Systemic delivery of RafsiRNA using cationic cardiolipin liposomes silences Raf-1 expression and inhibits tumor growth in xenograft model of human prostate cancer

Pal, Ajai; Ahmad, Ateeq; Khan, Sumsullah; Sakabe, Isamu; Zhang, Chuanbo; Kasid, Usha N.; Ahmad, Imran

doi:10.3892/ijo.26.4.1087

Cited by 64 publications

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“…So far, depletion of either B-RAF or mutant V600E B-RAF by small-interfering RNAs (siRNAs) reduced proliferation and invasiveness of melanoma cell lines, [146][147][148] and also the growth and vascular development of malignant melanoma tumors. 149 Reduction of in vivo tumor growth by application of C-RAF siRNA was also reported in xenograft models of human prostate 150 and also breast cancer. 151 The benzoquinone ansamycin Geldanamycin (GA) was originally isolated as compound with antifungal activities and was later found to reduce oncogene-dependent proliferation of tumor cells; for review see Ref.…”

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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“…11, 12), AtuFECT (AtuPLEX; refs. 5, 13), or other cationic lipids (14)(15)(16)(17) have been developed for efficient complexation and delivery of siRNAs. The addition of targeting ligands (transferrin, anisamide, RGD-peptide, poly-arginine, anti-TfR single-chain antibody fragment/TfRscFv, DNA) and additional lipid moieties (PEG-lipids, cholesterol, endosomolytic helper lipids, or peptides) or the overall morphology of the generated nanoparticles (characterized by charge and particle size) supposedly confer targeting specificity to either cancer cells and/or tumor vasculature.…”

Section: Introductionmentioning

confidence: 99%

Atu027, a Liposomal Small Interfering RNA Formulation Targeting Protein Kinase N3, Inhibits Cancer Progression

et al. 2008

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We have previously described a small interfering RNA (siRNA) delivery system (AtuPLEX) for RNA interference (RNAi) in the vasculature of mice. Here we report preclinical data for Atu027, a siRNA-lipoplex directed against protein kinase N3 (PKN3), currently under development for the treatment of advanced solid cancer. In vitro studies revealed that Atu027-mediated inhibition of PKN3 function in primary endothelial cells impaired tube formation on extracellular matrix and cell migration, but is not essential for proliferation. Systemic administration of Atu027 by repeated bolus injections or infusions in mice, rats, and nonhuman primates results in specific, RNAi-mediated silencing of PKN3 expression. We show the efficacy of Atu027 in orthotopic mouse models for prostate and pancreatic cancers with significant inhibition of tumor growth and lymph node metastasis formation. The tumor vasculature of Atu027-treated animals showed a specific reduction in lymph vessel density but no significant changes in microvascular density. [Cancer Res 2008;68(23):9788-98]

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“…Efficacy of B-RafV600E-targeting siRNA has been demonstrated in B-RAF mutant papillary thyroid cancer (PTC) cells [76]. Together with observation of effective anti-tumor activity of C-Raf siRNAs in prostate [77] and breast cancer cell models in vitro and in vivo [78] these results offer a new avenue for development of mRNA-targeted therapeutics.…”

Section: Small Interfering Rnas (Sirnas) Against B-rafv600e and C-rafmentioning

confidence: 89%

Selective Raf inhibition in cancer therapy

Khazak¹,

Astsaturov

Serebriiskii

et al. 2007

Expert Opinion on Therapeutic Targets

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Over the past 5 years, the Raf kinase family has emerged as a promising target for protein-directed cancer therapy development. The goal of this review is to first provide a concise summary of the data validating Raf proteins as high-interest therapeutic targets. We then outline the mode of action of Raf kinases, emphasizing how Raf activities and protein interactions suggest specific approaches to inhibiting Raf. We then summarize the set of drugs, antisense reagents, and antibodies available or in development for therapeutically targeting Raf or Raf-related proteins, as well as current strategies combining these and other therapeutic agents. Finally, we discuss recent results from systems biology analyses that have the potential to increasingly guide the intelligent selection of combination therapies involving Raf-targeting agents and other therapeutics.

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Systemic delivery of RafsiRNA using cationic cardiolipin liposomes silences Raf-1 expression and inhibits tumor growth in xenograft model of human prostate cancer

Cited by 64 publications

References 0 publications

Raf kinases: Oncogenesis and drug discovery

Raf kinases: Oncogenesis and drug discovery

Atu027, a Liposomal Small Interfering RNA Formulation Targeting Protein Kinase N3, Inhibits Cancer Progression

Selective Raf inhibition in cancer therapy

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