In vivo siRNA distribution and pharmacokinetics assessed by nuclear imaging are modulated according to radiolabelling site

Garin, D.; Ahmadi, Mitra; Gauchez, Anne-Sophie; Bohic, Sylvain; Boccard, Sandra; Cloetens, Peter; Fagret, Daniel; Berger, F.; Briat, Arnaud; Ghezzi, Cathérine; Pelletier, Laurent

doi:10.1016/j.nucmedbio.2015.04.007

Cited by 3 publications

(2 citation statements)

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“…The delivery of drugs to the central nervous system (CNS) is a crucial issue in medical management. We and others have demonstrated the poor capacity of siRNAs packaged with polyethylenimine (PEI) to pass through the blood brain barrier [ 63 – 65 ] and among the numerous other vectors or strategies investigated for targeting brain and intracranial tumors, none has been validated to date. This is the reason why we chose to use ectopically implanted tumor instead of intracranial ones.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of DNA-repair genes Ercc1 and Mgmt enhances temozolomide efficacy in gliomas treatment: a pre-clinical study

et al. 2015

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Gliomas are the most common primary brain tumors. To date, therapies do not allow curing patients, and glioblastomas (GBMs) are associated with remarkably poor prognosis. This situation is at least partly due to intrinsic or acquired resistance to treatment, especially to chemotherapy. In 2005, temozolomide (TMZ) has become the first chemotherapeutic drug validated for GBM. Nevertheless TMZ efficacy depends on Mgmt status. While the methylation of Mgmt promoter was considered so far as a prognostic marker, its targeting is becoming an effective therapeutic opportunity. Thus, arrival of both TMZ and Mgmt illustrated that considerable progress can still be realized by optimizing adjuvant chemotherapy. A part of this progress could be accomplished in the future by overcoming residual resistance. The aim of the present study was to investigate the involvement of a set of other DNA-repair genes in glioma resistance to temozolomide. We focused on DNA-repair genes located in the commonly deleted chromosomal region in oligodendroglioma (1p/19q) highly correlated with patient response to chemotherapy. We measured effects of inhibition of ten DNA-repair genes expression using siRNAs on astrocytoma cell response to cisplatin (CDDP) and TMZ. SiRNAs targeting ercc1, ercc2, mutyh, and pnkp significantly sensitized cells to chemotherapy, increasing cell death by up to 25%. In vivo we observed a decrease of subcutaneous glioma tumor growth after injection of siRNA in conjunction with absorption of TMZ. We demonstrated in this pre-clinical study that targeting of DNA-repair genes such as Ercc1 could be used as an adjuvant chemosensitization treatment, similarly to Mgmt inhibition.

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Section: Discussionmentioning

confidence: 99%

Inhibition of DNA-repair genes Ercc1 and Mgmt enhances temozolomide efficacy in gliomas treatment: a pre-clinical study

et al. 2015

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“…To construct EGFP-tagged and GST-tagged expression plasmids, the inserts of the above Myc-tagged CCDC106 expression plasmids were subcloned into the pEGFP-C3 vector at EcoRI/KpnI sites and the pGEX-4 T-2 vector at EcoRI/NotI sites. siRNAs against the CCDC106 gene and CK2β have been validated by our group [9] and Garin D et al [23], respectively. Bax, Bcl2, phospho-CCDC106 (S130) and phospho-CCDC106 (S147) antibodies were purchased from ABclonal Technology (Wuhan, China).…”

Section: Methodsmentioning

confidence: 99%

CK2-mediated CCDC106 phosphorylation is required for p53 degradation in cancer progression

