Table of Contents

Volume 10, Issue 1

  July 1, 2010

  Pages 1 - 110

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 Issue Catalogue (MARC XML)

REVIEW

Open Access Article

The molecular pathogenesis of small cell lung cancer

Sandra P. D’Angelo and M. Catherine Pietanza
Pages 1 - 10
http://dx.doi.org/10.4161/cbt.10.1.12045
Abstract | PDF

Small cell lung cancer (SCLC) represents 13% of all lung cancer cases diagnosed in the United States.  Although a chemotherapy- and radiation-sensitive disease, SCLC recurs rapidly with only 5% of patients surviving five years.  This dismal prognosis likely is secondary to few improvements in its treatment, without significant changes in its standard of care over the last three decades.  SCLC has a unique biology with specific molecular and cellular changes, which are the subject of active investigation.  Here, we summarize the alterations leading to the pathogenesis of SCLC:  chromosomal changes; dysregulation of tumor suppressor genes, oncogenes, and signaling pathways; upregulation of receptor tyrosine kinases, growth factors, and cellular markers; and the persistence of developmental pathways.  Each of these represents potential targets for therapy and many biologic agents are being studied.




JOURNAL CLUB

Open Access Article

The use of 5-alpha-reductase inhibitors for the prevention of prostate cancer

Eun-mi Yu, Walid El-Ayass and Jeanny B. Aragon-Ching
Pages 11 - 12
http://dx.doi.org/10.4161/cbt.10.1.12368
Abstract | PDF

The use of 5-alpha-reductase inhibitors has been studied not only in benign prostatic hyperplasia, but as a chemopreventive strategy in prostate cancer. Both finasteride & dutasteride, 5 alpha-reductase inhibitors (5ARI), have been shown to decrease the risk of prostate cancer. The results of the REDUCE trial using the dual alpha-reductase isoenzyme inhibitor dutasteride, has recently been published by Andriole et. al. in the New England Journal of Medicine. Certain considerations regarding its use and applicability to men with high risk of developing prostate cancer are herein discussed.




CLINICAL STUDY

Open Access Article

Genetic polymorphisms in XRCC1 associated with radiation therapy in prostate cancer

Rui Gao, Douglas K. Price, William L. Dahut, Eddie Reed and William D. Figg, II
Pages 13 - 18
http://dx.doi.org/10.4161/cbt.10.1.12172
Abstract | PDF

Radiation therapy is a potentially curative, important treatment option in localized prostate cancer. However, at 8 years after radiation therapy, even in the best risk subset of patients, approximately 10% of patients will experience clinical disease recurrence. The identification of molecular markers of treatment success or failure may allow for the development of strategies to further improve treatment outcomes. Herein, we investigated five molecular markers of DNA repair. 513 patients with castrate-resistant prostate cancer (CRPC), including 284 patients who received radiotherapy, 229 patients without radiotherapy, and 152 healthy individuals were genotyped for 5 polymorphisms in DNA excision repair genes: ERCC1 N118N (500C>T), XPD K751Q (2282A>C), XRCC1 R194W (685C>T), XRCC1 R399Q (1301G>A) and PARP1 V762A (2446T>C). The distribution of genetic polymorphisms in the patients with CRPC and in healthy controls was compared, and the association between the polymorphisms and overall survival was investigated. The polymorphisms evaluated did not show differences between the patient group and the healthy controls, nor did they show a trend toward an association with survival. However, in the radiation treated subgroup, the median survival time was associated with the XRCC1 haplotype. The median survival time was 11.75 years for patients with the R399Q AA/R194W CC haplotype, 12.17 years for patients with the R399Q AG/R194W CC haplotype, 6.665 years for patients with the R399Q AG/R194W CT haplotype, and 6.21 years for patients with the R399Q GG/R194W CT haplotype (p=0.034). This association was not found when all patients were investigated. We conclude that the genetic polymorphisms in XRCC1 may affect the outcome in patients who received radiotherapy for localized prostate cancer.




