scholarly journals One-Two Punch Therapy for the Treatment of T-Cell Malignancies Involving p53-Dependent Cellular Senescence

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Yingjie Qing ◽  
Hui Li ◽  
Yunzi Zhao ◽  
Po Hu ◽  
Xiangyuan Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
T Cell ◽  
Cellular Senescence ◽  
Apoptotic Cell ◽  
Telomerase Activity ◽  
Flavonoid Compound ◽  
Antitumor Effects ◽  
Drug Induced ◽  
Human Telomerase Reverse Transcriptase ◽  
T Cell Malignancies

T-cell malignancies are still difficult to treat due to a paucity of plans that target critical dependencies. Drug-induced cellular senescence provides a permanent cell cycle arrest during tumorigenesis and cancer development, particularly when combined with senolytics to promote apoptosis of senescent cells, which is an innovation for cancer therapy. Here, our research found that wogonin, a well-known natural flavonoid compound, not only had a potential to inhibit cell growth and proliferation but also induced cellular senescence in T-cell malignancies with nonlethal concentration. Transcription activity of senescence-suppression human telomerase reverse transcriptase (hTERT) and oncogenic C-MYC was suppressed in wogonin-induced senescent cells, resulting in the inhibition of telomerase activity. We also substantiated the occurrence of DNA damage during the wogonin-induced aging process. Results showed that wogonin increased the activity of senescence-associated β-galactosidase (SA-β-Gal) and activated the DNA damage response pathway mediated by p53. In addition, we found the upregulated expression of BCL-2 in senescent T-cell malignancies because of the antiapoptotic properties of senescent cells. Following up this result, we identified a BCL-2 inhibitor Navitoclax (ABT-263), which was highly effective in decreasing cell viability and inducing apoptotic cell death in wogonin-induced senescent cells. Thus, the “one-two punch” approach increased the sensibility of T-cell malignancies with low expression of BCL-2 to Navitoclax. In conclusion, our research revealed that wogonin possesses potential antitumor effects based on senescence induction, offering a better insight into the development of novel therapeutic methods for T-cell malignancies.

scholarly journals Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence

2016 ◽  
Vol 113 (34) ◽  
pp. E5024-E5033 ◽  
Author(s):  
Priyanka L. Patel ◽  
Anitha Suram ◽  
Neena Mirani ◽  
Oliver Bischof ◽  
Utz Herbig
Keyword(s):  
Dna Damage ◽  
Cancer Progression ◽  
Ectopic Expression ◽  
Telomerase Activity ◽  
Early Event ◽  
Telomere Dysfunction ◽  
Telomeric Dna ◽  
Human Telomerase Reverse Transcriptase ◽  
Htert Gene ◽  
In Cells

Oncogene-induced senescence (OIS) is a critical tumor-suppressing mechanism that restrains cancer progression at premalignant stages, in part by causing telomere dysfunction. Currently it is unknown whether this proliferative arrest presents a stable and therefore irreversible barrier to cancer progression. Here we demonstrate that cells frequently escape OIS induced by oncogenic H-Ras and B-Raf, after a prolonged period in the senescence arrested state. Cells that had escaped senescence displayed high oncogene expression levels, retained functional DNA damage responses, and acquired chromatin changes that promoted c-Myc–dependent expression of the human telomerase reverse transcriptase gene (hTERT). Telomerase was able to resolve existing telomeric DNA damage response foci and suppressed formation of new ones that were generated as a consequence of DNA replication stress and oncogenic signals. Inhibition of MAP kinase signaling, suppressing c-Myc expression, or inhibiting telomerase activity, caused telomere dysfunction and proliferative defects in cells that had escaped senescence, whereas ectopic expression of hTERT facilitated OIS escape. In human early neoplastic skin and breast tissue, hTERT expression was detected in cells that displayed features of senescence, suggesting that reactivation of telomerase expression in senescent cells is an early event during cancer progression in humans. Together, our data demonstrate that cells arrested in OIS retain the potential to escape senescence by mechanisms that involve derepression of hTERT expression.

scholarly journals Efficacy-enhanced and cytokine release syndrome-attenuated anti-CD7 universal chimeric antigen receptor-T cell therapy for relapsed/refractory CD7-positive hematological malignancies: A phase I clinical study

2021 ◽  
Author(s):  
He Huang ◽  
Yongxian Hu ◽  
Yali Zhou ◽  
Mingming Zhang ◽  
Houli Zhao ◽  
...  
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Objective Response ◽  
Antigen Receptor ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Single Chain ◽  
Antitumor Effects ◽  
Car T ◽  
T Cell Malignancies

