Chandipura virus induces cell death in cancer cell lines of human origin and promotes tumour regression in vivo.

Clinical outcomes for patients with ovarian and uterine cancers have not improved greatly in the past twenty years. To identify ovarian and uterine cancer vulnerabilities, we analyzed genome-scale CRISPR/ Cas9 loss-of-function screens across 739 human cancer cell lines. We found that many ovarian cancer cell lines overexpress the phosphate importer SLC34A2, which renders them sensitive to loss of the phosphate exporter XPR1. We extensively validated the XPR1 vulnerability in cancer cell lines and found that the XPR1 dependency was retained in vivo. Overexpression of SLC34A2 is frequently observed in tumor samples and is regulated by PAX8 - a transcription factor required for ovarian cancer survival. XPR1 overexpression and copy number amplifications are also frequently observed. Mechanistically, SLC34A2 overexpression and impaired phosphate efflux leads to the accumulation of intracellular phosphate and cell death. We further show that proper localization and phosphate efflux by XPR1 requires a novel binding partner, KIDINS220. Loss of either XPR1 or KIDINS220 results in acidic vacuolar structures which precede cell death. These data point to the XPR1:KIDINS220 complex - and phosphate dysregulation more broadly - as a therapeutic vulnerability in ovarian cancer.

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SB365, Pulsatilla Saponin D Induces Caspase-Independent Cell Death and Augments the Anticancer Effect of Temozolomide in Glioblastoma Multiforme Cells

Molecules ◽

10.3390/molecules24183230 ◽

2019 ◽

Vol 24 (18) ◽

pp. 3230 ◽

Cited By ~ 2

Author(s):

Jun-Man Hong ◽

Jin-Hee Kim ◽

Hyemin Kim ◽

Wang Jae Lee ◽

Young-il Hwang

Keyword(s):

Cell Death ◽

Glioblastoma Multiforme ◽

Cell Lines ◽

Cancer Cell ◽

Cathepsin B ◽

Cytotoxic Effect ◽

Cancer Cell Lines ◽

Autophagic Flux

SB365, a saponin D extracted from the roots of Pulsatilla koreana, has been reported to show cytotoxicity in several cancer cell lines. We investigated the effects of SB365 on U87-MG and T98G glioblastoma multiforme (GBM) cells, and its efficacy in combination with temozolomide for treating GBM. SB365 exerted a cytotoxic effect on GBM cells not by inducing apoptosis, as in other cancer cell lines, but by triggering caspase-independent cell death. Inhibition of autophagic flux and neutralization of the lysosomal pH occurred rapidly after application of SB365, followed by deterioration of mitochondrial membrane potential. A cathepsin B inhibitor and N-acetyl cysteine, an antioxidant, partially recovered cell death induced by SB365. SB365 in combination with temozolomide exerted an additive cytotoxic effect in vitro and in vivo. In conclusion, SB365 inhibits autophagic flux and induces caspase-independent cell death in GBM cells in a manner involving cathepsin B and mainly reactive oxygen species, and its use in combination with temozolomide shows promise for the treatment of GBM.

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Nanorobots Sense Local Physiochemical Heterogeneities of Tumor Matrisome

10.26434/chemrxiv.12063420 ◽

2020 ◽

Author(s):

