Precision delivery of RAS-inhibiting siRNA to pancreatic cancer via peptide-based nanoparticles.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 287-287 ◽  
Author(s):  
Matthew S. Strand ◽  
Hua Pan ◽  
Bradley Krasnick ◽  
Xiuli Zhang ◽  
Peter S. Goedegebuure ◽  
...  
Keyword(s):  
Cell Death ◽  
Fluorescence Microscopy ◽  
Cell Viability ◽  
Imaging System ◽  
Sirna Delivery ◽  
Ph Sensing ◽  
Stromal Component ◽  
Cancer Types

287 Background: Greater than 95% of pancreatic adenocarcinomas (PDACs) are driven by KRAS activation; yet, despite decades of work, no RAS inhibitors have reached the clinic. Furthermore, the delivery of therapeutic agents of any kind to PDAC has been hindered by the extensive desmoplasia that accompanies these tumors. Herein, we show that serum-stable and pH-sensing nanoparticles (NPs) are taken up by PDAC cells, can deliver KRAS-specific siRNA into the cytoplasm and inhibit KRAS expression, thereby causing cell death. We go on to use a spontaneous model of pancreas cancer to show that this system can effectively deliver siRNA to stroma-rich tumors. Methods: The murine PDAC cell line KP1 was tested for NP uptake in vitro utilizing fluorescent siRNA NPs (fNPs) in combination with confocal microscopy and flow cytometry. KP1 cells were treated with KRAS-siRNA NP, and KRAS expression and cell viability were assessed with RT-PCR and CellTiter-Glo, respectively. Mice bearing subcutaneous KP1 tumors and KPPC mice with spontaneous PDAC were injected with fNP, and tumor fluorescence was assessed using an in vivo imaging system and fluorescence microscopy. Results: KP1 cells take up fNP in vitro, with > 99% of cells positive for fluorescent signal at 24 hours. Treatment with KRAS-siRNA NP of KP1 cells reduced KRAS expression by 69% (see Figure) and reduced cell viability by 45% compared to untreated and scramble-siRNA treated controls. Gemcitabine demonstrated an additive effect with anti-KRAS therapy. Tumors from KP1 cells grown in mice, and tumors from KPPC mice, were strongly fluorescent 24 hours after IV injection of fNP. Fluorescence microscopy showed successful delivery of fNP to tumors. Conclusions: Our NP system can precisely deliver siRNA to KP1 cells and spontaneous PDAC, overcoming the predominant stromal component in these tumors. KRAS-siRNA delivery downregulates KRAS expression, leading to cell death. This represents a novel treatment for PDAC. Furthermore, with its ability to deliver siRNA into the tumor microenvironment and suppress a known oncogene, this platform could be used to target other putative drivers of tumor progression across various cancer types.

scholarly journals Pyrrolizidine Alkaloids Induce Cell Death in Human HepaRG Cells in a Structure-Dependent Manner

2020 ◽  
Vol 22 (1) ◽  
pp. 202
Author(s):  
Josephin Glück ◽  
Julia Waizenegger ◽  
Albert Braeuning ◽  
Stefanie Hessel-Pras
Keyword(s):  
Cell Death ◽  
Cell Viability ◽  
Pyrrolizidine Alkaloids ◽  
Defense Mechanism ◽  
Hepatoma Cell ◽  
Hepatoma Cell Line ◽  
Dependent Manner ◽  
Human Hepatoma Cell

Pyrrolizidine alkaloids (PAs) are a group of secondary metabolites produced in various plant species as a defense mechanism against herbivores. PAs consist of a necine base, which is esterified with one or two necine acids. Humans are exposed to PAs by consumption of contaminated food. PA intoxication in humans causes acute and chronic hepatotoxicity. It is considered that enzymatic PA toxification in hepatocytes is structure-dependent. In this study, we aimed to elucidate the induction of PA-induced cell death associated with apoptosis activation. Therefore, 22 structurally different PAs were analyzed concerning the disturbance of cell viability in the metabolically competent human hepatoma cell line HepaRG. The chosen PAs represent the main necine base structures and the different esterification types. Open-chained and cyclic heliotridine- and retronecine-type diesters induced strong cytotoxic effects, while treatment of HepaRG with monoesters did not affect cell viability. For more detailed investigation of apoptosis induction, comprising caspase activation and gene expression analysis, 14 PA representatives were selected. The proapoptotic effects were in line with the potency observed in cell viability studies. In vitro data point towards a strong structure–activity relationship whose effectiveness needs to be investigated in vivo and can then be the basis for a structure-associated risk assessment.