Abstract Chimeric antigen receptor-T cell (CAR-T) therapy in T cell malignancies faces fratricide, T cell aplasia, and product contamination. Here, we successfully developed a universal anti-CD7 CAR-T product (RD13-01). RD13-01 contains a bbzg-CAR comprising an anti-CD7 single-chain variable fragment, a 4-1BB costimulatory domain, a CD3ζ signaling domain, the intracellular domain of the common γ chain, and a natural killer cell inhibitory molecule (E-cadherin). TRAC, CD7 and HLA-II were disrupted to avoid graft versus host disease (GvHD), fratricide and rejection. Bbzg-CAR-T exerted antitumor effects superior to those of conventional CAR-T, while exhibiting reduced cytokine production. Among 11 evaluable relapsed/refractory (r/r) patients, no dose-limited toxicity, GvHD, immune effector cell-associated neurotoxicity or severe cytokine release syndrome (grade≥3) occurred. Nine (82%) showed objective response. For r/r leukemia and NHL, complete response rates were 75% and 33.3% respectively. Outstanding safety and efficacy of this universal CAR-T product was achieved in CD7+ T cell malignancies.

scholarly journals Western and Chinese Antirheumatic Drug-Induced T Cell Apoptotic DNA Damage Uses Different Caspase Cascades and Is Independent of Fas/Fas Ligand Interaction

2001 ◽  
Vol 166 (11) ◽  
pp. 6914-6924 ◽  
Author(s):  
Jenn-Haung Lai ◽  
Ling-Jun Ho ◽  
Kuo-Cheng Lu ◽  
Deh-Ming Chang ◽  
Men-Fang Shaio ◽  
...  
Keyword(s):  
Dna Damage ◽  
T Cell ◽  
Fas Ligand ◽  
Antirheumatic Drug ◽  
Drug Induced ◽  
Ligand Interaction ◽  
Caspase Cascades

scholarly journals FV-429 induces autophagy blockage and lysosome-dependent cell death of T-cell malignancies via lysosomal dysregulation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Po Hu ◽  
Jubo Wang ◽  
Yingjie Qing ◽  
Hui Li ◽  
Wenzhuo Sun ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Single Agent ◽  
Tumor Development ◽  
Flavonoid Compound ◽  
Autophagy Flux ◽  
Dependent Cell ◽  
T Cell Malignancies ◽  
Chemotherapy Agents ◽  
Autophagy Inhibition

AbstractIt is widely accepted that lysosomes are essential for cell homeostasis, and autophagy plays an important role in tumor development. Here, we found FV-429, a synthetic flavonoid compound, inhibited autophagy flux, promoted autophagosomes accumulation, and inhibited lysosomal degradation in T-cell malignancies. These effects were likely to be achieved by lysosomal dysregulation. The destructive effects of FV-429 on lysosomes resulted in blockage of lysosome-associated membrane fusion, lysosomal membrane permeabilization (LMP), and cathepsin-mediated caspase-independent cell death (CICD). Moreover, we initially investigated the effects of autophagy inhibition by FV-429 on the therapeutic efficacy of chemotherapy and found that FV-429 sensitized cancer cells to chemotherapy agents. Our findings suggest that FV-429 could be a potential novel autophagy inhibitor with notable antitumor efficacy as a single agent.

scholarly journals Lw-218, a New Flavonoid Compound, Exerts Anti-T-Cell Malignancies Effects Via Autophagy-Mediated Apoptosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5756-5756
Author(s):  
Po Hu ◽  
Hui Li ◽  
Bao-An Chen ◽  
Hua Tang ◽  
Zheng Ge ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Cell Lines ◽  
Cell Apoptosis ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Flavonoid Compound ◽  
Autophagy Flux ◽  
Fluorescent Intensity ◽  
T Cell Malignancies