RESEARCH PAPER

Open Access Article

β₂-adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NF-κB and AP-1

Dong Zhang, Qing Yong Ma, Heng-Tong Hu and Min Zhang
Pages 19 - 29
http://dx.doi.org/10.4161/cbt.10.1.11944
Abstract | PDF

Smoking and chronic stress are well-documented risk factors that are associated with β-adrenoceptors in the development of pancreatic cancer. Stimulation of β-adrenoceptors can activate cyclic adenosine monophosphate (cAMP)/ protein kinase A (PKA) and mitogen-activated protein kinase (MAPK) pathways in pancreatic cancer cells. Many recent studies have focused on the function of β-adrenoceptors in cancer invasion. Thus, we hypothesized that β-adrenoceptors may play a role in pancreatic cancer invasion, and β-blockers may suppress the pancreatic cancer invasion and proliferation. MIA PaCa-2 and BxPC-3 cell lines express mRNA and protein of both β₁ and β₂-adrenoceptors. β₂-adrenergic antagonist ICI118,551 and β_1/2-adrenergic antagonist propranolol significantly suppressed cell invasion and proliferation in comparison to β₁-adrenergic antagonist metoprolol and control in a Matrigel invasion assay and subrenal capsular assay. Treatment with β₂-adrenoceptor antagonists inhibited activation of transcription factors nuclear factor κB (NF-κB), activator protein 1 (AP-1) and cAMP response element binding protein (CREB) as demonstrated by electrophoretic mobility shift assays and Western blotting. β₂-adrenoceptor antagonists also significantly altered vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), matrix metalloproteinase 2 (MMP-2) and MMP-9 expression. The β₂-adrenergic antagonists suppressed invasion and proliferation by inhibiting both cAMP/PKA and Ras, which regulate activation of the MAPK pathway and transcription factors, such as NF-κB, AP-1 and CREB, as well as expression of its target genes, MMP-9, MMP-2 and VEGF. However, β₁-adrenergic antagonists suppressed invasion by inhibiting only the cAMP/PKA pathway, suggesting that they may be useful as novel preventive and therapeutic strategies for pancreatic cancer.




COMMENTARY

Open Access Article

Role for catecholamines in tumor progression: Possible use for ß-blockers in the treatment of cancer

Eric V. Yang
Pages 30 - 32
http://dx.doi.org/10.4161/cbt.10.1.12260
Abstract | PDF

Commentary to:

β2-adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NF-κB and AP-1

Dong Zhang, Qing Yong Ma, Heng-Tong Hu and Min Zhang




RESEARCH PAPERS

Open Access Article

Novel somatic mutations in heterotrimeric G proteins in melanoma

L. Isabel Cárdenas-Navia, Pedro Cruz, Jimmy C. Lin, NISC Comparative Sequencing Program, Steven A. Rosenberg and Yardena Samuels
Pages 33 - 37
http://dx.doi.org/10.4161/cbt.10.1.11949
Abstract | PDF

  Heterotrimeric guanine nucleotide-binding proteins (G proteins) mediate signals between G-protein coupled receptors and their downstream pathways, and have been shown to be mutated in cancer.  In particular, GNAQ was found to be frequently mutated in blue nevi of the skin and uveal melanoma, acting as an oncogene in its mutated form.  To further examine the role of heterotrimeric G proteins in malignant melanoma, we performed a comprehensive mutational analysis of the 35 genes in the heterotrimeric G protein gene family in a panel of 80 melanoma samples.  Somatic alterations in a G protein subunit were detected in 17% of samples spanning 7 genes.  The highest rates of somatic, non-synonymous mutations were found in GNG10 and GNAZ, neither of which has been previously reported to be mutated in melanoma. Our study is the first systematic analysis of the heterotrimeric G proteins in melanoma and indicates that multiple mutated heterotrimeric G proteins may be involved in melanoma progression.

Open Access Article

Bioluminescent imaging study: FAK inhibitor, PF-562,271, preclinical study in PC3M-luc-C6 local implant and metastasis xenograft models

Haihao Sun, Stephen Pisle, Erin R. Gardner and William D. Figg, II
Pages 38 - 43
http://dx.doi.org/10.4161/cbt.10.1.11993
Abstract | PDF

 

Focal adhesion kinase (FAK) is essential in regulating integrin signaling pathways responsible for cell survival and proliferation, as well as motility, making FAK a distinctive target in the field of anticancer drug development, especially with regards to metastatic disease.¹ Our objective was to demonstrate tumor growth inhibition by PF-562,271, a selective inhibitor of FAK and FAK2, or Pyk2,­² in mouse xenograft models, both subcutaneous and metastatic, employing the human prostate cancer cell line PC3M-luc-C6, a modified PC3M cell line that expresses luciferase. After two weeks of treatment with PF-562,271, 25 mg/kg PO BID 5x/wk, the subcutaneous model showed a 62 % tumor growth inhibition compared to control based on tumor measurements (p < 0.05), with a 88% vs. a 490% increase in bioluminescent signal for treatment and control respectively (p < 0.05). In the metastasis model, the percent change from baseline, after 18 days of treatment, of the treatment group was 2,854% vs. 14,190% for the vehicle (p < 0.01). These results show that PF-562,271 has a potent effect on metastatic prostate cancer growth in vivo.

