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Patricia L Judson,
Entidhar Al Sawah,
Douglas C Marchion,
Yin Xiong,
Elona Bicaku,
Nadim Bou Zgheib, Hye Sook Chon,
Xiaomang B Stickles,
Ardeshir Hakam,
Robert M Wenham,
Sachin M Apte,
Jesus Gonzalez-Bosquet,
Dung-Tsa Chen,
Johnathan M Lancaster
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ABSTRACT: Most women with advanced-stage epithelial ovarian cancer (OVCA) ultimately develop chemoresistant recurrent disease. Therefore, a great need to develop new, more active, and less toxic agents and/or to optimize the efficacy of existing agents exists.
In this study, we investigated the activity of Avemar, a natural, nontoxic, fermented wheat germ extract (FWGE), against a range of OVCA cell lines, both alone and in combination with cisplatin chemotherapy and delineated the molecular signaling pathways that underlie FWGE activity at a genome-wide level.
We found that FWGE exhibited significant antiproliferative effects against 12 human OVCA cell lines and potentiated cisplatin-induced apoptosis. Pearson correlation of FWGE sensitivity and gene expression data identified 2142 genes (false discovery rate < 0.2) representing 27 biologic pathways (P < 0.05) to be significantly associated with FWGE sensitivity. A parallel analysis of genomic data for 59 human cancer cell lines matched to chemosensitivity data for 2,6-dimethoxy-p-benzoquinone, a proposed active component of FWGE, identified representation of 13 pathways common to both FWGE and 2,6-dimethoxy-p-benzoquinone sensitivity.
Our findings confirm the value of FWGE as a natural product with anticancer properties that may also enhance the activity of existing therapeutic agents. Furthermore, our findings provide substantial insights into the molecular basis of FWGE's effect on human cancer cells. RESEARCH HIGHLIGHTS:
International Journal of Gynecological Cancer 07/2012; 22(6):960-7. · 1.65 Impact Factor
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Nadim Bou Zgheib,
Yin Xiong,
Douglas C Marchion,
Elona Bicaku, Hye Sook Chon,
Xiaomang Ba Stickles,
Entidhar Al Sawah,
Patricia L Judson,
Ardeshir Hakam,
Jesus Gonzalez-Bosquet,
Robert M Wenham,
Sachin M Apte,
Christopher L Cubitt,
Dung Tsa Chen,
Johnathan M Lancaster
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ABSTRACT: Ovarian cancer (OVCA) is the most lethal gynecological malignancy. The high mortality rate associated with this disease is due in large part to the development of resistance to chemotherapy; however, the biological basis of this remains unclear. Gemcitabine is frequently used for the treatment of patients with platinum-resistant OVCA. We report molecular signaling pathways associated with OVCA response to gemcitabine. Forty-one OVCA cell lines were subjected to gene expression analysis; in parallel, IC50 values for gemcitabine were quantified using CellTiter-Blue viability assays. Pearson's correlation coefficients were calculated for gene expression and gemcitabine IC50 values. The genes associated with gemcitabine sensitivity were subjected to pathway analysis. For the identified pathways, principal component analysis was used to derive pathway signatures and corresponding scores, which represent overall measures of pathway expression. Expression levels of the identified pathways were then evaluated in a series of clinico-genomic datasets from 142 patients with stage III/IV serous OVCA. We found that in vitro gemcitabine sensitivity was associated with expression of 131 genes (p<0.001). These genes include significant representation of three molecular signaling pathways (p<0.02): O-glycan biosynthesis, Role of Nek in cell cycle regulation and Antiviral actions of Interferons. In an external clinico-genomic OVCA dataset (n=142), expression of the O-glycan pathway was associated with overall survival, independent of surgical cytoreductive status, grade and age (p<0.001). Expression levels of Role of Nek in cell cycle regulation and Antiviral actions of Interferons were not associated with survival (p=0.31 and p=0.54, respectively). Collectively, expression of the O-glycan biosynthesis pathway, which modifies protein function via post-translational carbohydrate binding, is independently associated with overall survival from OVCA. Our findings shed light on the molecular basis of OVCA responsiveness to gemcitabine and also identify a signaling pathway that may influence patient survival.
