Dexamethasone alleviates pemetrexed-induced senescence in Non-Small-Cell Lung Cancer

Ge, Heng; Ke, Jun; Xu, Nuo; Li, Hongqing; Gong, Jin; Li, Xiangyang; Song, Yuanlin; Zhu, Huili; Bai, Chunxue

doi:10.1016/j.fct.2018.05.025

Cited by 19 publications

(13 citation statements)

References 49 publications

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“…Treatment with the broad anti-inflammatory drug dexamethasone, however, induced proliferation, exemplary inhibition of the IL1 pathway, and suppression of the SASP in DKFZ-BT66 cells in OIS. These results are in line with previously published data indicating that the SASP is inhibited by glucocorticoids (50,51). As dexamethasone is a drug commonly used in pediatric clinical practice, this result is potentially of high clinical relevance.…”

Section: Il1b But Not Il6 Signaling Reduces Proliferation Of Pilocysupporting

confidence: 92%

“…As inhibition of single SASP factors did not suffice to overcome growth arrest of pilocytic astrocytoma cells in OIS, we attempted to bypass OIS by treatment with dexamethasone, a broad antiinflammatory drug, known to inhibit the SASP (50,51). Treatment of senescent DKFZ-BT66 cells with 100 nmol/L dexamethasone for 20 days resulted in a significant increase in cell proliferation compared with solvent control (Fig.…”

Section: Il1b But Not Il6 Signaling Reduces Proliferation Of Pilocymentioning

confidence: 99%

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The Senescence-associated Secretory Phenotype Mediates Oncogene-induced Senescence in Pediatric Pilocytic Astrocytoma

Buhl

Selt

Hielscher

et al. 2019

Clinical Cancer Research

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Purpose: Pilocytic astrocytoma is the most common childhood brain tumor, characterized by constitutive MAPK activation. MAPK signaling induces oncogene-induced senescence (OIS), which may cause unpredictable growth behavior of pilocytic astrocytomas. The senescence-associated secretory phenotype (SASP) has been shown to regulate OIS, but its role in pilocytic astrocytoma remains unknown.Experimental Design: The patient-derived pilocytic astrocytoma cell culture model, DKFZ-BT66, was used to demonstrate presence of the SASP and analyze its impact on OIS in pilocytic astrocytoma. The model allows for doxycyclineinducible switching between proliferation and OIS. Both states were studied using gene expression profiling (GEP), Western blot, ELISA, and cell viability testing. Primary pilocytic astrocytoma tumors were analyzed by GEP and multiplex assay.Results: SASP factors were upregulated in primary human and murine pilocytic astrocytoma and during OIS in DKFZ-BT66 cells. Conditioned medium induced growth arrest of proliferating pilocytic astrocytoma cells. The SASP factors IL1B and IL6 were upregulated in primary pilocytic astrocytoma, and both pathways were regulated during OIS in DKFZ-BT66. Stimulation with rIL1B but not rIL6 reduced growth of DKFZ-BT66 cells and induced the SASP. Anti-inflammatory treatment with dexamethasone induced regrowth of senescent cells and inhibited the SASP. Senescent DKFZ-BT66 cells responded to senolytic BCL2 inhibitors. High IL1B and SASP expression in pilocytic astrocytoma tumors was associated with favorable progression-free survival.Conclusions: We provide evidence for the SASP regulating OIS in pediatric pilocytic astrocytoma, with IL1B as a relevant mediator. SASP expression could enable prediction of progression in patients with pilocytic astrocytoma. Further investigation of the SASP driving the unpredictable growth of pilocytic astrocytomas, and its possible therapeutic application, is warranted.

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Section: Il1b But Not Il6 Signaling Reduces Proliferation Of Pilocysupporting

confidence: 92%

Section: Il1b But Not Il6 Signaling Reduces Proliferation Of Pilocymentioning

confidence: 99%

The Senescence-associated Secretory Phenotype Mediates Oncogene-induced Senescence in Pediatric Pilocytic Astrocytoma

Buhl

Selt

Hielscher

et al. 2019

Clinical Cancer Research

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“…In NSCLC cells it was shown to inhibit TGF-β1-induced migration as well as EMT via the AKT/ERK signaling pathways [ 89 ], suggesting a modulatory effect on CSC properties. Nevertheless, dexamethasone is also suggested to impair chemotherapy efficacy, as co-administration was shown to decrease chemosensitivity in NSCLC xenograft models [ 90 ]. Next to dexamethasone, PDTC is commonly known to inhibit the IkBα degradation and p65 nuclear import [ 91 ], and was likewise shown to reduce survival of NSCLC-derived LCSC-like cells in the present study.…”

Section: Discussionmentioning

confidence: 99%

Novel Primary Human Cancer Stem-Like Cell Populations from Non-Small Cell Lung Cancer: Inhibition of Cell Survival by Targeting NF-κB and MYC Signaling

Windmöller

Beshay²,

Helweg

et al. 2021

Cells

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There is growing evidence that cancer stem cells (CSCs), a small subpopulation of self-renewal cancer cells, are responsible for tumor growth, treatment resistance, and cancer relapse and are thus of enormous clinical interest. Here, we aimed to isolate new CSC-like cells derived from human primary non-small cell lung cancer (NSCLC) specimens and to analyze the influence of different inhibitors of NF-κB and MYC signaling on cell survival. CSC-like cells were established from three squamous cell carcinomas (SCC) and three adenocarcinomas (AC) of the lung and were shown to express common CSC markers such as Prominin-1, CD44-antigen, and Nestin. Further, cells gave rise to spherical cancer organoids. Inhibition of MYC and NF-κB signaling using KJ-Pyr-9, dexamethasone, and pyrrolidinedithiocarbamate resulted in significant reductions in cell survival for SCC- and AC-derived cells. However, inhibition of the protein–protein interaction of MYC/NMYC proto-oncogenes with Myc-associated factor X (MAX) using KJ-Pyr-9 revealed the most promising survival-decreasing effects. Next to the establishment of six novel in vitro models for studying NSCLC-derived CSC-like populations, the presented investigations might provide new insights into potential novel therapies targeting NF-κB/MYC to improve clinical outcomes in NSCLC patients. Nevertheless, the full picture of downstream signaling still remains elusive.

