Hypoxia inhibition of camptothecin-induced apoptosis by Bax loss

Biologia ◽  
2012 ◽  
Vol 67 (3) ◽  
Author(s):  
Kyoungsook Park ◽  
Abdela Woubit ◽  
Cesar Fermin ◽  
Gopal Reddy ◽  
Tsegaye Habtemariam ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cancer Therapies ◽  
Normoxic Condition ◽  
Protein Levels ◽  
Cancer Chemotherapeutics ◽  
Apoptotic Protein ◽  
Anti Cancer ◽  
Cell Hypoxia ◽  
Human Solid Tumors ◽  
Induced Apoptosis

AbstractTumor cell hypoxia is linked to the resistance of human solid tumors to the various anti-cancer therapies: thus, its exploitation has been considered to be a potential target for cancer treatment. Previously, we demonstrated for the first time that hypoxia inhibits apoptosis induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) through blocking translocation of Bax, a pro-apoptotic protein, from the cytosol to the mitochondria. Nevertheless, the molecular mechanism coupling hypoxia to resistance for drugs, especially for anti-cancer chemotherapeutics, still remains to be elucidated. Here, we demonstrate that hypoxia attenuates camptothecin (CPT)-induced apoptosis by decreasing the protein levels of Bax, thereby leading to resistance to the drug. DNA damage after exposure to CPT resulted in an increase of p53, and a concomitant up-regulation of p21, regardless of oxygen content. Under normoxic condition, CPT induced expression of p53 and its down-stream target molecule Bax as well, in the presence of increased p21. In contrast, when preexposed to hypoxia, Bax-inducing activity of CPT was completely lost and the Bax level was even decreased, although CPT increased both p53 and p21 as observed under normoxic condition. Our data indicate that hypoxia attenuates apoptosis via Bax. Our data also suggest that hypoxia regulates tumor cell apoptosis differentially, through regulating Bax translocation or through down-regulating Bax levels, depending on death-inducing signals as shown by TRAIL- or CPT-induced apoptosis.

The Anticancer Effect of Sanguinarine: A Review

2018 ◽  
Vol 24 (24) ◽  
pp. 2760-2764 ◽  
Author(s):  
Chenxing Fu ◽  
Guiping Guan ◽  
Hongbing Wang
Keyword(s):  
Tumor Cell ◽  
In Vivo Studies ◽  
Inhibitory Effects ◽  
Anticancer Effect ◽  
Growth Inhibitory ◽  
Cell Proliferation Inhibition ◽  
Anti Cancer ◽  
Induced Apoptosis

In vitro and in vivo studies have revealed that Sanguinarine has antioxidant, anti-inflammatory, proapoptotic, and growth inhibitory effects on tumor cells of a variety of cancers. Previous research showed that sanguinarine induced apoptosis (cell death) and/or antiproliferative while reducing tumor cell antiangiogenic and anti-invasive properties. This paper describes various sanguinarine anti-cancer mechanisms, including inhibition of erroneously-activated signal transduction pathways, apoptosis, and tumor cell proliferation inhibition.

scholarly journals Honokiol Enhances TRAIL-Mediated Apoptosis through STAMBPL1-Induced Survivin and c-FLIP Degradation

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 838 ◽  
Author(s):  
Seon Min Woo ◽  
Seung Un Seo ◽  
Peter Kubatka ◽  
Kyoung-jin Min ◽  
Taeg Kyu Kwon
Keyword(s):  
Chinese Medicine ◽  
Cancer Cells ◽  
Tumor Necrosis ◽  
Biological Effects ◽  
Ectopic Expression ◽  
Protein Levels ◽  
Anti Cancer ◽  
Trail Resistance ◽  
Induced Apoptosis ◽  
Necrosis Factor