Background:T-cell malignancies are characterized by the excessive proliferation of hematopoietic precursor cells of T-cell lineage lymphocytes in bone marrow. T-cell malignancies consist of T-cell lymphoblastic leukemia (T-ALL) and T-cell non-Hodgkin lymphoma (T-NHL). Effective therapeutic options are limited for T-cell malignancies patients. Apoptosis is one of the most important means to cure cancer. Autophagy, a conserved process that sequesters and targets cellular components for lysosomal degradation, also plays highly context-specific roles in mediating cell death. Our research found that LW-218, a new synthetic flavonoid compound, exerted anti-T-cell malignancies cell lines effects by autophagy-mediated apoptosis induction. Methods: In vitrostudy, T-ALL cell lines (Jurkat, Molt4) and T-NHL cell lines (Hut102, Hut78) were used to investigated LW-218-induced apoptosis effects by survival assays (Flow cytometry, Annexin V/PI). A series of experiment were used to assess the autophagy flux triggered by LW-218, by using mCherry-GFP-LC3 construct, Lysotracker Red staining, and determining the expression ratio of LC3-II/LC3-I. Western blot assay, RT-qPCR, transfection with siRNA, and immunofluorescence were used to investigate the underlying mechanism. In vivostudies, the anti-tumor effects of LW-218 were evaluate in T-ALL xenografts which established by subcutaneous injection of Jurkat cells. Results:Mechanistic studies demonstrated that LW-218-induced cell apoptosis in T-cell malignancies cell lines was correlated with activation of caspase 8, caspase 3 and caspases 9, and the substrate PARP1. In addition, LW-218 induced autophagy flux in T-cell malignancies, as increased ratios of LC3B-II/LC3B-I and reductions of P62 expression. The increased numbers of GFP-mCherry puncta and fluorescent intensity also indicated the increase in autolysosomes. The autophagy-mediated cell death must strictly follow the criteria that the inhibition of autophagy, through either genetic or chemical means, prevents cell death. LW-218-induced cell apoptosis and the activation of caspases3/8/9 could be prevented when the autophagy flux was blocked by autophagy inhibitors. mTOR is a master regulator of cellular metabolism and governs the programmed cell death pathways of apoptosis and autophagy. The results showed that LW-218 inhibited the expression of p-mTOR (Ser2448). And the restored activation of mTOR correlated with the inhibition of autophagy flux, which indicated mTOR might be involved in LW-218-induced autophagy. LW-218 also induced cleavage of Bid, the substrate of caspases 8, which indicated that the apoptosis mediated by autophagy might via caspases 8 and Bid activation. Thein vivostudies also verified that LW-218 inhibited the growth of tumors. Conclusions:Our study provides a new insight into the mechanism of LW-218-induced autophagy-mediated apoptosis, suggesting the potency of LW-218 to be a promising agent against T-cell malignancies. Disclosures No relevant conflicts of interest to declare.

scholarly journals cGAS is essential for cellular senescence

2017 ◽  
Vol 114 (23) ◽  
pp. E4612-E4620 ◽  
Author(s):  
Hui Yang ◽  
Hanze Wang ◽  
Junyao Ren ◽  
Qi Chen ◽  
Zhijian J. Chen
Keyword(s):  
Dna Damage ◽  
Cellular Senescence ◽  
Proliferating Cells ◽  
Antitumor Effects ◽  
Embryonic Fibroblasts ◽  
Dna Damaging Agents ◽  
Damage Response ◽  
Secretory Phenotype ◽  
Spontaneous Immortalization

Cellular senescence is a natural barrier to tumorigenesis and it contributes to the antitumor effects of several therapies, including radiation and chemotherapeutic drugs. Senescence also plays an important role in aging, fibrosis, and tissue repair. The DNA damage response is a key event leading to senescence, which is characterized by the senescence-associated secretory phenotype (SASP) that includes expression of inflammatory cytokines. Here we show that cGMP-AMP (cGAMP) synthase (cGAS), a cytosolic DNA sensor that activates innate immunity, is essential for senescence. Deletion of cGAS accelerated the spontaneous immortalization of mouse embryonic fibroblasts. cGAS deletion also abrogated SASP induced by spontaneous immortalization or DNA damaging agents, including radiation and etoposide. cGAS is localized in the cytoplasm of nondividing cells but enters the nucleus and associates with chromatin DNA during mitosis in proliferating cells. DNA damage leads to accumulation of damaged DNA in cytoplasmic foci that contain cGAS. In human lung adenocarcinoma patients, low expression of cGAS is correlated with poor survival. These results indicate that cGAS mediates cellular senescence and retards immortalization. This is distinct from, and complementary to, the role of cGAS in activating antitumor immunity.

