Novel approaches to target pancreatic cancer.
ABSTRACT Despite remarkable progress that has been made in the recent years in the treatment of gastrointestinal tumors, in particular colorectal cancer, the prognosis of pancreatic cancer remains dismal. Five years after diagnosis almost all patients have died. At early stages of the disease surgery is the only modality to achieve long term survival. In the palliative setting gemcitabine confers some benefit to patients with advanced pancreatic cancer. A large number of chemotherapy combinations has been tested in patients with advanced pancreatic cancer. Only one combination showed significant improvement of survival, however also increased toxicity. The introduction of targeted therapies raised hopes for a better treatment of pancreatic cancer. However, most of the compounds tested so far failed to improve the survival of patients with pancreatic cancer. This review summarizes molecular targets examined so far in pancreatic cancer including matrix metalloproteinase inhibitors, farnesyltransferase inhibitors, vascular endothelial growth factor and epidermal growth factor receptor inhibitors and points out novel promising strategies for this difficult-to-treat tumor.
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ABSTRACT: Myc-induced nuclear antigen (Mina53) is a protein with a molecular weight of 53 kDa expression of which is induced by c-Myc. Increased expression of Mina53 is documented in some human carcinomas. In this study, we found markedly increased Mina53 expression in pancreatic cancer tissue specimens. This expression did not correlate with clinicopathological characteristics, such as sex, age, and presence of distant metastasis. However, there was a statistically significant association with histological differentiation, TNM stage, and lymph node metastases. To study functional role of Mina53, we silenced its expression by siRNA in PANC-1 cells. These cells were arrested in the G2/M phase, and apoptosis rates were increased. In conclusion, increased expression of Mina53 may play an important role in the development of human pancreatic cancer. Mina53 can be used as a marker for pancreatic cancer and may potentially be exploited as a target for treatment of pancreatic cancer.Cell biochemistry and biophysics 02/2014; · 3.34 Impact Factor
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ABSTRACT: Pancreatic cancer cell invasion, metastasis and angiogenesis are major challenges for the development of novel therapeutic strategies. Protein Kinase D (PKD) isoforms are involved in controlling tumor cell motility, angiogenesis and metastasis. In particular PKD2 expression is up-regulated in pancreatic cancer, whereas PKD1 expression is lower. We here report that both kinases control pancreatic cancer cell invasive properties in an isoform-specific manner. PKD2 enhances invasion in 3D-ECM cultures by stimulating expression and secretion of matrix-metalloproteinase 7 and 9 (MMP7/9), whereby MMP7 is likely to act upstream of MMP9. Knockdown of MMP7/9 blocks PKD2-mediated invasion in 3D-ECM assays and in-vivo utilizing tumors growing on chorioallantois membranes (CAM). Furthermore, MMP9 enhances PKD2-mediated tumor angiogenesis by releasing extracellular matrix-bound VEGF-A, thereby increasing its bio-availability and angiogenesis. Interestingly, specific knockdown of PKD1 in PKD2-expressing pancreatic cancer cells further enhanced the invasive properties in 3D-ECM systems by generating a high-motility phenotype. Loss of PKD1 thus may be beneficial for tumor cells to enhance their matrix-invading abilities. In conclusion, we define for the first time PKD1 and -2 isoform-selective effects on pancreatic cancer cell invasion and angiogenesis, in-vitro and in-vivo, addressing PKD isoform-specificity as a major factor for future therapeutic strategies.Molecular biology of the cell 12/2013; · 5.98 Impact Factor
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ABSTRACT: The adenovirus type 5 E1A protein (E1A) plays a critical role in anti-cancer gene therapy and has been tested in clinical trials. The expression of E1A significantly reduces tumorigenesis, promotes cell death, and inhibits cancer cell mobility. Chemosensitization is one of the anti-tumor effects of E1A, increasing in vitro and in vivo sensitization of anti-cancer drugs, including cisplatin, gemcitabine, etoposide, doxorubicin, paclitaxel, and tumor necrosis factor-related apoptosis-inducing ligand and histone deacetylase inhibitors in different types of cancer cells. E1A also demonstrates anti-metastasis activity through various molecular mechanisms such as the repression of protease expression, suppression of HER2/neu and downregulation of microRNA (miR-520h). Moreover, E1A has been reported to reprogram transcription in tumor cells and stabilize tumor suppressors such as PP2A/C, p21 and p53. Because E1A plays a potentially significant role in anti-tumor therapy, there exists an urgent need to study the anti-cancer activities of E1A. This paper presents a review of our current understanding of the tumor-suppressive functions and molecular regulation of E1A, as well as the potential clinical applications of E1A.Archivum Immunologiae et Therapiae Experimentalis 02/2014; · 2.38 Impact Factor