scholarly journals Docosahexaenoic Acid Enhances Oxaliplatin-Induced Autophagic Cell Death via the ER Stress/Sesn2 Pathway in Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 982 ◽  
Author(s):  
Soyeon Jeong ◽  
Dae Yeong Kim ◽  
Sang Hee Kang ◽  
Hye Kyeong Yun ◽  
Jung Lim Kim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Docosahexaenoic Acid ◽  
Cell Viability ◽  
Er Stress ◽  
Autophagic Cell Death ◽  
Omega 3 ◽  
Antitumor Effects

Oxaliplatin is an anticancer drug administered to colorectal cancer (CRC) patients in combination with 5-fluorouracil and antibodies (bevacizumab and cetuximab), thereby significantly improving the survival rate of CRC. However, due to various side effects associated with the above treatment strategy, the need for combinatorial therapeutic strategies has emerged. Based on the demand for new combinatorial therapies and the known antitumor effects of the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), we investigated the Oxaliplatin and DHA combination for its effect. Our results indicated that DHA further enhanced Oxaliplatin-induced cell viability and autophagic cell death, in vitro and in vivo. Oxaliplatin and DHA also increased the expression of Sestrin 2 (SESN2) and endoplasmic reticulum (ER) stress related C/EBP homologous protein (CHOP). Additionally, treatment with Oxaliplatin and DHA enhanced the binding of CHOP to the promotor region of SESN2, increasing SESN2 expression. These results suggested that DHA enhanced Oxaliplatin-induced reduction in cell viability and increase in autophagy via activating SESN2 and increasing ER stress. Thus, SESN2 may be an effective preclinical target for CRC treatment.

Striking Anti-Multiple Myeloma (MM) Activity with the In Vitro Use of the Multikinase Inhibitor Sorafenib (S), Cytotoxic Synergy Between Bortezomib (B) and S, but Not Between B and Epigallocatechin-3-Gallate (EGCG; E) Enlarge the Present Knowledge In MM and Promise Novel Insights for Innovative Substance Exploitation In MM-Treatment

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5020-5020
Author(s):  
Josefina Udi ◽  
Dagmar Wider ◽  
Julie Catusse ◽  
Gabriele Ihorst ◽  
Dominik Schnerch ◽  
...  
Keyword(s):  
Cell Death ◽  
Confocal Microscopy ◽  
Tumor Cell ◽  
Cell Viability ◽  
Present Knowledge ◽  
Tumor Cell Lines ◽  
Multikinase Inhibitor ◽  
Morphologic Changes