Corilagin Inhibits Esophageal Squamous Cell Carcinoma by Inducing DNA Damage and Down-Regulation of RNF8

2019 ◽  
Vol 19 (8) ◽  
pp. 1021-1028 ◽  
Author(s):  
Fanghua Qiu ◽  
Lifang Liu ◽  
Yu Lin ◽  
Zetian Yang ◽  
Feng Qiu
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Cell Apoptosis ◽  
Cell Counting ◽  
Antitumor Effects

Background:Esophageal squamous cell carcinoma (ESCC), the most prevalent histologic subtype of esophageal cancer, is an aggressive malignancy with poor prognosis and a high incidence in the East. Corilagin, an active component present in Phyllanthus niruri L., has been shown to suppress tumor growth in various cancers. However, the effects of corilagin on ESCC and the mechanisms for its tumor suppressive function remain unknown.Methods:Cell proliferation was measured by Cell Counting Kit-8 assay and colony formation assays. Annexin V/PI double-staining was performed to assess cell apoptosis. Immunofluorescence staining and western blotting were used to evaluate the protein expression. A xenograft mice model was used to assess the in vivo antitumor effects of corilagin alone or in combination with cisplatin.Results:We for the first time showed that corilagin was effectively able to inhibit ESCC cell proliferation and induce cell apoptosis. Additionally, our results validated its antitumor effects in vivo using a xenograft mouse model. Mechanistically, we found that corilagin caused significant DNA damage in ESCC cells. We found that corilagin could significantly attenuate the expression of the E3 ubiquitin ligase RING finger protein 8 (RNF8) through ubiquitin-proteasome pathway, leading to the inability of DNA damage repair response and eventually causing cell apoptosis. Furthermore, we also showed that corilagin substantially enhanced the antitumor effects of chemotherapy drug cisplatin both in vitro and in vivo.Conclusion:Our results not only provided novel and previously unrecognized evidences for corilagin-induced tumor suppression through inducing DNA damage and targeting RNF8 in ESCC, but also highlighted that corilagin might serve as an adjunctive treatment to conventional chemotherapeutic drugs in ESCC patients.

scholarly journals PD-L1 targeting and subclonal immune escape mediated by PD-L1 mutations in metastatic colorectal cancer

2021 ◽  
Vol 9 (7) ◽  
pp. e002844
Author(s):  
Alexander Stein ◽  
Donjete Simnica ◽  
Christoph Schultheiß ◽  
Rebekka Scholz ◽  
Joseph Tintelnot ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Metastatic Colorectal Cancer ◽  
Multispectral Imaging ◽  
Standard Treatment ◽  
Immune Escape ◽  
Killer Cell ◽  
Cell Killing ◽  
Antitumor Effects ◽  
High Affinity

BackgroundIn patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), immune checkpoint blockade is ineffective, and combinatorial approaches enhancing immunogenicity need exploration.MethodsWe treated 43 patients with predominantly microsatellite stable RAS/BRAF wild-type mCRC on a phase II trial combining chemotherapy with the epidermal growth factor receptor antibody cetuximab and the programmed cell death ligand 1 (PD-L1) antibody avelumab. We performed next-generation gene panel sequencing for mutational typing of tumors and liquid biopsy monitoring as well as digital droplet PCR to confirm individual mutations. Translational analyses included tissue immunohistochemistry, multispectral imaging and repertoire sequencing of tumor-infiltrating T cells. Detected PD-L1 mutations were mechanistically validated in CRISPR/Cas9-generated cell models using qRT-PCR, immunoblotting, flow cytometry, complement-dependent cytotoxicity assay, antibody-dependent cytotoxicity by natural killer cell degranulation assay and LDH release assay as well as live cell imaging of T cell mediated tumor cell killing.ResultsCirculating tumor DNA showed rapid clearance in the majority of patients mirroring a high rate of early tumor shrinkage. In 3 of 13 patients expressing the high-affinity Fcγ receptor 3a (FcγR3a), tumor subclones with PD-L1 mutations were selected that led to loss of tumor PD-L1 by nonsense-mediated RNA decay in PD-L1 K162fs and protein degradation in PD-L1 L88S. As a consequence, avelumab binding and antibody-dependent cytotoxicity were impaired, while T cell killing of these variant clones was increased. Interestingly, PD-L1 mutant subclones showed slow selection dynamics reversing on avelumab withdrawal and patients with such subclones had above-average treatment benefit. This suggested that the PD-L1 mutations mediated resistance to direct antitumor effects of avelumab, while at the same time loss of PD-L1 reduced biological fitness by enhanced T cell killing limiting subclonal expansion.ConclusionThe addition of avelumab to standard treatment appeared feasible and safe. PD-L1 mutations mediate subclonal immune escape to avelumab in some patients with mCRC expressing high-affinity FcγR3a, which may be a subset experiencing most selective pressure. Future trials evaluating the addition of avelumab to standard treatment in MSS mCRC are warranted especially in this patient subpopulation.Trial registration numberNCT03174405.

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