
†Edmonton PET Centre, Edmonton, Alberta, Canada
‡Department of Experimental Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada

The ability to image gene expression using 18F-labeled antisense oligonucleotides (asODNs) directed to specific mRNA transcripts during, or immediately following, radio- or chemotherapy would be a valuable clinical tool to monitor the early tumor response to treatment. Imaging of upregulated p21 mRNA postirradiation using 18F-labeled asODNs could offer insights into early tumor responses by detecting signs of accelerated cellular senescence. Thus, the aim of this work was to evaluate the uptake and distribution of a (radio)-fluorinated asODN in vitro in HCT116 p21+/+ human colon carcinoma cells. asODN and a random sequence oligonucleotide (rsODN) were conjugated with a (radio)fluorine prosthetic group. Irradiated HCT116 cells were treated with naked or liposome-transfected ODNs. Cell fractionation, confocal microscopy, immunofluorescence, and Western blot studies were performed to observe uptake, distribution, and antisense activity of the probes. [F]asODN demonstrated similar antisense binding ability as the unlabeled asODN to p21 mRNA. Liposomal-transfected 18F-labeled asODNs and rsODNs exhibited a three- to fivefold increase in uptake at 2.5 h compared to the naked [18F]ODNs. Distribution of transfected [18F]asODN in the cytoplasm and endosomes increased over time whereas no change in intracellular distribution was observed with transfected [18F]rsODN or naked ODNs. Antisense activity was not compromised with the addition of a fluorine moiety on asODN. The cellular accumulation and distribution of the (radio)fluorinated ODNs was not altered by the addition of the prosthetic group. Radiolabeled ODNs were able to penetrate the cell with preferential uptake observed with the liposome-transfected probes. Increased distribution of [18F]asODN in the cytoplasm suggests the probe is available for targeting its transcript mRNA. This warrants further investigations into the potential of [18F]asODN to image accelerated senescence postirradiation.

Key words: Antisense oligonucleotide; Fluorine-18; p21; Ionizing radiation; HCT116

Address correspondence to John R. Mercer, Edmonton PET Centre, 11560 University Ave, Edmonton, Alberta, T6G 1Z2, Canada. Tel: 780 989-4312; Fax: 780 432-8483; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 275–285, 2011
0965-0407/11 $90.00 + .00
DOI: 10.3727/096504011X13021877989838
E-ISSN 1555-3906
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Antidiabetic Drug Metformin Induces Apoptosis in Human MCF Breast Cancer via Targeting ERK Signaling

Ahmed Malki* and Amal Youssef†

*Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
†Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

Metformin is the most widely used antidiabetic drug for type II diabetes in the world. Recent studies provide clues that the use of metformin may be associated with reduced incidence and improved prognosis of certain cancers and there is increasing evidence of a potential efficacy of this agent as an anticancer drug. This observation led us to hypothesize that metformin might inhibit human breast cancer cells (MCF-7) growth. Here, we report that metformin induced apoptosis in human breast carcinoma cell lines MCF-7 cells via novel signaling pathway. Metformin induced apoptosis by arresting cells in G1 phase and reducing cyclin D level and increasing the expression of p21 and cyclin E. Molecular and cellular studies indicated that metformin significantly elevated p53 and Bax levels and reduced STAT3 and Bcl-2. Inhibitors of signaling proteins were used to study the mechanism(s) of metformin function. Receptor inhibitor studies indicated that p53 activation was mediated through insulin receptor (IR), not insulin-like growth factor-1 receptor (IGF-1R). Furthermore, MEK inhibitor significantly suppressed metformin-induced p53 and Bax elevation while ERK inhibitor generated a slight reduction in p53 levels. In contrast, PI3K inhibitor did not produce any effect on the metformin-elevated p53 levels. Finally, SAPK/JNK, known to be involved in apoptosis, was activated in cells treated with metformin and the activation appeared to occur downstream of ERK. All these results suggested that metformin activated p53, Bax, and induced tumor cell apoptosis through the ERK signaling pathway. This pathway has not been previously described for IR, p53, Bax activation, or apoptosis. Metformin, a novel inducer of apoptosis, and its analogs may offer a novel strategy for the treatment of cancer cells.