Honokiol is a natural biphenolic compound extracted from traditional Chinese medicine Magnolia species, which have been known to display various biological effects including anti-cancer, anti-proliferative, anti-angiogenic, and anti-metastatic activities in cancer cells. Here, we found that honokiol sensitizes cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through downregulation of anti-apoptotic proteins survivin and c-FLIP. Ectopic expression of survivin and c-FLIP markedly abolished honokiol and TRAIL-induced apoptosis. Mechanistically, honokiol induced protein degradation of c-FLIP and survivin through STAMBPL1, a deubiquitinase. STAMBPL1 interacted with survivin and c-FLIP, resulted in reduction of ubiquitination. Knockdown of STAMBPL1 reduced survivin and c-FLIP protein levels, while overexpression of STAMBPL1 inhibited honokinol-induced survivin and c-FLIP degradation. Our findings provided that honokiol could overcome TRAIL resistance through survivin and c-FLIP degradation induced by inhibition of STAMBPL1 expression.

scholarly journals VLA-4 Induces Chemoresistance of T Cell Acute Lymphoblastic Leukemia Cells via PYK2-Mediated Drug Efflux

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3512
Author(s):  
Sofiane Berrazouane ◽  
Alexie Doucet ◽  
Marc Boisvert ◽  
Frédéric Barabé ◽  
Fawzi Aoudjit
Keyword(s):  
Cell Adhesion ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Cancer Therapies ◽  
Anti Cancer ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Stromal Cell Derived Factor ◽  
Induced Apoptosis ◽  
Inhibition Studies

Cell adhesion plays a critical role in the development of chemoresistance, which is a major issue in anti-cancer therapies. In this study, we have examined the role of the VLA-4 integrin, a major adhesion molecule of the immune system, in the chemoresistance of T-ALL cells. We found that attachment of Jurkat and HSB-2 T-ALL cells to VCAM-1, a VLA-4 ligand, inhibits doxorubicin-induced apoptosis. However, their adhesion to fibronectin, which is mainly mediated via VLA-5, had no effect. Even the presence of the chemoattractant SDF1α (Stromal cell-derived factor-1α), which enhances the adhesion of T-ALL cells to fibronectin, did not modify the sensitivity of the cells attached on fibronectin towards doxorubicin-induced apoptosis. Mechanistically, we found that VLA-4 promoted T-ALL chemoresistance by inducing doxorubicin efflux. Our results showed that cell adhesion to both fibronectin and VCAM-1-induced Focal adhesion kinase (FAK) phosphorylation in T-ALL cells. However, only cell adhesion to VCAM-1 led to PYK2 phosphorylation. Inhibition studies indicated that FAK is not involved in doxorubicin efflux and chemoresistance, whereas PYK2 inhibition abrogated both VLA-4-induced doxorubicin efflux and chemoresistance. Together, these results indicate that the VLA-4/PYK2 pathway could participate in T-ALL chemoresistance and its targeting could be beneficial to limit/avoid chemoresistance and patient relapse.

Effect of dexrazoxane on doxorubicin-induced testicular toxicity.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2556-2556
Author(s):  
Irit Ben-Aharon ◽  
Moran Tzabari ◽  
Naftaly Savion ◽  
Ruth Shalgi ◽  
Salomon M. Stemmer
Keyword(s):  
Oxidative Stress ◽  
Young Male ◽  
Potential Effect ◽  
Testicular Toxicity ◽  
Stress Determination ◽  
Protein Levels ◽  
Testicular Weight ◽  
Anti Cancer ◽  
Induced Apoptosis ◽  
Therapy Result