Open Access Article

DNA methylation-related vitamin D receptor insensitivity in breast cancer

Radharani Marik, MaryJo Fackler, Edward Gabrielson, Martha A. Zeiger, Saraswati Sukumar, Vered Stearns and Christopher B. Umbricht
Pages 44 - 53
http://dx.doi.org/10.4161/cbt.10.1.11994
Abstract | PDF

 

Calcitriol (1α, 25(OH)-Vitamin D3) binds to the vitamin D receptor (VDR) and regulates differentiation of the normal mammary gland, may therefore be useful in breast cancer treatment or prevention.Many breast cancer cells are, however, resistant to Calcitriol. In this study, we investigated the resistance mechanism and the role of epigenetic silencing of VDR by promoter hypermethylation.Bisulfite sequencing of the VDR promoter region revealed methylated CpG islands at -700 base pairs (bp) upstream and near the transcription start site.VDR CpG islands were demethylated by 5'deoxy-azacytidine treatment, and this was accompanied by a parallel increase in VDR mRNA levels in breast cancer cell lines. Quantitative methylation-specific PCR analyses confirmed hypermethylation of these CpG islands in primary tumors, and its absence in normal breast tissue.VDR transcripts detected in breast cancers were predominantly 5'-truncated, while normal breast tissue expressed full-length transcripts. Consistent with this observation, genes containing the VDR-responsive element (VDRE), such as cytochrome p450 hydroxylases,p21, or C/EBP were underexpressed in breast cancers compared to normal breast samples. Expression of the active longer transcripts of VDR was restored with 5'deoxy-Azacytidine (AZA) treatment, with a concurrent increase in expression of VDRE-containing genes. Thus, promoter methylation-mediated silencing of expression of the functional variants of VDR may contribute to reduced expression of downstream effectors of the VDR pathway and subsequent Calcitriol insensitivity in breast cancer. These data suggest that pharmacological reversal of VDR methylation may re-establish breast cancer cell susceptibility to differentiation therapy using Calcitriol.

Open Access Article

Osteopontin but not osteonectin favors the metastatic growth of pancreatic cancer cell lines

Maria Zhivkova-Galunska, Hassan Adwan, Ergül Eyol, Jörg Kleeff, Armin Kolb, Frank Bergmann and Martin R. Berger
Pages 54 - 64
http://dx.doi.org/10.4161/cbt.10.1.12161
Abstract | PDF

 

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer- related death in Western countries and among the malignancies with the worst prognosis. Osteonectin and osteopontin, two proteins of the extracellular matrix, have been found to be up-regulated in PDAC. In the present study the expression of osteopontin mRNA as determined in a panel of 14 hu­man pancreatic cancer cell lines was significantly related to the growth these cell lines in the liver of nude rats (p=0.001) whereas osteonectin showed a trend of being negatively related to pancreatic cancer cell growth in vivo (p=0.10). In an in vitro co-culture model of human Suit2-007 and rat AsML PDAC cells with rat hepatocytes, a clearly increased expression of OPN mRNA was found in the tumor cells. In addition both, down-regulation of osteopontin with specific antisense oligonucleotides and treatment with exogenous rh-osteonectin were associated with reduced cell proliferation. In accordance with the latter finding down-regula­tion of osteonectin was coupled with increased proliferation. This evidence supports a protu­morigenic role of osteopontin and points to an anti-tumorigenic role of osteonectin in PDAC.




