Chemoresistance of Lung Cancer Cells: 2D and 3D In Vitro Models for Anticancer Drug Screening

Kaushik, Vivek; Yakisich, Juan Sebastián; Kulkarni, Yogesh; NeelamAzad,; Iyer, Anand Krishnan V.

doi:10.5772/intechopen.78946

Cited by 6 publications

(5 citation statements)

References 88 publications

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“…Conversely, Fingolimod induced reduced cell growth but only at the highest dose of 10 µM ( Figure S4D ). Moreover, 3D models have been shown to better mimic drug response and resistance and showed generally less drug sensitivity including in lung cancer models [ 50 , 51 , 52 ]. Such phenomena might participate to explain the observed difference in Fingolimod sensitivity between the 2D and 3D experiments.…”

Section: Resultsmentioning

confidence: 99%

Therapeutic Potential of Fingolimod and Dimethyl Fumarate in Non-Small Cell Lung Cancer Preclinical Models

Rupp

Debasly

Genest

et al. 2022

IJMS

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New therapies are required for patients with non-small cell lung cancer (NSCLC) for which the current standards of care poorly affect the patient prognosis of this aggressive cancer subtype. In this preclinical study, we aim to investigate the efficacy of Fingolimod, a described inhibitor of sphingosine-1-phosphate (S1P)/S1P receptors axis, and Dimethyl Fumarate (DMF), a methyl ester of fumaric acid, both already approved as immunomodulators in auto-immune diseases with additional expected anti-cancer effects. The impact of both drugs was analyzed with in vitro cell survival analysis and in vivo graft models using mouse and human NSCLC cells implanted in immunocompetent or immunodeficient mice, respectively. We demonstrated that Fingolimod and DMF repressed tumor progression without apparent adverse effects in vivo in three preclinical mouse NSCLC models. In vitro, Fingolimod did not affect either the tumor proliferation or the cytotoxicity, although DMF reduced tumor cell proliferation. These results suggest that Fingolimod and DMF affected tumor progression through different cellular mechanisms within the tumor microenvironment. Fingolimod and DMF might uncover potential therapeutic opportunities in NSCLC.

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Section: Resultsmentioning

confidence: 99%

Therapeutic Potential of Fingolimod and Dimethyl Fumarate in Non-Small Cell Lung Cancer Preclinical Models

Rupp

Debasly

Genest

et al. 2022

IJMS

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“…Spheroid cell cultures are useful models to mimic chemotherapeutic resistance in cancer and have been used to screen for more effective anticancer compounds and new drug combinations. − Several approaches to generating spheroids have been established, and evidence suggests that scaffold-free spheroid cultures, such as those used in the current study, preserve in vivo -like cell–cell interactions and nutrient gradients . Unlike monolayers, spheroid cells can also reflect tumor-like differences in cell layers that may consist of proliferating, quiescent, and/or necrotic cells .…”

Section: Discussionmentioning

confidence: 99%

Proteomic Changes in the Monolayer and Spheroid Melanoma Cell Models of Acquired Resistance to BRAF and MEK1/2 Inhibitors

et al. 2022

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Extracellular signal-regulated kinase-1/2 (ERK1/2) pathway inhibitors are important therapies for treating many cancers. However, acquired resistance to most protein kinase inhibitors limits their ability to provide durable responses. Approximately 50% of malignant melanomas contain activating mutations in BRAF, which promotes cancer cell survival through the direct phosphorylation of the mitogen-activated protein kinase MAPK/ERK 1/2 (MEK1/2) and the activation of ERK1/2. Although the combination treatment with BRAF and MEK1/2 inhibitors is a recommended approach to treat melanoma, the development of drug resistance remains a barrier to achieving long-term patient benefits. Few studies have compared the global proteomic changes in BRAF/MEK1/2 inhibitor-resistant melanoma cells under different growth conditions. The current study uses high-resolution label-free mass spectrometry to compare relative protein changes in BRAF/MEK1/2 inhibitor-resistant A375 melanoma cells grown as monolayers or spheroids. While approximately 66% of proteins identified were common in the monolayer and spheroid cultures, only 6.2 or 3.6% of proteins that significantly increased or decreased, respectively, were common between the drug-resistant monolayer and spheroid cells. Drug-resistant monolayers showed upregulation of ERK-independent signaling pathways, whereas drug-resistant spheroids showed primarily elevated catabolic metabolism to support oxidative phosphorylation. These studies highlight the similarities and differences between monolayer and spheroid cell models in identifying actionable targets to overcome drug resistance.

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“…Tumor heterogeneity is responsible for superior drug resistance in 3D spheroids when compared to 2D culture models, which are devoid of essential tumor microenvironment 82,83 . Poor penetration of drugs through the scaffolds and spheroidal microenvironment barriers are also responsible for superior drug resistance in 3D spheroids [84][85][86] . Thus, there is a need to develop drugs with better penetrating ability to the most interior sections of tumors.…”

Section: Discussionmentioning

confidence: 99%

Polysaccharide hydrogel based 3D printed tumor models for chemotherapeutic drug screening

Gebeyehu

Surapaneni

Huang³

et al. 2021

Sci Rep

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A series of stable and ready-to-use bioinks have been developed based on the xeno-free and tunable hydrogel (VitroGel) system. Cell laden scaffold fabrication with optimized polysaccharide-based inks demonstrated that Ink H4 and RGD modified Ink H4-RGD had excellent rheological properties. Both bioinks were printable with 25–40 kPa extrusion pressure, showed 90% cell viability, shear-thinning and rapid shear recovery properties making them feasible for extrusion bioprinting without UV curing or temperature adjustment. Ink H4-RGD showed printability between 20 and 37 °C and the scaffolds remained stable for 15 days at temperature of 37 °C. 3D printed non-small-cell lung cancer (NSCLC) patient derived xenograft cells (PDCs) showed rapid spheroid growth of size around 500 µm in diameter and tumor microenvironment formation within 7 days. IC50 values demonstrated higher resistance of 3D spheroids to docetaxel (DTX), doxorubicin (DOX) and erlotinib compared to 2D monolayers of NSCLC-PDX, wild type triple negative breast cancer (MDA-MB-231 WT) and lung adenocarcinoma (HCC-827) cells. Results of flow property, shape fidelity, scaffold stability and biocompatibility of H4-RGD suggest that this hydrogel could be considered for 3D cell bioprinting and also for in-vitro tumor microenvironment development for high throughput screening of various anti-cancer drugs.

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Chemoresistance of Lung Cancer Cells: 2D and 3D In Vitro Models for Anticancer Drug Screening

Cited by 6 publications

References 88 publications

Therapeutic Potential of Fingolimod and Dimethyl Fumarate in Non-Small Cell Lung Cancer Preclinical Models

Therapeutic Potential of Fingolimod and Dimethyl Fumarate in Non-Small Cell Lung Cancer Preclinical Models

Proteomic Changes in the Monolayer and Spheroid Melanoma Cell Models of Acquired Resistance to BRAF and MEK1/2 Inhibitors

Polysaccharide hydrogel based 3D printed tumor models for chemotherapeutic drug screening

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