ArticlePloS one2013
Sequential dosing in chemosensitization: targeting the PI3K/Akt/mTOR pathway in neuroblastoma.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
32 citing papers in PubMed, 1 synthesis or guideline pooled it, 51 citations in OpenAlex.
- Meta analysis of bioactive compounds, miRNA, siRNA and cell death regulators as sensitizers to doxorubicin induced chemoresistance.Apoptosis : an international journal on programmed cell death · 2022Pooled it
- Targeting the ubiquitin-proteasome system: a novel therapeutic strategy for neuroblastoma.Frontiers in oncology · 2024Review
- Synergistic anti-proliferative and apoptotic effect of NVP-BEZ235 and curcumin on human SH-SY5Y neuroblastoma cells.Medical oncology (Northwood, London, England) · 2023Article
- Lidocaine promotes apoptosis in breast cancer cells by affecting VDAC1 expression.BMC anesthesiology · 2022Article
- Article
- Response Predictive Markers and Synergistic Agents for Drug Repositioning of Statins in Ovarian Cancer.Pharmaceuticals (Basel, Switzerland) · 2022Article
- The MicroRNA-Based Strategies to Combat Cancer ChemoresistanceFrontiers in oncology · 2022Review
- P2X7 receptor isoform B is a key drug resistance mediator for neuroblastoma.Frontiers in oncology · 2022Article
- The role of long non-coding RNAs in mediating chemoresistance by modulating autophagy in cancer.RNA biology · 2020Article
- Inhibition of PI3K signalling increases the efficiency of radiotherapy in glioblastoma cells.International journal of oncology · 2018Article
- Precision medicine in pediatric oncology.Molecular and cellular pediatrics · 2018Review
- miR‑21‑5p confers doxorubicin resistance in gastric cancer cells by targeting PTEN and TIMP3.International journal of molecular medicine · 2018Article
- Cell death-based treatment of childhood cancer.Cell death & disease · 2018Review
- Cell death-based treatment of neuroblastoma.Cell death & disease · 2018Review
- Delayed Sequential Co-Delivery of Gefitinib and Doxorubicin for Targeted Combination Chemotherapy.Molecular pharmaceutics · 2017Article
- The effects of PI3K-mediated signalling on glioblastoma cell behaviour.Oncogenesis · 2017Article
- p53 Nongenotoxic Activation and mTORC1 Inhibition Lead to Effective Combination for Neuroblastoma Therapy.Clinical cancer research : an official journal of the American Association for Cancer Research · 2017Article
- Silencing Intersectin 1 Slows Orthotopic Neuroblastoma Growth in Mice.Journal of pediatric hematology/oncology · 2017Article
- A signaling visualization toolkit to support rational design of combination therapies and biomarker discovery: SiViT.Oncotarget · 2017Article
- Neuroblastoma treatment in the post-genomic era.Journal of biomedical science · 2017Review
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Breaking resistance to chemotherapy is a major goal of combination therapy in many tumors, including advanced neuroblastoma. We recently demonstrated that increased activity of the PI3K/Akt network is associated with poor prognosis, thus providing an ideal target for chemosensitization. Here we show that targeted therapy using the PI3K/mTOR inhibitor NVP-BEZ235 significantly enhances doxorubicin-induced apoptosis in neuroblastoma cells. Importantly, this increase in apoptosis was dependent on scheduling: while pretreatment with the inhibitor reduced doxorubicin-induced apoptosis, the sensitizing effect in co-treatment could further be increased by delayed addition of the inhibitor post chemotherapy. Desensitization for doxorubicin-induced apoptosis seemed to be mediated by a combination of cell cycle-arrest and autophagy induction, whereas sensitization was found to occur at the level of mitochondria within one hour of NVP-BEZ235 posttreatment, leading to a rapid loss of mitochondrial membrane potential with subsequent cytochrome c release and caspase-3 activation. Within the relevant time span we observed marked alterations in a ∼30 kDa protein associated with mitochondrial proteins and identified it as VDAC1/Porin protein, an integral part of the mitochondrial permeability transition pore complex. VDAC1 is negatively regulated by the PI3K/Akt pathway via GSK3β and inhibition of GSK3β, which is activated when Akt is blocked, ablated the sensitizing effect of NVP-BEZ235 posttreatment. Our findings show that cancer cells can be sensitized for chemotherapy induced cell death - at least in part - by NVP-BEZ235-mediated modulation of VDAC1. More generally, we show data that suggest that sequential dosing, in particular when multiple inhibitors of a single pathway are used in the optimal sequence, has important implications for the general design of combination therapies involving molecular targeted approaches towards the PI3K/Akt/mTOR signaling network.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.