Gene Expression Signature of Acquired Chemoresistance in Neuroblastoma Cells

Jèmaà, Mohamed; Sime, Wondossen; Abassi, Yasmin; Lasorsa, Vito Alessandro; Køhler, Julie Bonne; Michaelis, Martin; Činátl, Jindřich; Capasso, Mario; Massoumi, Ramin

doi:10.3390/ijms21186811

Cited by 5 publications

(8 citation statements)

References 39 publications

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“…Whereas the sensitive IMR-32 cells displayed very high basal ROS levels, the less-responsive cell lines exhibited only low basal ROS levels, suggesting that cells with a high degree of basal oxidative stress respond better to the treatment (Figure 2c). To test this assumption, we analyzed a vincristine resistant and vincristine non-resistant neuroblastoma cell line pair, generated through long-term cultivation of the parental cell line in vincristine or solvent containing medium [40]. Consistent with our hypothesis, the chemotherapy resistant cell model displayed significantly increased ROS-levels, and in turn increased APR-246 sensitivity, when compared to its chemotherapy non-resistant control counterpart (Figure 2d,e).…”

Section: Apr-246 Impairs Oxygene Species Elimination and Basal Reactive Oxygen Species Level Indicate Apr-246 Sensitivitysupporting

confidence: 53%

“…Vincristine resistant and non-resistant SK-N-BE(2)-C (passage 30 to 45, kindly provided by M. Michaelis, University of Kent, and J. Cinatl, Goethe University, Frankfurt am Main) were cultured using IMDM with L-Glutamine, 2 mM HEPES (Gibco, Thermo Fisher Scientific Inc., Waltham, MA, USA) supplemented with 10% FCS; for the resistant cells, 20 ng/mL vincristine was added to the medium. The cells were made to be resistant to vincristine-treatment through long-term cultivation in a vincristine containing medium [40].…”

Section: Cell Culturementioning

confidence: 99%

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Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma

Müller

Rösch

Najafi

et al. 2021

Cancers

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APR-246 (Eprenetapopt/PRIMA-1Met) is a very potent anti-cancer drug in clinical trials and was initially developed as a p53 refolding agent. As an alternative mode of action, the elevation of reactive oxygen species (ROS) has been proposed. Through an in silico analysis, we investigated the responses of approximately 800 cancer cell lines (50 entities; Cancer Therapeutics Response Portal, CTRP) to APR-246 treatment. In particular, neuroblastoma, lymphoma and acute lymphocytic leukemia cells were highly responsive. With gene expression data from the Cancer Cell Line Encyclopedia (CCLE; n = 883) and patient samples (n = 1643) from the INFORM registry study, we confirmed that these entities express low levels of SLC7A11, a previously described predictive biomarker for APR-246 responsiveness. Combining the CTRP drug response data with the respective CCLE gene expression profiles, we defined a novel gene signature, predicting the effectiveness of APR-246 treatment with a sensitivity of 90% and a specificity of 94%. We confirmed the predicted APR-246 sensitivity in 8/10 cell lines and in ex vivo cultures of patient samples. Moreover, the combination of ROS detoxification-impeding APR-246 with approved HDAC-inhibitors, known to elevate ROS, substantially increased APR-246 sensitivity in cell cultures and in vivo in two zebrafish neuroblastoma xenograft models. These data provide evidence that APR-246, in combination with HDAC-inhibitors, displays a novel potent targeted treatment option for neuroblastoma patients.

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Section: Apr-246 Impairs Oxygene Species Elimination and Basal Reactive Oxygen Species Level Indicate Apr-246 Sensitivitysupporting

confidence: 53%

Section: Cell Culturementioning

confidence: 99%

Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma

Müller

Rösch

Najafi

et al. 2021

Cancers

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“…We can explain the results summarised above in terms of clonal competition. Our calibrated parameters and the experimental data we used for calibration [ 27 , 28 ] indicate that the resistant clone has a lower proliferation rate (drug resistance lowers fitness when the drug is absent): resistance to VCR, which confers no advantage on the resistant cells in the absence of VCR, comes at the expense of growth. When a population comprises fully sensitive and VCR-resistant cells, using CPM at its MTD fully exploits the sensitive clone, which is fitter than the VCR-resistant clone in the presence of CPM, to stop the VCR-resistant clone from expanding, thus helping CPM kill the VCR-resistant cells.…”

Section: Resultsmentioning

confidence: 99%

“…The resistance levels with respect to vincristine and cyclophosphamide are denoted by i and j , respectively. In order to inform the model, experimental data regarding neuroblastoma cells’ responses to vincristine and cyclophosphamide were aggregated from different sources [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. First, armed with in vitro data about the growth kinetics of neuroblastoma cell lines with different levels of drug resistance, collected in the absence of treatment, we calibrated the growth rates (

).…”

