Comparison of strategies targeting Raf-1 mRNA in ovarian cancer

Mullen, Peter; McPhillips, Fiona; Monia, Brett P.; Smyth, John F.; Langdon, Simon P.

doi:10.1002/ijc.21520

Cited by 8 publications

(9 citation statements)

References 16 publications

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“…[138][139][140][141] In addition, the use of ISIS 13650, a second generation antisense oligonucleotide with further modifications in the sugar moiety targeting the same C-RAF sequence as ISIS 5132, has not been superior in certain preclinical settings. 142 LErafAON, a C-RAF antisense oligodeoxyribonucleotide applied as a liposomeencapsulated formulation, which is supposed to increase the stability and the cellular uptake of the antisense inhibitor, 143 is currently evaluated in several Phase I clinical trials as monotherapy as well as in combination with either radiation or chemotherapy. 144,145 Moreover, additional antisense approaches are currently tested for antitumor activity in preclinical models.…”

Section: Raf Kinases and Cancer Drug Discoverymentioning

confidence: 99%

Raf kinases: Oncogenesis and drug discovery

Schreck

Rapp

2006

Intl Journal of Cancer

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Raf kinase signaling has been thoroughly investigated over the last 20 years. A-Raf, B-Raf and C-Raf, the 3 mammalian members of the Raf family, are involved in a variety of cellular processes such as growth, proliferation, survival, differentiation and transformation. The detection of B-RAF mutations in a wide variety of human cancers, the description of wildtype and mutant B-RAF as tumor antigens in melanoma and the promising outcome of clinical trials evaluating the Raf inhibitor Nexavar 1 (Sorafenib, BAY 43-9006) have sparked a broad interest in the scientific community. After a short historical detour and an introduction into Raf kinase signaling, we are going to discuss here recent outcomes of Raf kinase research with respect to tumor formation and give an overview on current efforts to develop anticancer therapies interfering with aberrant Raf kinase signaling. ' 2006 Wiley-Liss, Inc.Key words: cancer; clinical trials; transformation; drug delivery; signal transduction; mitogenic cascade; Raf kinases Raf kinases: The historyIn 1983, the cloning of the acutely transforming replication-defective mouse type C virus 3611-MSV and characterization of its acquired oncogene was reported. 1 Since 3611-MSV induces rapidly growing f ibrosarcoma in mice, the transduced oncogene was called v-raf, whereas its cellular homologue was named c-raf. 1 Shortly thereafter, Bister and coworkers described the cloning of the avian acute leukemia retrovirus Mil Hill No. 2 (MH2). 2 MH2 was found to carry a second potential oncogene in addition to vmyc, which was termed v-mil, whereas its cellular counterpart was called c-mil. 3 Already a hybridization analysis and the gross comparison of restriction maps of v-raf and v-mil pointed at sequence homologies between these 2 genes. 4 By direct sequencing of both genes it was finally proven that 3611-MSV and MH2 have integrated orthologues of the same gene into their genomes. 5 In the following we are going to use the nomenclature for Raf kinases as proposed in a recent review from Wellbrock et al. 6 In contrast to all other oncogene kinases known at that time, no tyrosine kinase activity was detected in C-Raf. 7 Indeed, it was found that C-Raf is a serine/threonine kinase. 8,9 This and the observation that Raf coexists with the Myc oncogene in retroviruses 10 led to two novel concepts: (i) There is a tyrosine to serine phosphorylation switch as the growth factor signal enters the cell, and (ii) the mechanistic basis for cooperation between nuclear and cytoplasmic oncogenes as well as for signal transduction from cell surface receptors to the nucleus is the phosphorylation of transcription factor class oncogenes such as Myc. 11-13 Growth factor abrogation and oncogene cooperation studies were performed to corroborate this signaling scheme. 14-17 Additional important early findings were (i) the cooperation between Raf and Myc in growth factor independent proliferation, immortalization and tumor induction, 14,18,19 leading to the Raf-Myc balance model, 20 and (ii) the cell lineage-switch ...

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Section: Raf Kinases and Cancer Drug Discoverymentioning

confidence: 99%

Raf kinases: Oncogenesis and drug discovery

Schreck

Rapp

2006

Intl Journal of Cancer

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“…Gene transfection is regarded as a promising technique to improve the efficiency of oligonucleotides as a therapeutic agent for the treatment of genetic diseases such as carcinomas . Tremendous academic efforts and on‐going clinical trials on oligonucleotide transfection have been devoted to this field in the past few decades.…”

Section: Introductionmentioning

confidence: 99%

“…The antisense oligonucleotide ISIS 5132 inhibits the Raf‐1 expression and cellular growth. Raf‐1 is frequently activated in many tumors, either through mutation or through overexpression, and is essential for the regulation of cellular proliferation, differentiation, survival, angiogenesis, adhesion, and migration . Deregulated signalling through Raf‐1 has also been associated with hormone‐dependent cancers .…”