2556 Background: Seminal advances in anti-cancer therapy result in growing numbers of young male cancer survivors for whom treatment-induced infertility represents a major late-term concern. Doxorubicin (DXR) has been previously shown to exert toxic effect on the testicular germinal epithelium. Based upon the cardioprotective traits of dexrazoxane (DEX), we aimed to study its potential effect to reduce DXR-induced testicular toxicity. Methods: Male mice were injected intraperitoneally with 5mg/kg DXR or 100mg/kg DEX or the combination of both and scarified at one month post treatment. Saline-injected mice served as controls. Testes were excised, weighed and further processed. For oxidative stress determination glutathione assay was performed on testes' lysates and P38 protein levels were determined by western blot analysis. Bax levels were used to assess apoptosis. Immunohistochemistry and confocal microscopy were used to study the effect of DXR, DEX and their combination, on the testis histology as well as on the spermatogonial reserve. Results: One month after DEX and DXR treatment, a striking decline in testicular weight was observed (decrease by 60% compared with control values; decrease of 54% in DXR-only treated mice; p<0.05). DEX prevented DXR-induced oxidative stress. However, DEX enhanced DXR-induced apoptosis within the testes and furthermore, the combination depleted the spermatogonial reserve one month after treatment. Conclusions: DEX activity in the testis may differ from its activity in cardiomyocytes. Adding DEX to DXR may exacerbate DXR-induced testicular toxicity.

scholarly journals Expression of FGF8, FGF18, and FGFR4 in Gastroesophageal Adenocarcinomas

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1092 ◽  
Author(s):  
Jomrich ◽  
Hudec ◽  
Harpain ◽  
Winkler ◽  
Timelthaler ◽  
...  
Keyword(s):  
Survival Rates ◽  
Predictive Marker ◽  
The Cancer Genome Atlas ◽  
Cancer Therapies ◽  
Data Set ◽  
Protein Levels ◽  
Cox Proportional Hazard ◽  
Anti Cancer ◽  
Cancer Genome Atlas ◽  
Cox Proportional Hazard Regression

Even though distinctive advances in the field of esophageal cancer therapy have occurred over the last few years, patients’ survival rates remain poor. FGF8, FGF18, and FGFR4 have been identified as promising biomarkers in a number of cancers; however no data exist on expression of FGF8, FGF18, and FGFR4 in adenocarcinomas of the esophago-gastric junction (AEG). A preliminary analysis of the Cancer Genome Atlas (TCGA) database on FGF8, FGF18, and FGFR4 mRNA expression data of patients with AEG was performed. Furthermore, protein levels of FGF8, FGF18, and FGFR4 in diagnostic biopsies and post-operative specimens in neoadjuvantly treated and primarily resected patients using immunohistochemistry were investigated. A total of 242 patients was analyzed in this study: 87 patients were investigated in the TCGA data set analysis and 155 patients in the analysis of protein expression using immunohistochemistry. High protein levels of FGF8, FGF18, and FGFR4 were detected in 94 (60.7%), 49 (31.6%) and 84 (54.2%) patients, respectively. Multivariable Cox proportional hazard regression models revealed that high expression of FGF8 was an independent prognostic factor for diminished overall survival for all patients and for neoadjuvantly treated patients. By contrast, FGF18 overexpression was significantly associated with longer survival rates in neoadjuvantly treated patients. In addition, FGF8 protein level correlated with Mandard regression due to neoadjuvant therapy, indicating potential as a predictive marker. In summary, FGF8 and FGF18 are promising candidates for prognostic factors in adenocarcinomas of the esophago-gastric junction and new potential targets for new anti-cancer therapies.

scholarly journals Doxorubicin hydrochloride liposome and albumin-bound paclitaxel in cancer: a nanotechnology perspective

2021 ◽  
pp. 59-65
Author(s):  
Rajib Hossain ◽  
Rasel Ahmed Khan ◽  
Muhammad Torequl Islam ◽  
Divya Jain ◽  
Pracheta Janmeda ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Active Sites ◽  
Biosynthetic Pathway ◽  
Chemotherapeutic Agents ◽  
Cancer Therapies ◽  
Tumor Cell Membrane ◽  
Routes Of Administration ◽  
Anti Cancer ◽  
Specific Reactions ◽  
Cancerous Cells

