Evidence of drug-response heterogeneity rapidly generated from a single cancer cell

Wang, Rong; Jin, Chengmeng; Hu, Xun

doi:10.18632/oncotarget.17064

Cited by 14 publications

(12 citation statements)

References 39 publications

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“…6). Cells within a tumor and cancer line populations are heterogeneous, partially explaining why an entire cell population is not killed by Yoda1-TRAIL treatment 33,34 . To account for this heterogeneity, a random population of cells was generated by creating a random-normal distribution of cytosolic Bcl-2, as this altered the necessity of calcium (Fig.…”

Section: Resultsmentioning

confidence: 99%

Activation of Piezo1 sensitizes cells to TRAIL-mediated apoptosis through mitochondrial outer membrane permeability

et al. 2019

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TRAIL specifically induces apoptosis in cancer cells without affecting healthy cells. However, TRAIL’s cancer cytotoxicity was insufficient in clinical trials. Circulatory-shear stress is known to sensitize cancer cells to TRAIL. In this study, we examine the mechanism of this TRAIL sensitization with the goal of translating it to static conditions. GsMTx-4, a Piezo1 inhibitor, was found to reduce shear stress-related TRAIL sensitization, implicating Piezo1 activation as a potential TRAIL-sensitizer. The Piezo1 agonist Yoda1 recreated shear stress-induced TRAIL sensitization under static conditions. A significant increase in apoptosis occurred when PC3, COLO 205, or MDA-MB-231 cells were treated with Yoda1 and TRAIL in combination, but not in Bax-deficient DU145 cells. Calpastatin inhibited apoptosis in Yoda1-TRAIL treated cells, indicating that calpain activation is necessary for apoptosis by Yoda1 and TRAIL. Yoda1 and TRAIL treated PC3 cells showed increased mitochondrial outer membrane permeability (MOMP), mitochondrial depolarization, and activated Bax. This implies that Piezo1 activation sensitizes cancer cells to TRAIL through a calcium influx that activates calpains. The Calpains then induce MOMP by enhancing Bax activation. From these experiments a computational model was developed to simulate apoptosis for cells treated with TRAIL and increased calcium. The computational model elucidated the proapoptotic or antiapoptotic roles of Bax, Bcl-2, XIAP, and other proteins important in the mitochondrial-apoptotic signaling pathway.

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Section: Resultsmentioning

confidence: 99%

Activation of Piezo1 sensitizes cells to TRAIL-mediated apoptosis through mitochondrial outer membrane permeability

et al. 2019

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“…Similar arguments can be made as lower complex 4 concentrations take longer to affect a heterogeneous cell population. 4T1-luc cells are known to be highly heterogeneous regarding genetic profiles [241] and effects of chemotherapeutic drugs [242]. Thus, it is not unexpected that 4T1-luc cells have different levels of sensitivity to complex 4 with higher concentration affecting some cells rapidly (2 h) and affecting a more resistant population later (6 h).…”

Section: Modulation Of the Mitochondrial Transmembrane Potential (δψ mentioning

confidence: 99%

Synthesis, characterization, DNA binding, topoisomerase inhibition, and apoptosis induction studies of a novel cobalt(III) complex with a thiosemicarbazone ligand

Beebe¹,

Celestine

Bullock

et al. 2020

Journal of Inorganic Biochemistry

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× 10 5 and 1.6 × 10 4 M −1 , respectively). Topoisomerase inhibition assays and cleavage studies proved that complex 4 was an efficient catalytic inhibitor of human topoisomerases I and IIα. Based upon the results obtained from the 3-(4,5-dimethylthiazol-2-yl)-5-(3carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay on 4T1-luc metastatic mammary breast cancer cells (IC 50 = 34.4 ± 5.2 μM when compared to IC 50 = 13.75 ± 1.08 μM for the control, cisplatin), further investigations into the molecular events initiated by exposure to complex 4 were investigated. Studies have shown that complex 4 activated both the apoptotic and autophagic signaling pathways in addition to causing dissipation of the mitochondrial membrane potential (ΔΨ m). Furthermore, activation of cysteine-aspartic proteases3 (caspase 3) in a time-and concentration-dependent manner coupled with the ΔΨ m , studies implicated the intrinsic apoptotic pathway as the major regulator of cell death mechanism.

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“…Heterogeneity of cellular drug response is a commonly reported phenomenon in cancer treatment, yet mechanisms underlying this are not well understood. 29 Analysis of cell volumes showed the mean volume of treated and untreated cells to be comparable for doxorubicin reflecting the fact that this treatment can induce G1, S or G2 cell cycle arrest. 30 However, for docetaxel treated cells, we found that clusters spanned a range of mean cell volumes beyond those of the untreated set for both cell lines.…”

Section: Discussionmentioning

confidence: 99%

CellPhe: a toolkit for cell phenotyping using time-lapse imaging and pattern recognition

Wilson

Wiggins

Lord

et al. 2021

Preprint

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With phenotypic heterogeneity in whole cell populations widely recognised, the demand for quantitative and temporal analysis approaches to characterise single cell morphology and dynamics has increased. We present CellPhe, a pattern recognition toolkit for the characterisation of cellular phenotypes within time-lapse videos. To maximise data quality for downstream analysis, our toolkit includes automated recognition and removal of erroneous cell boundaries induced by inaccurate tracking and segmentation. We provide an extensive list of features extracted from individual cell time series, with custom feature selection to identify variables that provide greatest discrimination for the analysis in question. We demonstrate the use of ensemble classification for accurate prediction of cellular phenotype and clustering algorithms for the characterisation of heterogeneous subsets. We validate and prove adaptability using different cell types and experimental conditions. Our methods could be extended to other imaging modalities, such as fluorescence, and would be suitable for all time-lapse studies including clinical applications.

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Evidence of drug-response heterogeneity rapidly generated from a single cancer cell

Cited by 14 publications

References 39 publications

Activation of Piezo1 sensitizes cells to TRAIL-mediated apoptosis through mitochondrial outer membrane permeability

Activation of Piezo1 sensitizes cells to TRAIL-mediated apoptosis through mitochondrial outer membrane permeability

Synthesis, characterization, DNA binding, topoisomerase inhibition, and apoptosis induction studies of a novel cobalt(III) complex with a thiosemicarbazone ligand

CellPhe: a toolkit for cell phenotyping using time-lapse imaging and pattern recognition

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