Section: Introductionmentioning

confidence: 99%

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An Oligonucleotide Transfection Vector Based on HSA and PDMAEMA Conjugation: Effect of Polymer Molecular Weight on Cell Proliferation and on Multicellular Tumor Spheroids

Jiang

Wong

Stenzel

2015

Macromolecular Bioscience

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A novel gene transfection vector was fabricated based on the conjugation of human serum albumin (HSA) and maleimide end functionalized poly[(N,N-dimethylamino) ethyl methacrylate] (PDMAEMA). The bioconjugation was achieved in a site-specific manner to yield well-defined polymer-protein conjugates. The biohybrid was able to bind DNA with high affinity resulting in nanoparticles with a HSA shell. This paper mainly focuses on the influence of polymeric chain length on the particle properties and their drug-carrying ability to deliver oligonucleotides into breast cancer cells. The cytotoxic agent of interest, ISIS5132, is an oligonucleotide which disrupts DNA function within the cell. There was no evidence that the polymeric chain length had any effects on the conjugation efficiency and the subsequent condensation ability of the conjugates to oligonucleotide. However, the polymeric chain length had an obvious effect on the size of the complex micelles. Low molecular weights only led to loosely compacted complexes with the oligonucleotide, while large molecular weight led to well-defined nanoparticle structures. More importantly, it was found that the variation in the length of the PDMAEMA block resulted in a change in cytotoxicity of the drug loaded complex micelle. That is, the concentration of 50% inhibition (IC50 ) of the complex micelle on MDA-MB-231 and MCF-7 cells reached the lowest value at a chain length of around 21 000 g mol(-1) . The IC50 value increased when the polymeric chain length was shorter (8000 g mol(-1) and 10 000 g mol(-1) ) while it increased again when PDMAMEA of M¯n = 47 000 g mol(-1) , probably due to insufficient release of the drug. These result were reflected when investigating the performance of the polyplex using MCF-7 multicellular tumor spheroids, where again the medium PDMAEMA chain length led to the best delivery vehicle for ISIS5132.

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“…Raf kinases are involved in “normal” physiological processes such as cellular metabolism, cell cycle progression, and cell death, as well as in tumorigenesis. Raf-1 is frequently activated in tumors, through either over-expression or mutation [2]. Thus, a comprehensive understanding of the process of Raf activation/deactivation is important.…”

Section: 0 Introductionmentioning

confidence: 99%

Integrated modulation of phorbol ester-induced Raf activation in EL4 lymphoma cells

Han

Meier

2009

Cellular Signalling

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The EL4 murine lymphoma cell line exists in variant phenotypes that differ with respect to responses to the tumor promoter phorbol 12-myristate 13-acetate (PMA1). Previous work showed that “PMA-sensitive” cells, characterized by a high magnitude of PMA-induced Erk activation, express RasGRP, a phorbol ester receptor that directly activates Ras. In “PMA-resistant” and “intermediate” EL4 cell lines, PMA induces Erk activation to lesser extents, but with a greater response in intermediate cells. In the current study, these cell lines were used to examine mechanisms of Raf-1 modulation. Phospho-specific antibodies were utilized to define patterns and kinetics of Raf-1 phosphorylation on several sites. Further studies showed that Akt is constitutively activated to a greater extent in PMA-resistant than in PMA-sensitive cells, and also to a greater extent in resistant than intermediate cells. Akt negatively regulates Raf-1 activation (Ser259), partially explaining the difference between resistant and intermediate cells. Erk activation exerts negative feedback on Raf-1 (Ser289/296/301), thus resulting in earlier termination of the signal in cells with a higher level of Erk activation. RKIP, a Raf inhibitory protein, is expressed at higher levels in resistant cells than in sensitive or intermediate cells. Knockdown of RKIP increases Erk activation and also negative feedback. In conclusion, this study delineates Raf-1 phosphorylation events occurring in response to PMA in cell lines with different extents of Erk activation. Variations in the levels of expression and activation of multiple signaling proteins work in an integrated fashion to modulate the extent and duration of Erk activation.

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Comparison of strategies targeting Raf-1 mRNA in ovarian cancer

Cited by 8 publications

References 16 publications

Raf kinases: Oncogenesis and drug discovery

Raf kinases: Oncogenesis and drug discovery

An Oligonucleotide Transfection Vector Based on HSA and PDMAEMA Conjugation: Effect of Polymer Molecular Weight on Cell Proliferation and on Multicellular Tumor Spheroids

Integrated modulation of phorbol ester-induced Raf activation in EL4 lymphoma cells

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