scholarly journals Combination of Inhibitors of USP7 and PLK1 has a Strong Synergism against Paclitaxel Resistance

2020 ◽  
Vol 21 (22) ◽  
pp. 8629
Author(s):  
Sol-Bi Shin ◽  
Chang-Hyeon Kim ◽  
Hay-Ran Jang ◽  
Hyungshin Yim
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Spindle Pole ◽  
Mitotic Catastrophe ◽  
Malignant Cells ◽  
Paclitaxel Resistance ◽  
Cancer Treatments ◽  
Mitotic Kinase ◽  
Promising Target ◽  
Multiple Spindle

USP7 is a promising target for the development of cancer treatments because of its high expression and the critical functions of its substrates in carcinogenesis of several different carcinomas. Here, we demonstrated the effectiveness of targeting USP7 in advanced malignant cells showing high levels of USP7, especially in taxane-resistant cancer. USP7 knockdown effectively induced cell death in several cancer cells of lung, prostate, and cervix. Depletion of USP7 induced multiple spindle pole formation in mitosis, and, consequently, resulted in mitotic catastrophe. When USP7 was blocked in the paclitaxel-resistant lung cancer NCI-H460TXR cells, which has resistance to mitotic catastrophe, NCI-H460TXR cells underwent apoptosis effectively. Furthermore, combination treatment with the mitotic kinase PLK1 inhibitor volasertib and the USP7 inhibitor P22077 showed a strong synergism through down-regulation of MDR1/ABCB1 in paclitaxel-resistant lung cancer. Therefore, we suggest USP7 is a promising target for cancer therapy, and combination therapy with inhibitors of PLK1 and USP7 may be valuable for treating paclitaxel-resistant cancers, because of their strong synergism.

Caffeine induces cytoskeletal changes and cell death in H1299 cells

2014 ◽  
Vol 9 (8) ◽  
pp. 727-738 ◽  
Author(s):  
Marta Hałas ◽  
Magdalena Izdebska ◽  
Anna Klimaszewska-Wiśniewska ◽  
Maciej Gagat ◽  
Dorota Radciniewska ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cell Line ◽  
Apoptotic Cell ◽  
Lung Cancer Cell Line ◽  
Cytoskeletal Proteins ◽  
Mitotic Catastrophe ◽  
High Dose ◽  
H1299 Cell ◽  
Caffeine Treatment

AbstractCaffeine is the most common natural neuroactive substance around the world. The exact mechanism of the anticancer effects of caffeine is not clear, especially in the contexts of the cytoskeletal changes. It is known that caffeine exerts an effect on cell cycle, cell proliferation, radiosensivity of cells, and also induces cell death. The aim of the study was to determine the effect of 10 and 20 mM L−1 caffeine on the major cytoskeletal proteins in non-small lung cancer cell line H1299. Caffeine treatment induced abnormalities in morphology and ultrastructure of cells. Moreover, the fluorescence studies showed changes in organization of vimentin, β-tubulin, lamin A/C and F-actin, which were attributed to the induction of cell death. The results also demonstrated that caffeine induced formation of two cell populations: giant, mono- or multinucleated cells, with the phenotype of mitotic catastrophe and shrunken cells with condensation of chromatin, typical of apoptosis. This study for the first time shows the effect of caffeine on the cytoskeleton of H1299 cell line. In conclusion, a high-dose caffeine treatment induces apoptotic cell death and makes it a powerful anticancer agent that should be considered for the treatment of non-small cell lung cancer.

scholarly journals Ferroptosis: A New Promising Target for Lung Cancer Therapy

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Rui Xiong ◽  
Ruyuan He ◽  
Bohao Liu ◽  
Wenyang Jiang ◽  
Bo Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Lipid Peroxides ◽  
Cancer Therapies ◽  
Biological Processes ◽  
Promising Target ◽  
Underlying Basis ◽  
Lung Cancer Therapy ◽  
New Type ◽  
Growth Of Tumor