COMMENTARY

Open Access Article

Matricellular proteins osteopontin and osteonectin/SPARC in pancreatic carcinoma

Anne M. Delany
Pages 65 - 67
http://dx.doi.org/10.4161/cbt.10.1.12452
Abstract | PDF

Commentary to:

Osteopontin but not osteonectin favors the metastatic growth of pancreatic cancer cell lines

Maria Zhivkova-Galunska, Hassan Adwan, Ergül Eyol, Jörg Kleeff, Armin Kolb, Frank Bergmann and Martin R. Berger




RESEARCH PAPER

Open Access Article

SU11248 (sunitinib) directly inhibits the activity of mammalian 5'-AMP-activated protein kinase (AMPK)

Keith Laderoute, Joy M. Calaoagan, Peter B. Madrid, Anthony E. Klon and Paula J. Ehrlich
Pages 68 - 76
http://dx.doi.org/10.4161/cbt.10.1.12162
Abstract | PDF

 

AMPK has been termed the fuel sensor of mammalian cells because it directly responds to the depletion of the fuel molecule ATP. In previous work, we found that AMPK is strongly activated by tumor-like hypoxia and glucose deprivation, independently of the oxygen response system associated with HIF-1. We also observed high levels of AMPK activity in tumor cells in vivo, using different model tumors. These findings suggested the hypothesis that modulation of AMPK activity could have therapeutic value for the treatment of solid tumors. To investigate this hypothesis, we have been conducting a SAR study of potential small-molecule modulators of AMPK activity. Here we report that the chemotherapeutic drug SU11248 (sunitinib) is at least as potent an inhibitor of AMPK as compound C, which is a commonly used experimental direct inhibitor of the enzyme. We also provide a computational model of the binding pose of SU11248 to an AMPKa subunit, which suggests a structural basis for the affinity of the drug for the ATP site of the catalytic domain. The ability of SU11248 to inhibit AMPK has potential clinical significance-there may be populations of SU11248-treated patients in which AMPK activity is inhibited in normal as well as in tumor tissue.




COMMENTARY

Open Access Article

Close encounters of a novel kind: A multi-targeted cancer drug meets a metabolic sensor

Marc Billaud and Benoit Viollet
Pages 77 - 78
http://dx.doi.org/10.4161/cbt.10.1.12538
Abstract | PDF

Commentary to:

SU11248 (Sunitinib) directly inhibits the activity of mammalian 5'-AMP-activated protein kinase (AMPK)

Keith Laderoute, Joy M. Calaoagan, Peter B. Madrid, Anthony E. Klon and Paula J. Ehrlich




RESEARCH PAPERS

Open Access Article

Assessing the efficacy of the Hedgehog pathway inhibitor vitamin D3 in a murine xenograft model for pancreatic cancer

Lois W. Brüggemann, Karla C. S. Queiroz, Khatera Zamani, Amber van Straaten, C Arnold Spek and Maarten F. Bijlsma
Pages 79 - 88
http://dx.doi.org/10.4161/cbt.10.1.12165
Abstract | PDF

 

The developmental Hedgehog (Hh) pathway has been shown to cause malignancies in the adult organism, specifically in the proximal gastrointestinal tract. Previous studies have used the Hh-inhibitory alkaloid cyclopamine to treat Hh-dependent tumor growth. The present study aimed to determine the efficacy and specificity of the recently discovered endogenous inhibitor of the Hh pathway, vitamin D3, on inhibition of pancreatic adenocarcinoma cell growth in vitro and in vivo. Vitamin D3 was found to inhibit cell growth specifically through inactivation of Smo and the downstream Hh pathway, rather than activation of the vitamin D3 receptor. However, in in vivo models vitamin D3 was not found to be effective against tumor cell growth.

Open Access Article

Oligomannurarate sulfate, a novel antimitotic agent, exerts anti-cancer activity by binding to tubulin on novel site

Benchun Miao, Yi Chen, Jing Li, Xianliang Xin, Li Gan, Xueyan Fu and Meiyu Geng
Pages 89 - 98
http://dx.doi.org/10.4161/cbt.10.1.12167
Abstract | PDF

 

Tubulin-binding agents have received considerable interest as potential anti-cancer drugs. These compounds interfere with tubulin dynamics and microtubule organization and thereby induce cell growth arrest at G2/M phase, and eventually lead to apoptotic cell death. Herein, we report that sulfated oligosaccharide JG3 was effective at inhibiting viability of cancer cells, and suppressing tumor growth in vivo. Our studies showed that JG3 significantly arrested cell cycle at G2/M phase and led cancer cells to apoptotic death. Consistent with this, tubulin was identified as a binding protein of JG3 using affinity chromatography and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The interaction between JG3 and tubulin was characterized by surface plasmon resonance (SPR) analysis. Furthermore, it was demonstrated both at cellular level and in cell free system that JG3 potently prevented tubulin polymerization, thereby demolished microtubule organization in cancer cells. The underlying mechanism lies in its binding to tubulin on a unique site distinct from other conventional binding sites. All these suggest that JG3 is a novel antimitotic reagent, and this might shed new light on the understanding of anti-cancer activities and mechanisms of novel antimitotic reagents, and help develop new antimitotic agents in cancer therapy.