International Journal of Oncology 04/2012; 41(1):179-88. · 2.40 Impact Factor
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Hye Sook Chon,
Douglas C Marchion,
Yin Xiong,
Ning Chen,
Elona Bicaku,
Xiaomang Ba Stickles,
Nadim Bou Zgheib,
Patricia L Judson,
Ardeshir Hakam,
Jesus Gonzalez-Bosquet,
Robert M Wenham,
Sachin M Apte,
Johnathan M Lancaster
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ABSTRACT: To identify pathways that influence endometrial cancer (EC) cell sensitivity to cisplatin and to characterize the BCL2 antagonist of cell death (BAD) pathway as a therapeutic target to increase cisplatin sensitivity.
Eight EC cell lines (Ishikawa, MFE296, RL 95-2, AN3CA, KLE, MFE280, MFE319, HEC-1-A) were subjected to Affymetrix Human U133A GeneChip expression analysis of approximately 22,000 probe sets. In parallel, endometrial cell line sensitivity to cisplatin was quantified by MTS assay, and IC(50) values were calculated. Pearson's correlation test was used to identify genes associated with response to cisplatin. Genes associated with cisplatin responsiveness were subjected to pathway analysis. The BAD pathway was identified and subjected to targeted modulation, and the effect on cisplatin sensitivity was evaluated.
Pearson's correlation analysis identified 1443 genes associated with cisplatin resistance (P<0.05), which included representation of the BAD-apoptosis pathway. Small interfering RNA (siRNA) knockdown of BAD pathway protein phosphatase PP2C expression was associated with increased phosphorylated BAD (serine-155) levels and a parallel increase in cisplatin resistance in Ishikawa (P=0.004) and HEC-1-A (P=0.02) cell lines. In contrast, siRNA knockdown of protein kinase A expression increased cisplatin sensitivity in the Ishikawa (P=0.02) cell line.
The BAD pathway influences EC cell sensitivity to cisplatin, likely via modulation of the phosphorylation status of the BAD protein. The BAD pathway represents an appealing therapeutic target to increase EC cell sensitivity to cisplatin.
Gynecologic Oncology 01/2012; 124(1):119-24. · 3.89 Impact Factor
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Douglas C Marchion,
Hope M Cottrill,
Yin Xiong,
Ning Chen,
Elona Bicaku,
William J Fulp,
Nisha Bansal, Hye Sook Chon,
Xiaomang B Stickles,
Siddharth G Kamath, [......],
Patricia L Judson,
Andrew Berchuck,
Robert M Wenham,
Sachin M Apte,
Jesus Gonzalez-Bosquet,
Gregory C Bloom,
Steven A Eschrich,
Said Sebti,
Dung-Tsa Chen,
Johnathan M Lancaster
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ABSTRACT: Despite initial sensitivity to chemotherapy, ovarian cancers (OVCA) often develop drug resistance, which limits patient survival. Using specimens and/or genomic data from 289 patients and a panel of cancer cell lines, we explored genome-wide expression changes that underlie the evolution of OVCA chemoresistance and characterized the BCL2 antagonist of cell death (BAD) apoptosis pathway as a determinant of chemosensitivity and patient survival.
Serial OVCA cell cisplatin treatments were performed in parallel with measurements of genome-wide expression changes. Pathway analysis was carried out on genes associated with increasing cisplatin resistance (EC(50)). BAD-pathway expression and BAD protein phosphorylation were evaluated in patient samples and cell lines as determinants of chemosensitivity and/or clinical outcome and as therapeutic targets.