Abstract Abstract 5020 Introduction: As the development of novel anti-MM therapies is pursued worldwide in order to further improve survival in this disease, various innovative agents have to be eagerly tested in in vitro and in vivo models; the former being applied here. Bortezomib (B) has been shown to induce cell death in MMCLs and cytotoxic synergy with sorafenib (S) on various tumor cell lines. S, an oral multikinase inhibitor, targets several cancer-specific pathways and directly affects tumor cell proliferation, cell survival and neovascularization. EGCG (E), one main green tea constituent, causes MM cell toxicity also, but seems to prevent tumor cell death induced by B in vitro and in vivo, this extend not being fully understood as yet. Methods: RPMI8226, U266 and L363 were cultured with RPMI1640/10% FCS. On day (d) 0, cells were treated with increasing concentrations of B, S and/or E. Cell viability and cytotoxicity were assessed on d3 and d6 via trypan blue and PI-staining. CD138 expression and morphologic changes were evaluated via FACS, immunocytochemistry and confocal microscopy. The effect of S on the chemotactic behaviour of L363 in response to conditioned media (CM = supernatant of M210B4 stromal cells) using 96-well chemotaxis chamber plates was also evaluated. Phosphorylation of ERK1/2 was determined by Western blot. The combined effect of S and B was determined using Calcusyn software: the resulting combination index (CI) defines additive effects (CI=1), synergism (CI<1) and antagonism (CI>1). Results: With 10 and 100μM S in L363, we observed increased median PI+ cells (62% and 94% on d3, respectively) as compared to the control (median PI+ d0: 11%), with similar increases on d6 (median 81% and 92%, respectively). In line with PI-observations, viable cells and CD138 expression substantially decreased in a dose- and time-dependent manner. After 3 days pre-incubation with increasing S-concentrations, MM cells were stained with Dapi, Phalloidin-Alexa-549 and CD138-FITC and analyzed by confocal microscopy: L363 cells highly expressed CD138 in the absence of S, whereas impressive CD138 downregulation, morphologic changes and reduction of F-actin content were observed with S-concentrations as low as 1μM. L363 cells exhibited a migratory response to CM, whereas after 3 days of preincubation with 10, 20 and 50μM S, L363 cells showed reduced migratory capacity in response to CM. Western blots showed a decrease in p-ERK1/2 expression levels after 24h inbubation of L363 cells with 10μM S. With 100nM B, PI in L363 increased from 11% on d0 to 84% on d3, albeit not as pronounced with 10nM B as was observed with 10μM S. E induced cytotoxicity in L363, particularly with 50 and 100μM, albeit - different to prior reports - B-induced cell death was preserved when the B-E-combination was tested: of note, however, after addition of increasing E-concentrations, no synergism or additive effect, rather than a plateau cytotoxic effect was observed. Combined B and S use showed synergism with 10nM and 10μM, respectively (CI=0.80). MMCLs stably co-expressing fluorescently labelled cytochrome C and histone H2 will allow the detection of induced apoptosis using live-cell imaging after anti-MM agent treatment. Conclusions: Our MM-based in vitro model revealed that B and S show remarkable therapeutic efficacy as single agents and synergism when combined, which confirms results in other tumor cell lines. E alone induced dose-dependent cell death and decreases in MM cell viability and when combined with B did neither synergize nor abolish B-induced cell death. Our results further enlarge the present knowledge in MM therapy and promise novel insights for innovative substances in the treatment of MM. Disclosures: No relevant conflicts of interest to declare.

Multi-mode light microscopy of microtubule assembly dynamics and chromosome movement in vivo and In vitro

1996 ◽  
Vol 54 ◽  
pp. 730-731
Author(s):  
E. D. Salmon ◽  
J. C. Waters ◽  
C. Waterman-Storer
Keyword(s):  
Imaging System ◽  
Ccd Camera ◽  
Transmitted Light ◽  
Microtubule Assembly ◽  
Live Cells ◽  
Optical Efficiency ◽  
Multiple Band ◽  
Multi Mode

We have developed a multi-mode digital imaging system which acquires images with a cooled CCD camera (Figure 1). A multiple band pass dichromatic mirror and robotically controlled filter wheels provide wavelength selection for epi-fluorescence. Shutters select illumination either by epi-fluorescence or by transmitted light for phase contrast or DIC. Many of our experiments involve investigations of spindle assembly dynamics and chromosome movements in live cells or unfixed reconstituted preparations in vitro in which photodamage and phototoxicity are major concerns. As a consequence, a major factor in the design was optical efficiency: achieving the highest image quality with the least number of illumination photons. This principle applies to both epi-fluorescence and transmitted light imaging modes. In living cells and extracts, microtubules are visualized using X-rhodamine labeled tubulin. Photoactivation of C2CF-fluorescein labeled tubulin is used to locally mark microtubules in studies of microtubule dynamics and translocation. Chromosomes are labeled with DAPI or Hoechst DNA intercalating dyes.

