In vitro and in vivo characterisation of a novel c-FLIP-targeted antisense phosphorothioate oligonucleotide

Logan, Andrew E.; Wilson, Timothy R.; Fenning, Catherine; Cummins, Raymond L.; Kay, Elaine W.; Johnston, Patrick G.; Longley, Daniel B.

doi:10.1007/s10495-010-0533-5

Cited by 13 publications

(10 citation statements)

References 30 publications

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“…We have previously shown that RNAi- and antisense-mediated FLIP downregulation induces apoptosis in NSCLC cell lines in vitro and in vivo 7, 23 and that the sensitivity of NSCLC cells to FLIP downregulation is dependent on their elevated expression of procapase-8. 7 Thus, FLIP represents an attractive therapeutic target in this disease.…”

Section: Discussionmentioning

confidence: 99%

Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer

et al. 2013

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Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1–3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents.

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Section: Discussionmentioning

confidence: 99%

Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer

et al. 2013

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“…In a recent study, an antisense phosphorothioate oligonucleotide (AS PTO) targeting FLIP sensitized several cancer cell lines but not a normal lung cell line to TRAIL-induced apoptosis. This FLIP-targeted AS PTO also efficiently enhanced apoptosis in xenograft models (53). These studies suggest that direct targeting of FLIP may be beneficial as therapy in combination with TRAIL to circumvent and prevent TRAIL resistance.…”

Section: Flipmentioning

confidence: 99%

On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics

et al. 2012

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TRAIL and agonistic antibodies against TRAIL death receptors kill tumor cells while causing virtually no damage to normal cells. Several novel drugs targeting TRAIL receptors are currently in clinical trials. However, TRAIL resistance is a common obstacle in TRAIL based therapy and limits the efficiency of these drugs. In this review article we discuss different mechanisms of TRAIL resistance and how they can be predicted and therapeutically circumvented. In addition, we provide a brief overview of all TRAIL based clinical trials conducted so far. It is apparent that although the effects of TRAIL therapy are disappointingly modest overall, a small subset of patients responds very well to TRAIL. We argue that the true potential of targeting TRAIL death receptors in cancer can only be reached when we find efficient ways to select for those patients that are most likely to benefit from the treatment. To achieve this, it is crucial to identify biomarkers that can help us predict TRAIL sensitivity.

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“…Pretreatment with chemotherapeutic drugs including cisplatin, doxorubicin, or topoisomerase I inhibitors (camptothecin, 9-NC, irinotecan) downregulated c-FLIP variants expression in various tumor cells by inhibiting its transcription and rendering cells sensitive to death receptor-triggered apoptosis (Table 1) [69,143-148]. Successful inhibition of malignant cell growth and apoptosis induction using histone deacetylase inhibitor (HDACi) compounds has highlighted the potential use of these compounds as anticancer agents.…”

Section: Cellular Flice-like Inhibitory Protein (C-flip)mentioning

confidence: 99%

“…Logan et al [143] investigated whether using an antisense oligonucleotide to target c-FLIP was a clinically feasible approach (Table 2). These authors developed a novel c-FLIP-targeted antisense phosphorothioate oligonucleotide (AS PTO) and recently used it in vitro in transient transfection experiments and in vivo using xenograft models in Balb/c nude mice [143]. The AS PTO downregulated c-FLIP and resulted in caspase-8 activation and apoptosis induction in non-small cell lung cancer (NSCLC) cells, but not in normal lung cells.…”

Section: Cellular Flice-like Inhibitory Protein (C-flip)mentioning

confidence: 99%

Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy

Safa

Pollok

2011

Cancers

153

158

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Cellular FLICE (FADD-like IL-1beta-converting enzyme)-inhibitory protein (c-FLIP) is a major resistance factor and critical anti-apoptotic regulator that inhibits tumor necrosis factor-alpha (TNF-alpha), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis as well as chemotherapy-triggered apoptosis in malignant cells. c-FLIP is expressed as long (c-FLIPL), short (c-FLIPS), and c-FLIPR splice variants in human cells. c-FLIP binds to FADD and/or caspase-8 or -10 in a ligand-dependent and-independent fashion, which in turn prevents death-inducing signaling complex (DISC) formation and subsequent activation of the caspase cascade. Moreover, c-FLIPL and c-FLIPS are known to have multifunctional roles in various signaling pathways, as well as activating and/or upregulating several cytoprotective signaling molecules. Upregulation of c-FLIP has been found in various tumor types, and its downregulation has been shown to restore apoptosis triggered by cytokines and various chemotherapeutic agents. Hence, c-FLIP is an important target for cancer therapy. For example, small interfering RNAs (siRNAs) that specifically knockdown the expression of c-FLIPL in diverse human cancer cell lines augmented TRAIL-induced DISC recruitment and increased the efficacy of chemotherapeutic agents, thereby enhancing effector caspase stimulation and apoptosis. Moreover, small molecules causing degradation of c-FLIP as well as decreasing mRNA and protein levels of c-FLIPL and c-FLIPS splice variants have been found, and efforts are underway to develop other c-FLIP-targeted cancer therapies. This review focuses on (1) the functional role of c-FLIP splice variants in preventing apoptosis and inducing cytokine and drug resistance; (2) the molecular mechanisms that regulate c-FLIP expression; and (3) strategies to inhibit c-FLIP expression and function.

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In vitro and in vivo characterisation of a novel c-FLIP-targeted antisense phosphorothioate oligonucleotide

Cited by 13 publications

References 30 publications

Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer

Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer

On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics

Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy

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