scholarly journals Mechanisms Conferring Resistance to Pro-Apoptotic Cancer Gene Therapy

2011 ◽  
Vol 4 ◽  
pp. JCD.S4686
Author(s):  
Shona T. Dougherty ◽  
Graeme J. Dougherty
Keyword(s):  
Tumor Cell ◽  
Plasmid Vector ◽  
Death Domain ◽  
Tumor Cell Death ◽  
Surface Receptors ◽  
Novel Approach ◽  
Cell Clones ◽  
Ligand Expression

Recently, we have described a novel approach to the treatment of cancer that employs a series of vectors that encode surface expressed chimeric proteins in which the cytoplasmic death domain of Fas is fused in-frame to the extracellular domain of one of a number of cell surface receptors that recognize and bind various ligands that are differentially expressed within the tumor microenvironment. Although the majority of tumor cells transduced with such vectors are killed in the presence of the corresponding cognate ligand, a small percentage survive and in vivo may go on to repopulate a treated tumor. In order to understand the mechanisms employed by tumors to escape the cytotoxic effects of pro-apoptotic signals triggered via Fas, we isolated a large number of 293 tumor cell clones that survive following transfection with a plasmid vector encoding Flk-1/Fas, a chimeric receptor that induces tumor cell death in the presence of the pro-angiogenic cytokine VEGF. Characterization of Flk-1/Fas-positive clones revealed that while survival can most often be attributed simply to the down-regulation of VEGF ligand expression, in cells that express both receptor and ligand, other proteins involved in the regulation of apoptosis may be targeted. Specifically, a Flk-1/Fas-positive, VEGF-positive clone was identified in which expression of APAF-1 was almost completely abrogated.

Proteomic characterization of EL4 lymphoma-derived tumors upon chemotherapy treatment reveals potential roles for lysosomes and caspase-6 during tumor cell death in vivo

PROTEOMICS ◽  
2017 ◽  
Vol 17 (12) ◽  
pp. 1700060 ◽  
Author(s):  
David A. Kramer ◽  
Mohamed A. Eldeeb ◽  
Melinda Wuest ◽  
John Mercer ◽  
Richard P. Fahlman
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Chemotherapy Treatment ◽  
Tumor Cell Death ◽  
Caspase 6

Characterization of in vivo expanded OspA-specific human T-cell clones☆

2005 ◽  
Vol 115 (3) ◽  
pp. 313-322 ◽  
Author(s):  
L AUSUBEL ◽  
K OCONNOR ◽  
C BAECHERALLEN ◽  
C TROLLMO ◽  
B KESSLER ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Clones ◽  
Human T Cell ◽  
Cell Clones

scholarly journals Cytotoxic T cells are able to efficiently eliminate cancer cells by additive cytotoxicity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Bettina Weigelin ◽  
Annemieke Th. den Boer ◽  
Esther Wagena ◽  
Kelly Broen ◽  
Harry Dolstra ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Pore Formation ◽  
Cytotoxic T Cells ◽  
Target Cells ◽  
Interstitial Tissue ◽  
Tumor Cell Death ◽  
Membrane Pore ◽  
B Lymphoma Cells ◽  
Immune Efficacy

AbstractLethal hit delivery by cytotoxic T lymphocytes (CTL) towards B lymphoma cells occurs as a binary, “yes/no” process. In non-hematologic solid tumors, however, CTL often fail to kill target cells during 1:1 conjugation. Here we describe a mechanism of “additive cytotoxicity” by which time-dependent integration of sublethal damage events, delivered by multiple CTL transiting between individual tumor cells, mediates effective elimination. Reversible sublethal damage includes perforin-dependent membrane pore formation, nuclear envelope rupture and DNA damage. Statistical modeling reveals that 3 serial hits delivered with decay intervals below 50 min discriminate between tumor cell death or survival after recovery. In live melanoma lesions in vivo, sublethal multi-hit delivery is most effective in interstitial tissue where high CTL densities and swarming support frequent serial CTL-tumor cell encounters. This identifies CTL-mediated cytotoxicity by multi-hit delivery as an incremental and tunable process, whereby accelerating damage magnitude and frequency may improve immune efficacy.

scholarly journals Dominant-negative ATF5 rapidly depletes survivin in tumor cells

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Xiaotian Sun ◽  
James M. Angelastro ◽  
David Merino ◽  
Qing Zhou ◽  
Markus D. Siegelin ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Dominant Negative ◽  
Tumor Cell Death ◽  
Cell Penetrating ◽  
Selective Death ◽  
Tumor Types

Abstract Survivin (BIRC5, product of the BIRC5 gene) is highly expressed in many tumor types and has been widely identified as a potential target for cancer therapy. However, effective anti-survivin drugs remain to be developed. Here we report that both vector-delivered and cell-penetrating dominant-negative (dn) forms of the transcription factor ATF5 that promote selective death of cancer cells in vitro and in vivo cause survivin depletion in tumor cell lines of varying origins. dn-ATF5 decreases levels of both survivin mRNA and protein. The depletion of survivin protein appears to be driven at least in part by enhanced proteasomal turnover and depletion of the deubiquitinase USP9X. Survivin loss is rapid and precedes the onset of cell death triggered by dn-ATF5. Although survivin downregulation is sufficient to drive tumor cell death, survivin over-expression does not rescue cancer cells from dn-ATF5-promoted apoptosis. This indicates that dn-ATF5 kills malignant cells by multiple mechanisms that include, but are not limited to, survivin depletion. Cell-penetrating forms of dn-ATF5 are currently being developed for potential therapeutic use and the present findings suggest that they may pose an advantage over treatments that target only survivin.

Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid–based proteasome inhibitors

Blood ◽  
2009 ◽  
Vol 113 (23) ◽  
pp. 5927-5937 ◽  
Author(s):  
Encouse B. Golden ◽  
Philip Y. Lam ◽  
Adel Kardosh ◽  
Kevin J. Gaffney ◽  
Enrique Cadenas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Tumor Cell ◽  
Green Tea ◽  
Boronic Acid ◽  
Proteasome Inhibitors ◽  
Green Tea Polyphenols ◽  
Tumor Cell Death

Abstract The anticancer potency of green tea and its individual components is being intensely investigated, and some cancer patients already self-medicate with this “miracle herb” in hopes of augmenting the anticancer outcome of their chemotherapy. Bortezomib (BZM) is a proteasome inhibitor in clinical use for multiple myeloma. Here, we investigated whether the combination of these compounds would yield increased antitumor efficacy in multiple myeloma and glioblastoma cell lines in vitro and in vivo. Unexpectedly, we discovered that various green tea constituents, in particular (-)-epigallocatechin gallate (EGCG) and other polyphenols with 1,2-benzenediol moieties, effectively prevented tumor cell death induced by BZM in vitro and in vivo. This pronounced antagonistic function of EGCG was evident only with boronic acid–based proteasome inhibitors (BZM, MG-262, PS-IX), but not with several non–boronic acid proteasome inhibitors (MG-132, PS-I, nelfinavir). EGCG directly reacted with BZM and blocked its proteasome inhibitory function; as a consequence, BZM could not trigger endoplasmic reticulum stress or caspase-7 activation, and did not induce tumor cell death. Taken together, our results indicate that green tea polyphenols may have the potential to negate the therapeutic efficacy of BZM and suggest that consumption of green tea products may be contraindicated during cancer therapy with BZM.

miR-15a regulation of endothelial radiation sensitivity in colorectal cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 709-709
Author(s):  
Shushan Rajesh Rana ◽  
Cristina Espinosa ◽  
Rebecca Ruhl ◽  
Latroy Robinson ◽  
Charles R. Thomas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Background Radiation ◽  
Acid Sphingomyelinase ◽  
High Dose ◽  
Tumor Cell Death ◽  
Caspase 1

709 Background: Radiation dose escalation causes significant changes within the tumor microenvironment (TME) to enhance tumor cell death including altered microRNA (miR) levels. Among endothelial miRs, we identified miR-15a exhibits dose dependent differential regulation. miR-15a targets a key determinant of endothelial cell (EC) radiosensitivity, acid sphingomyelinase (SMPD1), an enzyme that drives rapid EC apoptosis via enhanced ceramide production. In colorectal cancer (CRC) (n = 182 patients), high miR-15a is associated with worse 5-year progression free and overall survival. miR-15a also affects immune function by promoting a pro-inflammatory TME milieu. We hypothesized miR-15a inhibition will increase tumor cell death through preservation of EC SMPD1, enhancing endothelial apoptosis and inflammatory cytokine upregulation. Methods: Using TaqMan Human miR panels, miRs were profiled in human umbilical vein ECs (HUVECs) after single 2 vs 20 Gy treatment. miR-target prediction programs identified miRs targeting SMPD1. In vitro gain and loss of function studies were performed with miR transfections in HUVECs and CT26 CRC cells. CXCL10 expression was measured by qRT-PCR. Caspase 1 activation was measured by a luminescence based assay. A CT26 syngeneic CRC flank murine model was used for in vivo miR-15a inhibitor assessment administered via tail vein injection unencapsulated or encapsulated in vascular-targeted 7C1 nanoparticles. Results: Among miRs targeting SMPD1, miR-15a exhibited the greatest differential change in HUVECs 6h post-IR between low and high dose radiation. Lower dose was associated with higher miR-15a and vice versa. Further, miR-15a levels inversely correlated with SMPD1. Exogenous miR-15a significantly decreased SMPD1 mRNA and protein. miR-15a inhibition decreased proliferation in both HUVECs and CT26 cells and increased apoptosis when combined with radiation. miR-15a inhibition increased endothelial CXCL10 expression and caspase-1 activation. Both systemic and vascular-targeted miR-15a inhibitor significantly diminished tumor growth in vivo. Conclusions: Our data suggests inhibition of vascular miR-15a is sufficient to decrease tumor growth likely due to rescue of endothelial SMPD1.

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