Section: Quick Guide To Methodologymentioning

confidence: 99%

Mathematical Model of Clonal Evolution Proposes a Personalised Multi-Modal Therapy for High-Risk Neuroblastoma

Italia

Wertheim

Taschner‐Mandl

et al. 2023

Cancers

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Neuroblastoma is the most common extra-cranial solid tumour in children. Despite multi-modal therapy, over half of the high-risk patients will succumb. One contributing factor is the one-size-fits-all nature of multi-modal therapy. For example, during the first step (induction chemotherapy), the standard regimen (rapid COJEC) administers fixed doses of chemotherapeutic agents in eight two-week cycles. Perhaps because of differences in resistance, this standard regimen results in highly heterogeneous outcomes in different tumours. In this study, we formulated a mathematical model comprising ordinary differential equations. The equations describe the clonal evolution within a neuroblastoma tumour being treated with vincristine and cyclophosphamide, which are used in the rapid COJEC regimen, including genetically conferred and phenotypic drug resistance. The equations also describe the agents’ pharmacokinetics. We devised an optimisation algorithm to find the best chemotherapy schedules for tumours with different pre-treatment clonal compositions. The optimised chemotherapy schedules exploit the cytotoxic difference between the two drugs and intra-tumoural clonal competition to shrink the tumours as much as possible during induction chemotherapy and before surgical removal. They indicate that induction chemotherapy can be improved by finding and using personalised schedules. More broadly, we propose that the overall multi-modal therapy can be enhanced by employing targeted therapies against the mutations and oncogenic pathways enriched and activated by the chemotherapeutic agents. To translate the proposed personalised multi-modal therapy into clinical use, patient-specific model calibration and treatment optimisation are necessary. This entails a decision support system informed by emerging medical technologies such as multi-region sequencing and liquid biopsies. The results and tools presented in this paper could be the foundation of this decision support system.

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“…Main available treatment strategy for NB patients is chemotherapy followed by surgical resection. Cisplatin (DDP) and doxorubicin (ADM) are common chemotherapeutics for NB ( Jemaà et al, 2020 ). However, the clinical efficacy of these drugs is limited by chemoresistance, which is the main cause of the treatment failure in NB patients ( Rodrigo et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Cathepsin L promotes chemresistance to neuroblastoma by modulating serglycin

Ding²,

Huang³

et al. 2022

Front. Pharmacol.

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Cathepsin L (CTSL), a lysosomal acid cysteine protease, is found to play a critical role in chemosencitivity and tumor progression. However, the potential roles and molecular mechanisms of CTSL in chemoresistance in neuroblastoma (NB) are still unclear. In this study, the correlation between clinical characteristics, survival and CTSL expression were assessed in Versteeg dataset. The chemoresistant to cisplatin or doxorubicin was detected using CCK-8 assay. Western blot was employed to detect the expression of CTSL, multi-drug resistance proteins, autophagy-related proteins and apoptosis-related proteins in NB cells while knocking down CTSL. Lysosome staining was analyzed to access the expression levels of lysosomes in NB cells. The expression of apoptosis markers was analyzed with immunofluorescence. Various datasets were analyzed to find the potential protein related to CTSL. In addition, a subcutaneous tumor xenografts model in M-NSG mice was used to assess tumor response to CTSL inhibition in vivo. Based on the validation dataset (Versteeg), we confirmed that CTSL served as a prognostic marker for poor clinical outcome in NB patients. We further found that the expression level of CTSL was higher in SK-N-BE (2) cells than in IMR-32 cells. Knocking down CTSL reversed the chemoresistance in SK-N-BE (2) cells. Furthermore, combination of CTSL inhibition and chemotherapy potently blocked tumor growth in vivo. Mechanistically, CTSL promoted chemoresistance in NB cells by up-regulating multi-drug resistance protein ABCB1 and ABCG2, inhibiting the autophagy level and cell apoptpsis. Furthermore, we observed six datasets and found that Serglycin (SRGN) expression was positively associated with CTSL expresssion. CTSL could mediate chemoresistance by up-regulating SRGN expression in NB cells and SRGN expression was positively correlated with poor prognosis of NB patients. Taken together, our findings indicate that the CTSL promotes chemoresistance to cisplatin and doxorubicin by up-regulating the expression of multi-drug resistance proteins and inhibiting the autophagy level and cell apoptosis in NB cells. Thus, CTSL may be a therapeutic target for overcoming chemoresistant to cisplatin and doxorubicin in NB patients.

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Gene Expression Signature of Acquired Chemoresistance in Neuroblastoma Cells

Cited by 5 publications

References 39 publications

Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma

Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma

Mathematical Model of Clonal Evolution Proposes a Personalised Multi-Modal Therapy for High-Risk Neuroblastoma

Cathepsin L promotes chemresistance to neuroblastoma by modulating serglycin

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