Ning

Wang

Liu

et al. 2019

J Exp Clin Cancer Res

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BackgroundDysfunction of p53 is a key cause of cancer development, while CCDC106 can reduce p53 stability and is associated with lung cancer. However, the roles of CCDC106 in other cancer types and its upstream regulators have not been investigated.MethodsThe phosphorylation status was investigated by in vitro kinase assay and Western blotting using phosphorylation-specific antibodies. Co-immunoprecipitation assay and GST-pulldown were used to detect protein interaction. Cell viability, apoptosis, colony formation, wound-healing and invasion assays were measured for in vitro functional analyses. The in vivo effect of CCDC106 on tumor growth was investigated using a subcutaneous xenograft tumor mouse model.ResultsWe demonstrated that CCDC106 knockdown enhanced apoptosis by stabilizing p53 and suppressed cell viability, colony formation, migration and invasion in cervical cancer HeLa and breast cancer MCF7 cells with wild-type p53 (wtp53), whereas CCDC106 overexpression exerted the opposite effects in normal breast epithelial HBL100 and cervical cancer SiHa cells with wtp53. However, CCDC106 had no similar effects on p53-mutant cervical and breast cancer cells (C33A and MDA-MB-231). Further study showed that CK2 interacts with CCDC106 through its regulatory β subunit and then phosphorylates CCDC106 at Ser-130 and Ser-147. The phosphorylation of CCDC106 at Ser-130 and Ser-147 is required for its interaction with p53 and nuclear localization, respectively. Inhibiting CCDC106 phosphorylation by substituting both Ser-130 and Ser-147 with alanine or treating cells with the CK2 inhibitor CX-4945 abrogated CCDC106-induced p53 degradation and its oncogenic function in cells with wtp53. Wildtype CCDC106, but not Ser-130/− 147 mutant CCDC106, enhanced tumor growth and p53 degradation in a xenograft mouse model. Moreover, suppression of CCDC106 increased CX-4945 sensitivity of cancer cells with wtp53.ConclusionThis study revealed a CK2/CCDC106/p53 signaling axis in the progression of breast and cervical cancers, which may provide a new therapeutic target for cancer treatment.Electronic supplementary materialThe online version of this article (10.1186/s13046-019-1137-8) contains supplementary material, which is available to authorized users.

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The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market

David²,

2017

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Ten years after Fire and Melo's Nobel Prize for discovery of gene silencing by double-stranded RNA, a remarkable progress was achieved in RNA interference (RNAi). Changes in the chemical structure of synthetic oligonucleotides make them more stable and specific, and new delivery strategies became progressively available. The attention of pharmaceutical industry rapidly turned to RNAi, as an opportunity to explore new drug targets. This review addresses nine small-interfering RNAs (siRNAs) and one unique microRNA (miRNA) inhibitor, which entered the phase 2-3 clinical trials. The siRNAs in focus are PF-04523655, TKM-080301, Atu027, SYL040012, SYL1001, siG12D-LODER (phase 2), QPI-1002, QPI-1007, and patisiran (phase 3). Regarding miRNAs, their content can be down- or up-regulated, by using miRNA inhibitors (AntimiRs) or miRNA mimics. Miravirsen is an AntimiR-122 for hepatitis C virus infection. The flexibility of RNAi technology is easily understood taking into account: (i) the different drug targets (i.e. p53, caspase 2, PKN3, β2-adrenergic receptor, mutated KRAS, microRNAs); (ii) therapeutic conditions, including ophthalmic diseases, kidney injury, amyloidosis, pancreatic cancer, viral hepatitis; and (iii) routes of administration (ocular, intravenous, subcutaneous, intratumoral). Although some issues are still matters of concern (delivery, toxicity, cost, and biological barriers), RNAi definitively opens a wide avenue for drug development.

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In vivo siRNA distribution and pharmacokinetics assessed by nuclear imaging are modulated according to radiolabelling site

Cited by 3 publications

References 37 publications

Inhibition of DNA-repair genes Ercc1 and Mgmt enhances temozolomide efficacy in gliomas treatment: a pre-clinical study

Inhibition of DNA-repair genes Ercc1 and Mgmt enhances temozolomide efficacy in gliomas treatment: a pre-clinical study

CK2-mediated CCDC106 phosphorylation is required for p53 degradation in cancer progression

The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market

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