In vivo Evaluation and Alzheimer’s Disease Treatment Outcome of siRNA Loaded Dual Targeting Drug Delivery System

2019 ◽  
Vol 20 (1) ◽  
pp. 56-62 ◽  
Author(s):  
Chi Zhang ◽  
Zhichun Gu ◽  
Long Shen ◽  
Xianyan Liu ◽  
Houwen Lin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Treatment Outcome ◽  
Neuroprotective Effect ◽  
Sirna Delivery ◽  
Repeated Administration ◽  
Spatial Learning And Memory ◽  
In Vivo Evaluation

Background: To deliver drugs to treat Alzheimer’s Disease (AD), nanoparticles should firstly penetrate through blood brain barrier, and then target neurons. Methods: Recently, we developed an Apo A-I and NL4 dual modified nanoparticle (ANNP) to deliver beta-amyloid converting enzyme 1 (BACE1) siRNA. Although promising in vitro results were obtained, the in vivo performance was not clear. Therefore, in this study, we further evaluated the in vivo neuroprotective effect and toxicity of the ANNP/siRNA. The ANNP/siRNA was 80.6 nm with good stability when incubated with serum. In vivo, the treatment with ANNP/siRNA significantly improves the spatial learning and memory of APP/PS1 double transgenic mice, as determined by mean escape latency, times of crossing the platform area during the 60 s swimming and the percentage of the distance in the target quadrant. Results and Conclusion: After the treatment, BACE1 RNA level of ANNP/siRNA group was greatly reduced, which contributed a good AD treatment outcome. Finally, after repeated administration, the ANNP/siRNA did not lead to significant change as observed by HE staining of main organs, suggesting the good biocompatibility of ANNP/siRNA. These results demonstrated that the ANNP was a good candidate for AD targeting siRNA delivery.

Stew in its Own Juice: Protein Homeostasis Machinery Inhibition Reduces Cell Viability in Multiple Myeloma Cell Lines

2019 ◽  
Vol 19 (2) ◽  
pp. 112-119 ◽  
Author(s):  
Mariana B. de Oliveira ◽  
Luiz F.G. Sanson ◽  
Angela I.P. Eugenio ◽  
Rebecca S.S. Barbosa-Dantas ◽  
Gisele W.B. Colleoni
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Cell Viability ◽  
Cell Lines ◽  
Treatment Options ◽  
Compensatory Mechanism ◽  
Protein Homeostasis ◽  
Protein Response ◽  
Rpmi 8226

Introduction:Multiple myeloma (MM) cells accumulate in the bone marrow and produce enormous quantities of immunoglobulins, causing endoplasmatic reticulum stress and activation of protein handling machinery, such as heat shock protein response, autophagy and unfolded protein response (UPR).Methods:We evaluated cell lines viability after treatment with bortezomib (B) in combination with HSP70 (VER-15508) and autophagy (SBI-0206965) or UPR (STF- 083010) inhibitors.Results:For RPMI-8226, after 72 hours of treatment with B+VER+STF or B+VER+SBI, we observed 15% of viable cells, but treatment with B alone was better (90% of cell death). For U266, treatment with B+VER+STF or with B+VER+SBI for 72 hours resulted in 20% of cell viability and both treatments were better than treatment with B alone (40% of cell death). After both triplet combinations, RPMI-8226 and U266 presented the overexpression of XBP-1 UPR protein, suggesting that it is acting as a compensatory mechanism, in an attempt of the cell to handle the otherwise lethal large amount of immunoglobulin overload.Conclusion:Our in vitro results provide additional evidence that combinations of protein homeostasis inhibitors might be explored as treatment options for MM.

scholarly journals MSCs-engineered biomimetic PMAA nanomedicines for multiple bioimaging-guided and photothermal-enhanced radiotherapy of NSCLC

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yipengchen Yin ◽  
Yongjing Li ◽  
Sheng Wang ◽  
Ziliang Dong ◽  
Chao Liang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Membranes ◽  
Imaging System ◽  
Fluorescence Signal ◽  
Bimodal Imaging ◽  
Red Blood Cell Membranes ◽  
Magnetic Resonance Imaging Mri ◽  
Tumor Accumulation