Ferroptosis is a new type of regulatory cell death that differs from autophagy, apoptosis, necrosis, and pyroptosis; it is caused primarily by the accumulation of iron and lipid peroxides in the cell. Studies have shown that many classical signaling pathways and biological processes are involved in the process of ferroptosis. In recent years, investigations have revealed that ferroptosis plays a crucial role in the progression of tumors, especially lung cancer. In particular, inducing ferroptosis in cells can inhibit the growth of tumor cells, thereby reversing tumorigenesis. In this review, we summarize the characteristics of ferroptosis from its underlying basis and role in lung cancer and provide possible applications for it in lung cancer therapies.

scholarly journals Subamolide A Induces Mitotic Catastrophe Accompanied by Apoptosis in Human Lung Cancer Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Jen-Yu Hung ◽  
Ching-Wen Wen ◽  
Ya-Ling Hsu ◽  
En-Shyh Lin ◽  
Ming-Shyan Huang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Lung Cancer ◽  
Nonsmall Cell Lung Cancer ◽  
Mitotic Catastrophe ◽  
Lung Cancer Cell ◽  
Atf3 Expression

This study investigated the anticancer effects of subamolide A (Sub-A), isolated fromCinnamomum subavenium, on human nonsmall cell lung cancer cell lines A549 and NCI-H460. Treatment of cancer cells with Sub-A resulted in decreased cell viability of both lung cancer cell lines. Sub-A induced lung cancer cell death by triggering mitotic catastrophe with apoptosis. It triggered oxidant stress, indicated by increased cellular reactive oxygen species (ROS) production and decreased glutathione level. The elevated ROS triggered the activation of ataxia-telangiectasia mutation (ATM), which further enhanced the ATF3 upregulation and subsequently enhanced p53 function by phosphorylation at Serine 15 and Serine 392. The antioxidant, EUK8, significantly decreased mitotic catastrophe by inhibiting ATM activation, ATF3 expression, and p53 phosphorylation. The reduction of ATM and ATF3 expression by shRNA decreased Sub-A-mediated p53 phosphorylation and mitotic catastrophe. Sub-A also caused a dramatic 70% reduction in tumor size in an animal model. Taken together, cell death of lung cancer cells in response to Sub-A is dependent on ROS generation, which triggers mitotic catastrophe followed by apoptosis. Therefore, Sub-A may be a novel anticancer agent for the treatment of nonsmall cell lung cancer.

Cytotoxicity and Cell Death Mechanisms Induced by a Novel Bisnaphthalimidopropyl Derivative against the NCI-H460 non-small Lung Cancer Cell Line

2013 ◽  
Vol 13 (3) ◽  
pp. 414-421 ◽  
Author(s):  
Raquel T. Lima ◽  
Gemma A. Barron ◽  
Joanna A. Grabowska ◽  
Giovanna Bermano ◽  
Simranjeet Kaur ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Lung Cancer Cell Line ◽  
Lung Cancer Cell ◽  
Cell Death Mechanisms

scholarly journals Immunogenomic Gene Signature of Cell-Death Associated Genes with Prognostic Implications in Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 155
Author(s):  
Pankaj Ahluwalia ◽  
Meenakshi Ahluwalia ◽  
Ashis K. Mondal ◽  
Nikhil Sahajpal ◽  
Vamsi Kota ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
High Risk ◽  
Lung Adenocarcinoma ◽  
Risk Group ◽  
High Risk Group ◽  
Free Survival ◽  
Cell Death Pathways

