High-Dose Compound Heat Map for 3D-Cultured Glioblastoma Multiforme Cells in a Micropillar and Microwell Chip Platform

Lee, Dong Woo; Lee, Sang-Yun; Doh, Il; Ryu, Gyu Ha; Nam, Do‐Hyun

doi:10.1155/2017/7218707

Cited by 11 publications

(6 citation statements)

References 22 publications

(23 reference statements)

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“…So far, many therapeutic approaches were developed to treat patients with EGFR vIII -positive glioblastoma (Table 1). Generally, average survival rate of GB patients does not exceed 12-14 months from the moment of diagnosis and there has been actually no improvement for many years [170]. Ideal drug directed against GB cells should be well tolerated by the patients, able to cross the blood-brain barrier, and specifically induce tumor cell death.…”

Section: Targeted Therapies Based On Tyrosine Kinase Inhibitors (Tki)mentioning

confidence: 99%

EGFR^vIII: An Oncogene with Ambiguous Role

Rutkowska

Stoczyńska-Fidelus

Janik

et al. 2019

Journal of Oncology

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Epidermal growth factor receptor variant III (EGFRvIII) seems to constitute the perfect therapeutic target for glioblastoma (GB), as it is specifically present on up to 28–30% of GB cells. In case of other tumor types, expression and possible role of this oncogene still remain controversial. In spite of EGFRvIII mechanism of action being crucial for the design of small active anticancer molecules and immunotherapies, i.e., CAR-T technology, it is yet to be precisely defined. EGFRvIII is known to be resistant to degradation, but it is still unclear whether it heterodimerizes with EGF-activated wild-type EGFR (EGFRWT) or homodimerizes (including covalent homodimerization). Constitutive kinase activity of this mutated receptor is relatively low, and some researchers even claim that a nuclear, but not a membrane function, is crucial for its activity. Based on the analyses of recurrent tumors that are often lacking EGFRvIII expression despite its initial presence in corresponding primary foci, this oncogene is suggested to play a marginal role during later stages of carcinogenesis, while even in primary tumors EGFRvIII expression is detected only in a small percentage of tumor cells, undermining the rationality of EGFRvIII-targeting therapies. On the other hand, EGFRvIII-positive cells are resistant to apoptosis, more invasive, and characterized with enhanced proliferation rate. Moreover, expression of this oncogenic receptor was also postulated to be a marker of cancer stem cells. Opinions regarding the role that EGFRvIII plays in tumorigenesis and for tumor aggressiveness are clearly contradictory and, therefore, it is crucial not only to determine its mechanism of action, but also to unambiguously define its role at early and advanced cancer stages.

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Section: Targeted Therapies Based On Tyrosine Kinase Inhibitors (Tki)mentioning

confidence: 99%

EGFR^vIII: An Oncogene with Ambiguous Role

Rutkowska

Stoczyńska-Fidelus

Janik

et al. 2019

Journal of Oncology

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“…A micropillar array as a type of quasi-three-dimensional cell culture substrate affords a unique biophysical cue to tune cell–material interactions and is a promising platform for biomedical research in drug screening and wound healing. − A quasi-three-dimensional or three-dimensional cellular microenvironment is valuable as a physiological or pathological model for gaining fundamental understandings of biology, diseases, and the more accurate prediction of drug responses. − …”

Section: Introductionmentioning

confidence: 99%

Proliferation of Cells with Severe Nuclear Deformation on a Micropillar Array

et al. 2018

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Cellular responses on a topographic surface are fundamental topics about interfaces and biology. Herein, a poly(lactide-co-glycolide) (PLGA) micropillar array was prepared and found to trigger significant self-deformation of cell nuclei. The time-dependent cell viability and thus cell proliferation was investigated. Despite significant nuclear deformation, all of the examined cell types (Hela, HepG2, MC3T3-E1, and NIH3T3) could survive and proliferate on the micropillar array yet exhibited different proliferation abilities. Compared to the corresponding groups on the smooth surface, the cell proliferation abilities on the micropillar array were decreased for Hela and MC3T3-E1 cells and did not change significantly for HepG2 and NIH3T3 cells. We also found that whether the proliferation ability changed was related to whether the nuclear sizes decreased in the micropillar array, and thus the size deformation of cell nuclei should, besides shape deformation, be taken into consideration in studies of cells on topological surfaces.

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“…Most of the targeted compounds exhibited high efficacy with 20 μM dosages in both single cell and multi-spheroid conditions. In previous work [ 25 ] when single cells were exposed to drug compounds for three days, cediranib exhibited high efficacy in all four patient-derived GBM cells and exhibited no cytotoxicity towards astrocytes. When treated for 7 days in the single cell condition, most compounds showed high cytotoxicity in astrocytes as well as high efficacy in four patient-derived GBM cells.…”

Section: Resultsmentioning

confidence: 84%

High-dose drug heat map analysis for drug safety and efficacy in multi-spheroid brain normal cells and GBM patient-derived cells

Lee

Teng²,

Son³

et al. 2021

PLoS ONE

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To test the safety and efficacy of drugs via a high does drug heat map, a multi-spheroids array chip was developed by adopting a micropillar and microwell structure. In the chip, patient-derived cells were encapsulated in alginate and grown to maturity for more than 7 days to form cancer multi-spheroids. Multi-spheroids grown in conventional well plates require many cells and are easily damaged as a result of multiple pipetting during maintenance culture or experimental procedures. To address these issues, we applied a micropillar and microwell structure to the multi-spheroids array. Patient-derived cells from patients with Glioblastoma (GBM), the most common and lethal form of central nervous system cancer, were used to validate the array chip performance. After forming multi-spheroids with a diameter greater than 100μm in a 12×36 pillar array chip (25mm × 75mm), we tested 70 drug compounds (6 replicates) using a high-dose to determine safety and efficacy for drug candidates. Comparing the drug response of multi-spheroids derived from normal cells and cancer cells, we found that four compounds (Dacomitinib, Cediranib, LY2835219, BGJ398) did not show toxicity to astrocyte cell and were efficacious to patient-derived GBM cells.

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High-Dose Compound Heat Map for 3D-Cultured Glioblastoma Multiforme Cells in a Micropillar and Microwell Chip Platform

Cited by 11 publications

References 22 publications

EGFR^vIII: An Oncogene with Ambiguous Role

EGFR^vIII: An Oncogene with Ambiguous Role

Proliferation of Cells with Severe Nuclear Deformation on a Micropillar Array

High-dose drug heat map analysis for drug safety and efficacy in multi-spheroid brain normal cells and GBM patient-derived cells

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High-Dose Compound Heat Map for 3D-Cultured Glioblastoma Multiforme Cells in a Micropillar and Microwell Chip Platform

Cited by 11 publications

References 22 publications

EGFRvIII: An Oncogene with Ambiguous Role

EGFRvIII: An Oncogene with Ambiguous Role

Proliferation of Cells with Severe Nuclear Deformation on a Micropillar Array

High-dose drug heat map analysis for drug safety and efficacy in multi-spheroid brain normal cells and GBM patient-derived cells

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Product

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EGFR^vIII: An Oncogene with Ambiguous Role

EGFR^vIII: An Oncogene with Ambiguous Role