Abstract Background The recently developed biomimetic strategy is one of the mostly effective strategies for improving the theranostic efficacy of diverse nanomedicines, because nanoparticles coated with cell membranes can disguise as “self”, evade the surveillance of the immune system, and accumulate to the tumor sites actively. Results Herein, we utilized mesenchymal stem cell memabranes (MSCs) to coat polymethacrylic acid (PMAA) nanoparticles loaded with Fe(III) and cypate—an derivative of indocyanine green to fabricate Cyp-PMAA-Fe@MSCs, which featured high stability, desirable tumor-accumulation and intriguing photothermal conversion efficiency both in vitro and in vivo for the treatment of lung cancer. After intravenous administration of Cyp-PMAA-Fe@MSCs and Cyp-PMAA-Fe@RBCs (RBCs, red blood cell membranes) separately into tumor-bearing mice, the fluorescence signal in the MSCs group was 21% stronger than that in the RBCs group at the tumor sites in an in vivo fluorescence imaging system. Correspondingly, the T1-weighted magnetic resonance imaging (MRI) signal at the tumor site decreased 30% after intravenous injection of Cyp-PMAA-Fe@MSCs. Importantly, the constructed Cyp-PMAA-Fe@MSCs exhibited strong photothermal hyperthermia effect both in vitro and in vivo when exposed to 808 nm laser irradiation, thus it could be used for photothermal therapy. Furthermore, tumors on mice treated with phototermal therapy and radiotherapy shrank 32% more than those treated with only radiotherapy. Conclusions These results proved that Cyp-PMAA-Fe@MSCs could realize fluorescence/MRI bimodal imaging, while be used in phototermal-therapy-enhanced radiotherapy, providing desirable nanoplatforms for tumor diagnosis and precise treatment of non-small cell lung cancer.

scholarly journals EXTH-46. ARTIFICIAL INTELLIGENCE-BASED IDENTIFICATION OF COMBINED VANDETANIB AND EVEROLIMUS IN THE TREATMENT OF ACVR1-MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii97-ii97
Author(s):  
Diana Carvalho ◽  
Peter Richardson ◽  
Nagore Gene Olaciregui ◽  
Reda Stankunaite ◽  
Cinzia Emilia Lavarino ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Cell Viability ◽  
Xenograft Model ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Serine Threonine Kinase ◽  
Orthotopic Xenografts ◽  
Extended Survival

Abstract Somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2 receptor, are found in a quarter of children with the currently incurable brain tumour diffuse intrinsic pontine glioma (DIPG). Treatment of ACVR1-mutant DIPG patient-derived models with multiple inhibitor chemotypes leads to a reduction in cell viability in vitro and extended survival in orthotopic xenografts in vivo, though there are currently no specific ACVR1 inhibitors licensed for DIPG. Using an Artificial Intelligence-based platform to search for approved compounds which could be used to treat ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an approved inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (Kd=150nM) and reduce DIPG cell viability in vitro, but has been trialed in DIPG patients with limited success, in part due to an inability to cross the blood-brain-barrier. In addition to mTOR, everolimus inhibits both ABCG2 (BCRP) and ABCB1 (P-gp) transporter, and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination is well-tolerated in vivo, and significantly extended survival and reduced tumour burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Based on these preclinical data, three patients with ACVR1-mutant DIPG were treated with vandetanib and everolimus. These cases may inform on the dosing and the toxicity profile of this combination for future clinical studies. This bench-to-bedside approach represents a rapidly translatable therapeutic strategy in children with ACVR1 mutant DIPG.

scholarly journals TNF-α Triggers RIP1/FADD/Caspase-8-Mediated Apoptosis of Astrocytes and RIP3/MLKL-Mediated Necroptosis of Neurons Induced by Angiostrongylus cantonensis Infection