Lung cancer is one of the leading causes of death worldwide. Cell death pathways such as autophagy, apoptosis, and necrosis can provide useful clinical and immunological insights that can assist in the design of personalized therapeutics. In this study, variations in the expression of genes involved in cell death pathways and resulting infiltration of immune cells were explored in lung adenocarcinoma (The Cancer Genome Atlas: TCGA, lung adenocarcinoma (LUAD), 510 patients). Firstly, genes involved in autophagy (n = 34 genes), apoptosis (n = 66 genes), and necrosis (n = 32 genes) were analyzed to assess the prognostic significance in lung cancer. The significant genes were used to develop the cell death index (CDI) of 21 genes which clustered patients based on high risk (high CDI) and low risk (low CDI). The survival analysis using the Kaplan–Meier curve differentiated patients based on overall survival (40.4 months vs. 76.2 months), progression-free survival (26.2 months vs. 48.6 months), and disease-free survival (62.2 months vs. 158.2 months) (Log-rank test, p < 0.01). Cox proportional hazard model significantly associated patients in high CDI group with a higher risk of mortality (Hazard Ratio: H.R 1.75, 95% CI: 1.28–2.45, p < 0.001). Differential gene expression analysis using principal component analysis (PCA) identified genes with the highest fold change forming distinct clusters. To analyze the immune parameters in two risk groups, cytokines expression (n = 265 genes) analysis revealed the highest association of IL-15RA and IL 15 (> 1.5-fold, p < 0.01) with the high-risk group. The microenvironment cell-population (MCP)-counter algorithm identified the higher infiltration of CD8+ T cells, macrophages, and lower infiltration of neutrophils with the high-risk group. Interestingly, this group also showed a higher expression of immune checkpoint molecules CD-274 (PD-L1), CTLA-4, and T cell exhaustion genes (HAVCR2, TIGIT, LAG3, PDCD1, CXCL13, and LYN) (p < 0.01). Furthermore, functional enrichment analysis identified significant perturbations in immune pathways in the higher risk group. This study highlights the presence of an immunocompromised microenvironment indicated by the higher infiltration of cytotoxic T cells along with the presence of checkpoint molecules and T cell exhaustion genes. These patients at higher risk might be more suitable to benefit from PD-L1 blockade or other checkpoint blockade immunotherapies.

scholarly journals Prolonged SARS-CoV-2-RNA Detection from Nasopharyngeal Swabs in an Oncologic Patient: What Impact on Cancer Treatment?

2021 ◽  
Vol 28 (1) ◽  
pp. 847-852
Author(s):  
Anna Ferrari ◽  
Marco Trevenzoli ◽  
Lolita Sasset ◽  
Elisabetta Di Liso ◽  
Toni Tavian ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Treatment ◽  
Cancer Patients ◽  
Clinical Symptoms ◽  
Palliative Radiotherapy ◽  
Rt Pcr ◽  
Cancer Treatments ◽  
Global Challenge ◽  
Viral Culture ◽  
Pcr Assays

The pandemic of SARS-CoV-2 is a serious global challenge affecting millions of people worldwide. Cancer patients are at risk for infection exposure and serious complications. A prompt diagnosis of SARS-CoV-2 infection is crucial for the timely adoption of isolation measures and the appropriate management of cancer treatments. In lung cancer patients the symptoms of infection 19 may resemble those exhibited by the underlying oncologic condition, possibly leading to diagnostic overlap and delays. Moreover, cancer patients might display a prolonged positivity of nasopharyngeal RT-PCR assays for SARS-CoV-2, causing long interruptions or delay of cancer treatments. However, the association between the positivity of RT-PCR assays and the patient’s infectivity remains uncertain. We describe the case of a patient with non-small cell lung cancer, and a severe ab extrinseco compression of the trachea, whose palliative radiotherapy was delayed because of the prolonged positivity of nasopharyngeal swabs for SARS-CoV-2. The patient did not show clinical symptoms suggestive of active infection, but the persistent positivity of RT-PCR assays imposed the continuation of isolation measures and the delay of radiotherapy for over two months. Finally, the negative result of SARS-CoV-2 viral culture allowed us to verify the absence of viral activity and to rule out the infectivity of the patient, who could finally continue her cancer treatment.

scholarly journals Survival Impact of Aggressive Treatment and PD-L1 Expression in Oligometastatic NSCLC