Key words: Metformin; Breast cancer; p53; p21; Bax; ERK; JNK

Address correspondence to Ahmed Malki, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt. Tel: 20 122267456; Fax: 20 33900042; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 287–295, 2011
0965-0407/11 $90.00 + .00
DOI: 10.3727/096504011X13021877989874
E-ISSN 1555-3906
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

A Conjugate of Gemcitabine With Bisphosphonate (Gem/BP) Shows Potential as a Targeted Bone-Specific Therapeutic Agent in an Animal Model of Human Breast Cancer Bone Metastases

A. A. El-Mabhouh, P. N. Nation, J. T. Abele, T. Riauka, E. Postema, A. J. B. McEwan, and J. R. Mercer

Department of Oncology, Faculty of Medicine and Dentistry, Cross Cancer Institute, Edmonton, Alberta, Canada

Bone metastases in advanced breast cancer patients remains a significant treatment challenge. Bisphosphonates are now a routine first line treatment for prevention and treatment of skeletal damage caused by malignancies and, moreover, have shown an ability to transport therapeutic drugs to the bone. Here, we describe the effect of a conjugate between the potent anticancer drug gemcitabine and a bisphosphonate molecule (Gem/BP) in an animal model of breast cancer metastases. We have previously demonstrated the targeting of this compound to bone in normal mice using an analog labeled with the radionuclide 99mTc. Using a bone metastasis model in nude mice produced by intracardiac injection of the human breast cancer cell line MDA-MB-231BO, we examined the effect of Gem/BP and gemcitabine in reducing the frequency and severity of osteolytic bone lesions. High-resolution radiographs and microPET images showed that Gem/BP reduced the number and size of bone metastases relative to the gemcitabine-treated and the untreated control groups. Histological examination of the humeri and femurs of the control and gemcitabine groups revealed large metastatic cancer lesions in the outer and inner cortices and the medullary cavities. In contrast, Gem/BP-treated mice showed occasional small wedge-shaped metastases under the periosteum of the outer cortex and very occasionally in the medulla. These findings suggest that Gem/BP should be further evaluated for use in the treatment of bone metastases in breast cancer.

Key words: Bone metastases; MDA-MB-231; Breast cancer; Gemcitabine; Bisphosphonate

Address correspondence to John R. Mercer, Ph.D., Division of Oncologic Imaging, Department of Oncology, Faculty of Medicine and Dentistry, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, Canada T6H 1P6. Tel: (780) 989-4312; Fax: (780) 989-4309; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 297–301, 2011
0965-0407/11 $90.00 + .00
DOI: 10.3727/096504011X13021877989919
E-ISSN 1555-3906
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Regulation of Matrix Metalloproteinases and Invasion by Gα12/13 Proteins in NIH3T3 Mouse Fibroblast Cells

Eun-Sook Kim,* Kyung-Min Lee,† Dong-Young Noh,† and Aree Moon*

*College of Pharmacy, Duksung Women’s University, Seoul, Korea
†College of Medicine, Seoul National University, Seoul, Korea

The G12 subfamily of the heterotrimeric G proteins, Gα12 and Gα13, has been implicated as an important signaling component in various cellular processes including oncogenesis and cells invasion. Our previous report showed that the expression of an activated mutant of Gα12 (Gα12QL) or Gα13 (Gα13QL) leads to cell invasion in MCF10A human breast epithelial cells. The present study aimed to investigate the role of Gα12 and Gα13 in the malignant phenotypic conversion of NIH3T3 mouse fibroblast cells. Gα12QL and Gα13QL induced an invasive phenotype in NIH3T3 cells. In addition, the activation of Gα12 and Gα13 upregulated matrix metalloproteinase (MMP)-2 while MMP-9 was not affected by either Gα12QL or Gα13QL. Using female NOD/SCID mice injected with NIH3T3 cells stably expressing Gα12QL, we provided in vivo confirmation of Gα12-mediated MMP-2 upregulation. Taken together, this study elucidated the role of Gα12/13 in regulating malignant phenotypic conversion of NIH3T3 fibroblast cells, validating the role of Gα12/13  in tumorigenesis.

Key words: Gα12/13; Cell invasion; Matrix metalloproteinase-2 (MMP-2)

Address correspondence to Dr. Aree Moon, College of Pharmacy, Duksung Women’s University, Seoul 132-714, Korea. Tel: +82-2-901-8394; Fax: +82-2-901-8386; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it