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“…In support of a role for p53 in mediating methotrexate-induced senescence, we had shown that MCF-7 breast tumor cells with attenuated p53 function were growth-arrested in response to methotrexate exposure, but did not express other markers associated with the senescent phenotype [76]. Pemetrexed, another important antifolate used for the treatment of blood, breast and lung malignancies, is also capable of inducing senescence and SASP in a variety of cancer cell lines in vitro [77,78].…”

Section: Antimetabolitesmentioning

confidence: 94%

“…Platinum-based Cisplatin A375, B16F10, B16F10 xenografts SASP, SA-β-gal [64] A2780 SAHF (HP1-γ), morphology, SA-β-gal [68] CNE1 Growth arrest, morphology, SA-β-gal [30] SKOV3, TOV-21G Morphology, SA-β-gal [69] HepG2, SMMC-7721 SA-β-gal, p53, p21 Cip1 , p16 INK4 [70] Follicular lymphoma 3D model SA-β-gal [49] In vivo mouse model (p16-3MR) p16 INK4 [28] Carboplatin H1299, patients' lung tumor samples Cell cycle arrest, SA-β-gal, p16 INK4 , RB, downregulation of cyclin B1 and cyclin D1 [71] Oxaliplatin PROb, CT26 SA-β-gal [72] HepG2, SMMC-7721, patients' colorectal tumor samples SA-β-gal [73] Antimetabolites Methotrexate C85 p53 [74] C85 SA-β-gal [75] MCF-7 SA-β-gal [76] Rat-derived BMSCs and ADSCs SA-β-gal [42] A549 p21 Cip1 , low Ki67, growth arrest, SA-β-gal, increased granularity, morphology, SASP (IL-6, IL-8), γH2AX [43] SH-SY-5Y p21 Cip1 , growth arrest, SA-β-gal, γH2AX [43] HCT116 p21 Cip1 , low Ki67, growth arrest, SA-β-gal, increased granularity, morphology, SASP (IL-8), γH2AX [43] MDA-MB-231 p21 Cip1 , growth arrest, SA-β-gal, morphology, SASP (IL-6, IL-8, VEGF) [43] MCF-7 p21 Cip1 , low Ki67, growth arrest, SA-β-gal, increased granularity, morphology, γH2AX [43] Pemetrexed H1650, A549, H2228, H292, H226 and H1650, A549 xenografts SA-β-gal, morphology, SASP (IL-6, IL-8, IL-1β and MCP-1) [77] A549 SASP, SA-β-gal [78] Gemcitabine Miapaca-2 and Panc-1 SA-β-gal [79] AsPc1, Panc1 SA-β-gal [80] Azacitidine U2OS, MCF7 SA-β-gal, p53, growth arrest [81] TPC-1 SA-β-gal [82] KKU100, HuCCA1, RMCCA1 Morphology, SA-β-gal [83] DU145, LNCaP Morphology, growth arrest, polyploidy [40] Bromodeoxyuridine MNA, STA-NB-10, CLB-Ma mouse xenograft (MYCN-amplified neuroblastoma)…”

Section: Drug Class Drug Name Model/cell Line Senescence Marker Refermentioning

confidence: 99%

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Saleh

Bloukh

Carpenter

et al. 2020

Cancers

208

150

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For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. However, a number of other forms of therapy have also been shown to induce senescence in tumor cells independently of direct genomic damage. This review attempts to provide a comprehensive summary of both conventional and targeted anticancer therapeutics that have been shown to induce senescence in vitro and in vivo. Still, the utility of promoting senescence as a therapeutic endpoint remains under debate. Since senescence represents a durable form of growth arrest, it might be argued that senescence is a desirable outcome of cancer therapy. However, accumulating evidence suggesting that cells have the capacity to escape from TIS would support an alternative conclusion, that senescence provides an avenue whereby tumor cells can evade the potentially lethal action of anticancer drugs, allowing the cells to enter a temporary state of dormancy that eventually facilitates disease recurrence, often in a more aggressive state. Furthermore, TIS is now strongly connected to tumor cell remodeling, potentially to tumor dormancy, acquiring more ominous malignant phenotypes and accounts for several untoward adverse effects of cancer therapy. Here, we argue that senescence represents a barrier to effective anticancer treatment, and discuss the emerging efforts to identify and exploit agents with senolytic properties as a strategy for elimination of the persistent residual surviving tumor cell population, with the goal of mitigating the tumor-promoting influence of the senescent cells and to thereby reduce the likelihood of cancer relapse.

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Dexamethasone alleviates pemetrexed-induced senescence in Non-Small-Cell Lung Cancer

Cited by 19 publications

References 49 publications

The Senescence-associated Secretory Phenotype Mediates Oncogene-induced Senescence in Pediatric Pilocytic Astrocytoma

The Senescence-associated Secretory Phenotype Mediates Oncogene-induced Senescence in Pediatric Pilocytic Astrocytoma

Novel Primary Human Cancer Stem-Like Cell Populations from Non-Small Cell Lung Cancer: Inhibition of Cell Survival by Targeting NF-κB and MYC Signaling

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

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