2021 ◽  
Vol 28 (1) ◽  
pp. 593-605
Author(s):  
Camille Gauvin ◽  
Vimal Krishnan ◽  
Imane Kaci ◽  
Danh Tran-Thanh ◽  
Karine Bédard ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Treatment Group ◽  
Programmed Cell Death ◽  
Prognostic Impact ◽  
Aggressive Treatment ◽  
Palliative Approach ◽  
Oligometastatic Disease ◽  
Group A ◽  
Group B

Background: Studies have shown that aggressive treatment of non-small cell lung cancer (NSCLC) with oligometastatic disease improves the overall survival (OS) compared to a palliative approach and some immunotherapy checkpoint inhibitors, such as anti-programmed cell death ligand 1 (PD-L1), anti-programmed cell death protein 1 (PD-1), and T-Lymphocyte-associated antigen 4 (CTLA-4) inhibitors are now part of the standard of care for advanced NSCLC. However, the prognostic impact of PD-L1 expression in the oligometastatic setting remains unknown. Methods: Patients with oligometastatic NSCLC were identified from the patient database of the Centre hospitalier de l’Université de Montréal (CHUM). “Oligometastatic disease” definition chosen is one synchronous metastasis based on the M1b staging of the eight IASLC (The International Association for the Study of Lung Cancer) Classification (within sixth months of diagnosis) or up to three cerebral metastasis based on the methodology of the previous major phase II randomized study of Gomez et al. We compared the OS between patients receiving aggressive treatment at both metastatic and primary sites (Group A) and patients receiving non-aggressive treatment (Group B). Subgroup analysis was performed using tumor PD-L1 expression. Results: Among 643 metastatic NSCLC patients, we identified 67 patients with oligometastasis (10%). Median follow-up was 13.3 months. Twenty-nine patients (43%) received radical treatment at metastatic and primary sites (Group A), and 38 patients (57%) received non-aggressive treatment (Group B). The median OS (mOS) of Group A was significantly longer than for Group B (26 months vs. 5 months, p = 0.0001). Median progression-free survival (mPFS) of Group A was superior than Group B (17.5 months vs. 3.4 months, p = 0.0001). This difference was still significant when controlled for primary tumor staging: stage I (p = 0.316), stage II (p = 0.024), and stage III (p = 0.001). In the cohort of patients who were not treated with PD-L1 inhibitors, PD-L1 expression negatively correlated with mOS. Conclusions: Aggressive treatments of oligometastatic NSCLC significantly improve mOS and mPFS compared to a more palliative approach. PD-L1 expression is a negative prognostic factor which suggests a possible role for immunotherapy in this setting.

scholarly journals Targeting BCL-2 in Cancer: Advances, Challenges, and Perspectives

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1292 ◽  
Author(s):  
Shirin Hafezi ◽  
Mohamed Rahmani
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Targeted Therapies ◽  
Single Agent ◽  
Therapeutic Agents ◽  
Malignant Cells ◽  
Future Perspectives ◽  
Comprehensive Overview ◽  
Antiapoptotic Proteins ◽  
Preclinical And Clinical Studies

The major form of cell death in normal as well as malignant cells is apoptosis, which is a programmed process highly regulated by the BCL-2 family of proteins. This includes the antiapoptotic proteins (BCL-2, BCL-XL, MCL-1, BCLW, and BFL-1) and the proapoptotic proteins, which can be divided into two groups: the effectors (BAX, BAK, and BOK) and the BH3-only proteins (BIM, BAD, NOXA, PUMA, BID, BIK, HRK). Notably, the BCL-2 antiapoptotic proteins are often overexpressed in malignant cells. While this offers survival advantages to malignant cells and strengthens their drug resistance capacity, it also offers opportunities for novel targeted therapies that selectively kill such cells. This review provides a comprehensive overview of the extensive preclinical and clinical studies targeting BCL-2 proteins with various BCL-2 proteins inhibitors with emphasis on venetoclax as a single agent, as well as in combination with other therapeutic agents. This review also discusses recent advances, challenges focusing on drug resistance, and future perspectives for effective targeting the Bcl-2 family of proteins in cancer.

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