scholarly journals Mechanisms of Hydroxyurea-Induced Cellular Senescence: An Oxidative Stress Connection?

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Sunčica Kapor ◽  
Vladan Čokić ◽  
Juan F. Santibanez
Keyword(s):  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Essential Medicine ◽  
Therapy Resistance ◽  
Water Soluble ◽  
Cell Functions ◽  
Intracellular Ros ◽  
Antiproliferative Agent ◽  
And Control

Hydroxyurea (HU) is a water-soluble antiproliferative agent used for decades in neoplastic and nonneoplastic conditions. HU is considered an essential medicine because of its cytoreduction functions. HU is an antimetabolite that inhibits ribonucleotide reductase, which causes a depletion of the deoxyribonucleotide pool and dramatically reduces cell proliferation. The proliferation arrest, depending on drug concentration and exposure, may promote a cellular senescence phenotype associated with cancer cell therapy resistance and inflammation, influencing neighboring cell functions, immunosuppression, and potential cancer relapse. HU can induce cellular senescence in both healthy and transformed cells in vitro, in part, because of increased reactive oxygen species (ROS). Here, we analyze the main molecular mechanisms involved in cytotoxic/genotoxic HU function, the potential to increase intracellular ROS levels, and the principal features of cellular senescence induction. Understanding the mechanisms involved in HU’s ability to induce cellular senescence may help to improve current chemotherapy strategies and control undesirable treatment effects in cancer patients and other diseases.

scholarly journals Proanthocyanidins against Oxidative Stress: From Molecular Mechanisms to Clinical Applications

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Lingyu Yang ◽  
Dehai Xian ◽  
Xia Xiong ◽  
Rui Lai ◽  
Jing Song ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Low Cost ◽  
Natural Agents ◽  
Molecular Damage ◽  
And Control

Proanthocyanidins (PCs) are naturally occurring polyphenolic compounds abundant in many vegetables, plant skins (rind/bark), seeds, flowers, fruits, and nuts. Numerousin vitroandin vivostudies have demonstrated myriad effects potentially beneficial to human health, such as antioxidation, anti-inflammation, immunomodulation, DNA repair, and antitumor activity. Accumulation of prooxidants such as reactive oxygen species (ROS) exceeding cellular antioxidant capacity results in oxidative stress (OS), which can damage macromolecules (DNA, lipids, and proteins), organelles (membranes and mitochondria), and whole tissues. OS is implicated in the pathogenesis and exacerbation of many cardiovascular, neurodegenerative, dermatological, and metabolic diseases, both through direct molecular damage and secondary activation of stress-associated signaling pathways. PCs are promising natural agents to safely prevent acute damage and control chronic diseases at relatively low cost. In this review, we summarize the molecules and signaling pathways involved in OS and the corresponding therapeutic mechanisms of PCs.

Cytotoxic and antitumoral activity of N-(9H-purin-6-yl) benzamide derivatives and related water-soluble prodrugs

2021 ◽  
Vol 14 ◽  
Author(s):  
Emeline Cros-Perrial ◽  
Steve Saulnier ◽  
Muhammad Zawwad Raza ◽  
Rémi Charmelot ◽  
David Egron ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Biological Evaluation ◽  
Water Soluble ◽  
Antitumoral Activity ◽  
Cell Cycle Distribution ◽  
Synergistic Activity ◽  
Benzamide Derivatives

Background: The development of small molecules as cancer treatments is still of both interest and importance. Objective: Having synthesized and identified the initial cytotoxic activity of a series of chemically related N-(9H-purin-6-yl) benzamide derivatives, we continued their evaluation on cancer cell models. We also synthesized water-soluble prodrugs of the main compound and performed in vivo experiments. Method: We used organic chemistry to obtain compounds of interest and prodrugs. The biological evaluation included MTT assays, synergy experiments, proliferation assays by CFSE, cell cycle distribution and in vivo antitumoral activity. Results: Our results show activities on cancer cell lines ranging from 3-39 µM for the best compounds, with both induction of apoptosis and decrease in cell proliferation. Two compounds evaluated in vivo showed weak antitumoral activity. In addition, the lead compound and its prodrug had a synergistic activity with the nucleoside analogue fludarabine in vitro and in vivo. Conclusion: Our work allowed us to gain better knowledge on the activity of N-(9H-purin-6-yl) benzamide derivatives and showed new examples of water-soluble prodrugs. More research is warranted to decipher the molecular mechanisms of the molecules.