Induced in vitro OVCA cisplatin resistance was associated with BAD-pathway expression (P < 0.001). In OVCA cell lines and primary specimens, BAD protein phosphorylation was associated with platinum resistance (n = 147, P < 0.0001) and also with overall patient survival (n = 134, P = 0.0007). Targeted modulation of BAD-phosphorylation levels influenced cisplatin sensitivity. A 47-gene BAD-pathway score was associated with in vitro phosphorylated BAD levels and with survival in 142 patients with advanced-stage (III/IV) serous OVCA. Integration of BAD-phosphorylation or BAD-pathway score with OVCA surgical cytoreductive status was significantly associated with overall survival by log-rank test (P = 0.004 and P < 0.0001, respectively).
The BAD apoptosis pathway influences OVCA chemosensitivity and overall survival, likely via modulation of BAD phosphorylation. The pathway has clinical relevance as a biomarker of therapeutic response, patient survival, and as a promising therapeutic target.
Clinical Cancer Research 08/2011; 17(19):6356-66. · 7.74 Impact Factor
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ABSTRACT: DNA microarray technology is a powerful genomic tool that has the potential to elucidate the relationship between clinical features of cancers and their underlying biological alterations.
We performed a systemic search in PubMed and Medline databases for recently published articles. The search terms used included "genome-wide," "microarrays," "ovarian cancer," "prognosis, " "gene expression profiling, " "molecular marker, " and "molecular biomarker. "
Genome-wide expression profiling using DNA microarray technology has enhanced our understanding of the genes that influence ovarian cancer development, histopathologic subtype, progression, response to therapy, and overall survival.
Gene expression profiling has demonstrated its utility in ovarian cancer research. It is hoped that with technologic, statistical, and bioinformatic advances, the reliability and reproducibility of this technique will increase, spawning clinical applications that may enhance our understanding of the disease and our ability to care for patients in the future.
Cancer control: journal of the Moffitt Cancer Center 01/2011; 18(1):8-15.
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ABSTRACT: Epithelial ovarian cancer is the most deadly gynecologic cancer in the United States. Multiple modalities of therapy are utilized in the management of the disease. The role of surgery remains important in the treatment of this disease and is described herein.
Medline and PubMed were utilized to search the English language medical literature up to March 2010. A broad range of studies and quality of data were analyzed, including prospective studies, case control analyses, and meta-analyses. When possible, the highest level of evidence was reviewed and presented.
For the medically fit patient, optimal cytoreductive surgery positively impacts survival. For some highly selected patients, there is a role for a minimally invasive approach. In the recurrent setting, factors such as interval to recurrence and the distribution of disease will determine the utility of secondary cytoreductive surgery. A subgroup of patients may benefit from palliative surgical procedures in the recurrent setting.
Despite advances in the use of chemotherapy and biologic agents, surgery remains an important modality in the diagnosis and treatment of ovarian cancer.
Cancer control: journal of the Moffitt Cancer Center 01/2011; 18(1):22-30.
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ABSTRACT: With the rapid development of high-throughput techniques for identifying novel specific molecular targets in human cancer over the past few years, attention to targeted cancer therapy has dramatically increased. The term "targeted cancer therapy" refers to a new generation of drugs designed to interfere with a specific molecular target that is believed to play a critical role in tumor growth or progression, is not expressed significantly in normal cells, and is correlated with clinical outcome. There has been a rapid increase in the identification of targets that have potential therapeutic application. The clinical success of the small-molecule kinase inhibitor imatinib mesylate in chronic myeloid leukemia and gastrointestinal stromal tumors has accelerated the development of a new era of molecular targeted cancer therapy. The number of agents under preclinical and clinical investigation has grown accordingly. This emphasis on molecular biology and genetics has also resulted in significant changes in the treatment of gynecologic cancers. Several promising drugs targeting tyrosine kinases (EGFR and Her-2/Neu), mTOR, Raf kinase, proteasome, and histone deacetylases, as well as drugs affecting apoptosis and mitosis, are under development for clinical application. However, some clinical trials of p53 gene therapies and farnesyl transferase inhibitors have had limited success. In this review, we will focus on potential novel targets in gynecologic cancer and the development of targeted therapy and its clinical applications in gynecologic cancer.
Current Cancer Drug Targets 07/2006; 6(4):333-63. · 4.33 Impact Factor