2021 ◽  
Author(s):  
Hongli Zhou ◽  
Minyu Zhou ◽  
Yue Hu ◽  
Yanin Limpanon ◽  
Yubin Ma ◽  
...  
Keyword(s):  
Cell Death ◽  
Enrichment Analysis ◽  
Angiostrongylus Cantonensis ◽  
Gene Set Enrichment Analysis ◽  
Caspase 8 ◽  
Cns Injury ◽  
Vitro Assay ◽  
Tnf Α

AbstractAngiostrongylus cantonensis (AC) can cause severe eosinophilic meningitis or encephalitis in non-permissive hosts accompanied by apoptosis and necroptosis of brain cells. However, the explicit underlying molecular basis of apoptosis and necroptosis upon AC infection has not yet been elucidated. To determine the specific pathways of apoptosis and necroptosis upon AC infection, gene set enrichment analysis (GSEA) and protein–protein interaction (PPI) analysis for gene expression microarray (accession number: GSE159486) of mouse brain infected by AC revealed that TNF-α likely played a central role in the apoptosis and necroptosis in the context of AC infection, which was further confirmed via an in vivo rescue assay after treating with TNF-α inhibitor. The signalling axes involved in apoptosis and necroptosis were investigated via immunoprecipitation and immunoblotting. Immunofluorescence was used to identify the specific cells that underwent apoptosis or necroptosis. The results showed that TNF-α induced apoptosis of astrocytes through the RIP1/FADD/Caspase-8 axis and induced necroptosis of neurons by the RIP3/MLKL signalling pathway. In addition, in vitro assay revealed that TNF-α secretion by microglia increased upon LSA stimulation and caused necroptosis of neurons. The present study provided the first evidence that TNF-α was secreted by microglia stimulated by AC infection, which caused cell death via parallel pathways of astrocyte apoptosis (mediated by the RIP1/FADD/caspase-8 axis) and neuron necroptosis (driven by the RIP3/MLKL complex). Our research comprehensively elucidated the mechanism of cell death after AC infection and provided new insight into targeting TNF-α signalling as a therapeutic strategy for CNS injury.

scholarly journals Impact of RARα and miR-138 on retinoblastoma etoposide resistance

Tumor Biology ◽  
2021 ◽  
Vol 43 (1) ◽  
pp. 11-26
Author(s):  
Maike Busch ◽  
Natalia Miroschnikov ◽  
Jaroslaw Thomas Dankert ◽  
Marc Wiesehöfer ◽  
Klaus Metz ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cell Lines ◽  
Cancer Progression ◽  
Treated Patient ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Gene Assay ◽  
The Impact

BACKGROUND: Retinoblastoma (RB) is the most common childhood eye cancer. Chemotherapeutic drugs such as etoposide used in RB treatment often cause massive side effects and acquired drug resistances. Dysregulated genes and miRNAs have a large impact on cancer progression and development of chemotherapy resistances. OBJECTIVE: This study was designed to investigate the involvement of retinoic acid receptor alpha (RARα) in RB progression and chemoresistance as well as the impact of miR-138, a potential RARα regulating miRNA. METHODS: RARα and miR-138 expression in etoposide resistant RB cell lines and chemotherapy treated patient tumors compared to non-treated tumors was revealed by Real-Time PCR. Overexpression approaches were performed to analyze the effects of RARα on RB cell viability, apoptosis, proliferation and tumorigenesis. Besides, we addressed the effect of miR-138 overexpression on RB cell chemotherapy resistance. RESULTS: A binding between miR-138 and RARα was shown by dual luciferase reporter gene assay. The study presented revealed that RARα is downregulated in etoposide resistant RB cells, while miR-138 is endogenously upregulated. Opposing RARα and miR-138 expression levels were detectable in chemotherapy pre-treated compared to non-treated RB tumor specimen. Overexpression of RARα increases apoptosis levels and reduces tumor cell growth of aggressive etoposide resistant RB cells in vitro and in vivo. Overexpression of miR-138 in chemo-sensitive RB cell lines partly enhances cell viability after etoposide treatment. CONCLUSIONS: Our findings show that RARα acts as a tumor suppressor in retinoblastoma and is downregulated upon etoposide resistance in RB cells. Thus, RARα may contribute to the development and progression of RB chemo-resistance.

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