scholarly journals Plumbagin Enhances the Anticancer Efficacy of Cisplatin by Increasing Intracellular ROS in Human Tongue Squamous Cell Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-21 ◽  
Author(s):  
Danfeng Xue ◽  
Shu-Ting Pan ◽  
Xiongming Zhou ◽  
Fangfei Ye ◽  
Qun Zhou ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Side Effects ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Molecular Mechanisms ◽  
Tongue Squamous Cell Carcinoma ◽  
Human Tongue ◽  
Intracellular Ros

Cisplatin is widely used in the treatment of tongue squamous cell carcinoma (TSCC), but its clinical efficacy is limited by drug resistance and toxic side effects. Hence, a novel compound capable of enhancing the anticancer effect of cisplatin while reducing the side effects is urgently needed. We have previously shown that plumbagin (PLB), an anticancer phytochemical, is able to inhibit the growth of TSCC in vitro and in vivo. The objective of this study was to investigate the effect of PLB in reversing the resistance of TSCC to cisplatin as well as its molecular mechanisms. Here, we found that PLB enhances cisplatin-induced cytotoxicity, apoptosis, and autophagy in CAL27 and cisplatin-resistant CAL27/CDDP cells. PLB could inhibit the viability and growth of TSCC cells by increasing the production of intracellular reactive oxygen species (ROS). In addition, the combination treatment of PLB and cisplatin resulted in a synergistic inhibition of TSCC viability, apoptosis, and autophagy by increasing intracellular ROS, which may be achieved by activating JNK and inhibiting AKT/mTOR signaling pathways. Finally, the synergistic treatment was also demonstrated in vivo. Therefore, PLB combined with cisplatin is a potential therapeutic strategy against therapy TSCC cisplatin resistance.

scholarly journals Anticancer Activity of Water-Soluble Olsalazine-PAMAM-Dendrimer-Salicylic Acid-Conjugates

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 360
Author(s):  
Sandra Cortez-Maya ◽  
Luis Daniel Pedro-Hernández ◽  
Elena Martínez-Klimova ◽  
Teresa Ramírez-Ápan ◽  
Marcos Martínez-García
Keyword(s):  
Salicylic Acid ◽  
Anticancer Agents ◽  
Drug Carrier ◽  
Pamam Dendrimer ◽  
Water Soluble ◽  
Mammary Adenocarcinoma ◽  
African Green Monkey Kidney ◽  
Mammary Adenocarcinoma Cell ◽  
Antiproliferative Agent

Improving the activity and selectivity profile of anticancer agents will require designing drug carrier systems that employ soluble macromolecules. Olsalazine-PAMAM-dendrimer-salicylic acid-conjugates with dendritic arms of different lengths have shown good stability regarding the chemical link between drug and spacer. In this study, the drug release was followed in vitro by ultraviolet (UV) studies. Evaluation of the cytotoxicity of the olsalazine-PAMAM-dendrimer-salicylic acid-conjugates employing a sulforhodamine B (SRB) assay in PC-3 (human prostatic adenocarcinoma) and MCF-7 (human mammary adenocarcinoma) cell lines demonstrated that conjugate 9 was more active as an antiproliferative agent than cisplatin, and no cytotoxicity towards the African green monkey kidney fibroblast (COS-7) cell line was observed in any of the conjugates synthesized in the present work.

scholarly journals IL-6 regulates CCR5 expression and immunosuppressive capacity of MDSC in murine melanoma

2020 ◽  
Vol 8 (2) ◽  
pp. e000949 ◽  
Author(s):  
Rebekka Weber ◽  
Zeno Riester ◽  
Laura Hüser ◽  
Carsten Sticht ◽  
Alina Siebenmorgen ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Ccr5 Expression ◽  
Myeloid Suppressor Cell ◽  
Cell Functions ◽  
Arginase 1