Nanoparticles (1-100 nanometres in size), products of nanotechnology, offer a modern way to transport anti-cancer drugs by acting as transporters of drugs into tumor cells, hence quenching tumor cell proliferation. Such nanoparticles may be formulated to bind to the tumor cell membrane or inhibit specific reactions of tumor biosynthetic pathway by gene repression, or directly bind to the active sites of essential enzymes in the biosynthetic pathway. Consequently, drugs are completely delivered to the desired cancerous cells without system interference. Liposomal doxorubicin and albumin-bound paclitaxel are two examples of nanotechnologically developed drugs for treating cancer. Modern knowledge of nanotechnology opens up new opportunities for innovative research on cancer therapies and administration and helps minimize harm to healthy cells. This review focuses on the doses and routes of administration of these chemotherapeutic agents used in treating cancers.

scholarly journals Combination of Anti-Cancer Drugs with Molecular Chaperone Inhibitors

2019 ◽  
Vol 20 (21) ◽  
pp. 5284 ◽  
Author(s):  
Maxim Shevtsov ◽  
Gabriele Multhoff ◽  
Elena Mikhaylova ◽  
Atsushi Shibata ◽  
Irina Guzhova ◽  
...  
Keyword(s):  
Heat Shock ◽  
Tumor Cell ◽  
Stress Factors ◽  
Cell Physiology ◽  
Cancer Therapies ◽  
Therapeutic Approaches ◽  
Pharmacological Stress ◽  
Proteotoxic Stress ◽  
Optimal Drug ◽  
Anti Cancer

Most molecular chaperones belonging to heat shock protein (HSP) families are known to protect cancer cells from pathologic, environmental and pharmacological stress factors and thereby can hamper anti-cancer therapies. In this review, we present data on inhibitors of the heat shock response (particularly mediated by the chaperones HSP90, HSP70, and HSP27) either as a single treatment or in combination with currently available anti-cancer therapeutic approaches. An overview of the current literature reveals that the co-administration of chaperone inhibitors and targeting drugs results in proteotoxic stress and violates the tumor cell physiology. An optimal drug combination should simultaneously target cytoprotective mechanisms and trigger the imbalance of the tumor cell physiology.

scholarly journals Chidamide Combined with Decitabine Synergistically Induce Apoptosis of Acute Myeloid Leukemia By up-Regulating Perp gene In Vivo and in Vitro