Debayan Dasgupta ◽

Dharma Pally ◽

Deepak K. Saini ◽

Ramray Bhat ◽

Ambarish Ghosh

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines ◽

Adhesive Force ◽

Surrounding Tissue ◽

Quantitative Measurements ◽

Malignant Breast Tumor ◽

Malignant Breast ◽

Cancer Dissemination

The dissemination of cancer is brought about by continuous interaction of malignant cells with their surrounding tissue microenvironment. Understanding and quantifying the remodeling of local extracellular matrix (ECM) by invading cells can therefore provide fundamental insights into the dynamics of cancer dissemination. In this paper, we use an active and untethered nanomechanical tool, realized as magnetically driven nanorobots, to locally probe a 3D tissue culture microenvironment consisting of cancerous and non-cancerous epithelia, embedded within reconstituted basement membrane (rBM) matrix. Our assay is designed to mimic the in vivo histopathological milieu of a malignant breast tumor. We find that nanorobots preferentially adhere to the ECM near cancer cells: this is due to the distinct charge conditions of the cancer-remodeled ECM. Surprisingly, quantitative measurements estimate that the adhesive force increases with the metastatic ability of cancer cell lines, while the spatial extent of the remodeled ECM was measured to be approximately 40 μm for all cancer cell lines studied here. We hypothesized and experimentally confirmed that specific sialic acid linkages specific to cancer-secreted ECM may be a major contributing factor in determining this adhesive behavior. The findings reported here can lead to promising applications in cancer diagnosis, quantification of cancer aggression, in vivo drug delivery applications, and establishes the tremendous potential of magnetic nanorobots for fundamental studies of cancer biomechanics.

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Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity

Molecules ◽

10.3390/molecules26071838 ◽

2021 ◽

Vol 26 (7) ◽

pp. 1838

Author(s):

Naglaa M. Ahmed ◽

Mahmoud M. Youns ◽

Moustafa K. Soltan ◽

Ahmed M. Said

Keyword(s):

Molecular Modeling ◽

Antitumor Activity ◽

Cell Lines ◽

Cancer Cell ◽

Antiproliferative Activity ◽

Antitumor Agents ◽

Cancer Cell Lines ◽

Normal Cells

Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay. Compounds 1–4 showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound 4g showed potent antiproliferative activity against these cell lines (IC50 = 5.1, 5.02, and 6.6 μM, respectively) comparable to the standard treatment (5-FU and erlotinib). In addition, the most promising group of compounds was further evaluated for their in vivo antitumor efficacy against EAC tumor bearing mice. Notably, compound 4g showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53–79 %) activity. Compound 4g was found to be the most active compound against EGFR (IC50 = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound 4g revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound 4g could be used as a potential anticancer agent.

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381 Efficacy of specific FGFR inhibitors against gatekeeper resistance mutations and shared mechanism of cell death in FGFR2-dependent endometrial cancer cell lines

European Journal of Cancer ◽

10.1016/s0959-8049(14)70507-6 ◽

2014 ◽

Vol 50 ◽

pp. 122

Author(s):

L. Packer ◽

S. Byron ◽

S. Stehbens ◽

D. Loch ◽

F. Dehkhoda ◽

...

Keyword(s):

Cell Death ◽

Endometrial Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines ◽

Resistance Mutations ◽

Endometrial Cancer Cell

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Tumorigenicity and Validity of Fluorescence Labelled Mesenchymal and Epithelial Human Oral Cancer Cell Lines in Nude Mice

BioMed Research International ◽

10.1155/2016/4897986 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Wei Xin Cai ◽

Li Wu Zheng ◽

Li Ma ◽

Hong Zhang Huang ◽

Ru Qing Yu ◽

...

Keyword(s):

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Nude Mice ◽

Tongue Cancer ◽

Cancer Cell Lines ◽

Fluorescent Imaging ◽

Cell Phenotype ◽

Human Tongue

Tumorigenicity and metastatic activity can be visually monitored in cancer cells that were labelled with stable fluorescence. The aim was to establish and validate local and distant spread of subcutaneously previously injected fluorescence transduced human tongue cancer cell lines of epithelial and mesenchymal phenotype in nude mice. A total of 32 four-week-old male athymic Balb/c nude mice were randomly allocated into 4 groups (n=8). A single dose of 0.3 mL PBS containing 1 × 107 of four different cancer cell-lines (UM1, UM1-GFP, UM2, and UM2-RFP) was injected subcutaneously into the right side of their posterolateral back. Validity assessment of the labelled cancer cells’ tumorigenicity was assessed by physical examination, imaging, and histology four weeks after the injection. The tumor take rate of cancer cells was similar in animals injected with either parental or transduced cancer cells. Transduced cancer cells in mice were easily detectable in vivo and after cryosection using fluorescent imaging. UM1 cells showed increased tumor take rate and mean tumor volume, presenting with disorganized histopathological patterns. Fluorescence labelled epithelial and mesenchymal human tongue cancer cell lines do not change in tumorigenicity or cell phenotype after injection in vivo.