Open Access Article

Combination effects of bortezomib with gemcitabine and EMAP II in experimental pancreatic cancer

Niranjan Awasthi, Margaret A. Schwarz and Roderich E. Schwarz
Pages 99 - 107
http://dx.doi.org/10.4161/cbt.10.1.12169
Abstract | PDF

 

The proteasome inhibitor bortezomib (B) has been shown to enhance gemcitabine (G) effects against pancreatic ductal adenocarcinoma (PDAC). Endothelial monocyte activating polypeptide II (EMAP, E) is an antiendothelial and antiangiogenic cytokine. We tested the combination effects of bortezomib, gemcitabine and EMAP in experimental PDAC. Bortezomib inhibited the in vitro proliferation of PDAC and endothelial cells, with additive effects in combination with gemcitabine or EMAP. Bortezomib induced apoptosis as observed by PARP-1 cleavage; it also increased the expression of p21 (>27-fold) and p27 (>2.5-fold), with additive effects in combination with gemcitabine and EMAP. Bortezomib caused a decrease in the expression of the antiapoptotic protein Bcl-2, and an increase in the proapoptotic protein Bax and in p53. Bortezomib had no effect on the intracellular levels of full length or mature EMAP. An in vivo murine xenograft model showed extended survival in all combination groups except B+E compared with control or monotherapy, but no benefit of B+E+G over E+G. The relative local tumor growth compared to controls after bortezomib, EMAP, gemcitabine, B+G, E+G or B+E+G was 92%, 52%, 48%, 36%, 18% and 35%, respectively. Our results show that in vitro bortezomib had an antiproliferative and proapoptotic effect, and it's combination with gemcitabine and EMAP increased these effects. In vivo, bortezomib had no anti-tumor effect by itself, enhanced gemcitabine effects in combination, but failed to further significantly improve the E+G combination benefit. The potential value of proteasome inhibition in experimental therapy approaches for PDAC appears to relate primarily to the combination with the cytotoxic drug rather than with the antiendothelial agent.




COMMENTARY

Open Access Article

Leveraging combinatorial chemotherapy to improve outcomes in patients with pancreatic cancer

Leonidas G. Koniaris, Xiaoling Jin, Alberto J. Montero and Teresa A. Zimmers
Pages 108 - 109
http://dx.doi.org/10.4161/cbt.10.1.12450
Abstract | PDF

Commentary to:

Combination effects of bortezomib with gemcitabine and EMAP II in experimental pancreatic cancer

Niranjan Awasthi, Margaret A. Schwarz and Roderich E. Schwarz




RETRACTION

Open Access Article

Retracted manuscript: Overexpression of transketolase protein TKTL1 is associated with occurrence and progression in nasopharyngeal carcinoma

Song Zhang, Jian Xin Yue, Ju Hong Yang, Peng-Cheng Cai and Wei Jia Kong
Page 110
http://dx.doi.org/10.4161/cbt.10.1.12828
Abstract | PDF

This article has been retracted at the request of the Editor-in-Chief.

Retraction:

Overexpression of transketolase protein TKTL1 is associated with occurrence and progression in nasopharyngeal carcinoma: A potential therapeutic target in nasopharyngeal carcinoma

Song Zhang, Jian-Xin Yue, Ju-Hong Yang, Peng-Cheng Cai and Wei-Jia Kong

Reason: In the process of investigating an accusation of misconduct in the above manuscript, the Editors have found significant evidence of fraud perpetrated by some of the authors.
1) Dr. Wei Jia Kong's name was used as the corresponding author without his knowledge or consent. Furthermore, Dr. Cai Pengcheng was unaware of his status as an author of the manuscript.
2) A fake email address for Dr. Kong was constructed and used by the authors to intercept any information that would be sent to the corresponding author.
3) Dr. Zhang Song and Ms. Yang Juhong have modified their accounts of the events several times during the investigation, making it difficult to determine exactly what occurred with respect to the data in question. However, The Editors have determined that Figure 4 of this manuscript is a re-publication of data in Cancer Letters (2007) 253:108-114. The authors have misrepresented their data as being from 2 separate cell lines.