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 536-536
Author(s):  
Qing Li ◽  
Yunfan Yang ◽  
Yu Wu
Keyword(s):  
Cell Lines ◽  
Drug Combination ◽  
Transcriptome Sequencing ◽  
Myeloid Leukemia ◽  
Protein Levels ◽  
Apoptotic Protein ◽  
Induced Apoptosis ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is a malignant clonal disease of hematopoietic stem cells. The long term survival of AML is not satisfactory, so new treatment should be explored. Here, we show that chidamide(CH), a histone deacetylase inhibitor, combined with decitabine(DE) induces apoptosis of AML cell lines and primary refractory/relapsed AML cells by up-regulating PERP. This may provide a new option for AML treatment. Methods and results: We first examined the half-inhibitory concentrations (IC50) of chidamide and decitabine against THP-1, MV4-11, HL60 and Kasumi-1 cell lines using MTT (Fig1 A-D). And the drug combination is performed according to the IC50. In the double-drug combination experiment, we used MTT to detect the effect of drugs on the proliferation of the four cell lines (Fig1 E-H), used calcusyn 2.0 software to calculate the synergistic effect (Fig2), flow cytometry to detect apoptosis (Fig3 A-D), and western blot to detect the pro-apoptotic protein (C-CASPASE 3 and C-CASPASE 9) and anti-apoptotic proteins (CASPASE 8, BCL-2 and BCL-XL) (Fig3 E-H). We found that chidamide combined with decitabine synergistically inhibited proliferation of AML cell lines, induced apoptosis, up-regulated pro-apoptotic protein levels and down-regulated anti-apoptotic protein levels. To investigate this combination therapeutic effect in vivo, we selected 5 refractory/relapsed AML patients, extracted primary AML cells, and used ATP chemiluminescence kit for drug sensitivity test. The results confirmed that four of the five patients with AML showed sensitivity to combinations (Fig4). To further explore the mechanism of action of CH combination with DE, we performed transcriptome sequencing (Fig5). Analysis of the sequencing results, the gene PERP, which shows the significant difference in the apoptotic pathway, was further examined. The PERP is a new member of the PMP-22/GAS3 family as an apoptosis-associated target of TP53. RT-QPCR and WB verified the role of PERP in apoptosis in DE and CH combination (Fig6). The results showed that the combination could up-regulate the PERP gene than the single drug. When we explored the role of the PERP gene in AML cell lines, we knocked down the PERP gene by lentivirus and detected cell proliferation after infection. Pretreated AML cell lines by lentivirus-infection (Fig7A-F), then we tested for proliferation (Fig7G-I) (Fig8A-C), apoptosis (Fig8D-E), and pro-apoptotic protein expression (Fig8G-I). The results showed that knocking down the PERP gene promoted the proliferation of AML cell lines and attenuated the sensitivity of AML cell lines to chemotherapeutic drugs. We also compare the mRNA level of PERP between 35 AML patients and 20 normal and found that the PERP mRNA of AML patients was significantly lower than the normal (Fig9). MV4-11 cells were exposed to CH and DE alone or in combination, and proteomic sequencing was performed to examine the effect of the drug on cellular protein. The result indicates to some extent that CH contributes more to the combined effect. And the drug causes changes in multiple pathways in the cell (Fig10). Conclusion: Our experiments revealed that CH combined with DE may have therapeutic effects on AML and, to some extent, reveal the mechanism of dual drug combination. Legends to figures Fig1. 50% inhibitory concentration (IC50) values of chidamide and decitabine alone treated AML cell lines. Fig2. Chidamide acts synergistically in AML with DE. Fig3. Chidamide in combination with decitabine significantly induced apoptosis in AML cell lines. Fig4. The sensitivity of relapsed or refractory AML primary cells to chidamide and decitabine alone or in combination. Fig5. Gene expression analysis showed an obvious difference based on treatment. Fig6. Verify transcriptome sequencing results by real-time QPCR and by western blotting with or without drug treatment. Fig7. The effect of down-regulation of PERP by Lentivirus-mediated RNAi on AML cells proliferation. Fig8. PERP knockdown causes AML cells to develop resistance to combination drugs. Fig9.The level of PERP mRNA in peripheral blood mononuclear cells of AML and normal humans. Fig10. Proteomics sequencing results show the differentially expressed protein and a cluster analysis of the functions or pathways enriched by differentially expressed proteins in GO and KEGG pathways compared to single agents. Disclosures No relevant conflicts of interest to declare.

ANTICANCER EFFECT OF UVARIA GENUS

2014 ◽  
pp. 98-101
Author(s):  
Thi Bich Hien Le ◽  
Viet Duc Ho ◽  
Thi Hoai Nguyen
Keyword(s):  
Biological Activities ◽  
Current Trend ◽  
Healthcare Systems ◽  
Chemical Compositions ◽  
Cancer Therapies ◽  
Pharmacological Effects ◽  
Anticancer Effect ◽  
Anti Cancer ◽  
Tropical Areas ◽  
Cancer Activity

Nowadays, cancer treatment has been a big challenge to healthcare systems. Most of clinical anti-cancer therapies are toxic and cause adverse effects to human body. Therefore, current trend in science is seeking and screening of natural compounds which possess antineoplastic activities to utilize in treatment. Uvaria L. - Annonaceae includes approximately 175 species spreading over tropical areas of Asia, Australia, Africa and America. Studies on chemical compositions and pharmacological effects of Uvaria showed that several compound classes in this genus such as alkaloid, flavonoid, cyclohexen derivaties, acetogenin, steroid, terpenoid, etc. indicate considerable biological activities, for example anti-tumor, anti-cancer, antibacterial, antifungal, antioxidant, etc. Specifically, anti-cancer activity of fractions of extract and pure isolated compounds stands out for cytotoxicity against many cancer cell lines. This study provides an overview of anti-cancer activity of Uvaria and suggests a potential for further studies on seeking and developing novel anti-cancer compounds. Key words: Anti-cancer, Uvaria.

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