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Antitumour activity of XR5944 in vitro and in vivo in combination with 5-fluorouracil and irinotecan in colon cancer cell lines

British Journal of Cancer ◽

10.1038/sj.bjc.6602403 ◽

2005 ◽

Vol 92 (4) ◽

pp. 722-728 ◽

Cited By ~ 17

Author(s):

S M Harris ◽

P Mistry ◽

C Freathy ◽

J L Brown ◽

P A Charlton

Keyword(s):

Colon Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Antitumour Activity ◽

Cancer Cell Lines ◽

Colon Cancer Cell ◽

Colon Cancer Cell Lines

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Modes of cell death induced by novel tetrahydroisoquinolinone-based analogues in breast- and lung cancer cell lines

European Journal of Cancer ◽

10.1016/s0959-8049(16)61194-2 ◽

2016 ◽

Vol 61 ◽

pp. S57

Author(s):

M. Verwey ◽

A.M. Joubert ◽

W. Dohle ◽

B.V.L. Potter ◽

A.E. Theron

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines ◽

Lung Cancer Cell

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Identification of Prostaglandin F2 Receptor Negative Regulator (PTGFRN) as an internalizable target in cancer cells for antibody-drug conjugate development

PLoS ONE ◽

10.1371/journal.pone.0246197 ◽

2021 ◽

Vol 16 (1) ◽

pp. e0246197

Author(s):

Jorge Marquez ◽

Jianping Dong ◽

Chun Dong ◽

Changsheng Tian ◽

Ginette Serrero

Keyword(s):

Flow Cytometry ◽

Western Blot ◽

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines ◽

Negative Regulator ◽

Target Validation ◽

Antibody Drug

Antibody-drug conjugates (ADC) are effective antibody-based therapeutics for hematopoietic and lymphoid tumors. However, there is need to identify new targets for ADCs, particularly for solid tumors and cancers with unmet needs. From a hybridoma library developed against cancer cells, we selected the mouse monoclonal antibody 33B7, which was able to bind to, and internalize, cancer cell lines. This antibody was used for identification of the target by immunoprecipitation and mass spectrometric analysis, followed by target validation. After target validation, 33B7 binding and target positivity were tested by flow cytometry and western blot analysis in several cancer cell lines. The ability of 33B7 conjugated to saporin to inhibit in vitro proliferation of PTFRN positive cell lines was investigated, as well as the 33B7 ADC in vivo effect on tumor growth in athymic mice. All flow cytometry and in vitro internalization assays were analyzed for statistical significance using a Welsh’s T-test. Animal studies were analyzed using Two-Way Analysis of Variance (ANOVA) utilizing post-hoc Bonferroni analysis, and/or Mixed Effects analysis. The 33B7 cell surface target was identified as Prostaglandin F2 Receptor Negative Regulator (PTGFRN), a transmembrane protein in the Tetraspanin family. This target was confirmed by showing that PTGFRN-expressing cells bound and internalized 33B7, compared to PTGFRN negative cells. Cells able to bind 33B7 were PTGFRN-positive by Western blot analysis. In vitro treatment PTGFRN-positive cancer cell lines with the 33B7-saporin ADC inhibited their proliferation in a dose-dependent fashion. 33B7 conjugated to saporin was also able to block tumor growth in vivo in mouse xenografts when compared to a control ADC. These findings show that screening antibody libraries for internalizing antibodies in cancer cell lines is a good approach to identify new cancer targets for ADC development. These results suggest PTGFRN is a possible therapeutic target via antibody-based approach for certain cancers.

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