BackgroundMyeloid-derived suppressor cells (MDSC) play a major role in the immunosuppressive melanoma microenvironment. They are generated under chronic inflammatory conditions characterized by the constant production of inflammatory cytokines, chemokines and growth factors, including IL-6. Recruitment of MDSC to the tumor is mediated by the interaction between chemokines and chemokine receptors, in particular C–C chemokine receptor (CCR)5. Here, we studied the mechanisms of CCR5 upregulation and increased immunosuppressive function of CCR5+ MDSC.MethodsThe immortalized myeloid suppressor cell line MSC-2, primary immature myeloid cells and in vitro differentiated MDSC were used to determine factors and molecular mechanisms regulating CCR5 expression and immunosuppressive markers at the mRNA and protein levels. The relevance of the identified pathways was validated on the RET transgenic mouse melanoma model, which was also used to target the identified pathways in vivo.ResultsIL-6 upregulated the expression of CCR5 and arginase 1 in MDSC by a STAT3-dependent mechanism. MDSC differentiated in the presence of IL-6 strongly inhibited CD8+ T cell functions compared with MDSC differentiated without IL-6. A correlation between IL-6 levels, phosphorylated STAT3 and CCR5 expression in tumor-infiltrating MDSC was demonstrated in the RET transgenic melanoma mouse model. Surprisingly, IL-6 overexpressing tumors grew significantly slower in mice accompanied by CD8+ T cell activation. Moreover, transgenic melanoma-bearing mice treated with IL-6 blocking antibodies showed significantly accelerated tumor development.ConclusionOur in vitro and ex vivo findings demonstrated that IL-6 induced CCR5 expression and a strong immunosuppressive activity of MDSC, highlighting this cytokine as a promising target for melanoma immunotherapy. However, IL-6 blocking therapy did not prove to be effective in RET transgenic melanoma-bearing mice but rather aggravated tumor progression. Further studies are needed to identify particular combination therapies, cancer entities or patient subsets to benefit from the anti-IL-6 treatment.

scholarly journals Senescent Cell-Secreted Netrin-1 Modulates Aging-Related Disorders by Recruiting Sympathetic Fibers

2020 ◽  
Vol 12 ◽  
Author(s):  
Ai Qing Yu ◽  
Jie Wang ◽  
Xiao Jia Zhou ◽  
Ke Yu Chen ◽  
You De Cao ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Human Colon ◽  
Senescent Cell ◽  
Aged Mouse ◽  
Age Related ◽  
Mouse Tissues ◽  
6 Hydroxydopamine

Cellular senescence is implicated in several lines of aging-related disorders. However, the potential molecular mechanisms by which cellular senescence modulates age-related pathologies remain largely unexplored. Herein, we report that the density of sympathetic fibers (SFs) is significantly elevated in naturally aged mouse tissues and human colon adenoma tissues compared to the SFs densities in the corresponding young mouse tissues and human non-lesion colon tissues. A dorsal root ganglion (DRG)-human diploid fibroblast coculture assay revealed that senescent cells promote the outgrowth of SFs, indicating that the senescent cells induce recruitment of SFs in vitro. Additionally, subcutaneous transplantation of 2BS fibroblasts in nude mice shows that transplanted senescent 2BS fibroblasts promote SFs infiltration. Intra-articular senolytic molecular injection can reduce SFs density and inhibit SFs infiltration caused by senescent cells in osteoarthritis (OA), suggesting senescent cells promote the infiltration of SFs in vivo in aged tissues. Notably, the elevated level of SFs contributes to impaired cognitive function in naturally aged mice, which can be reversed by treatment with propranolol hydrochloride, a non-selective β receptor blocker that inhibits sympathetic nerve activity (SNA) by blocking non-selective β receptors. Additionally, 6-hydroxydopamine (6-OHDA)-induced sympathectomy improved hepatic sympathetic overactivity mediated hepatic steatosis in high fat diet (HFD)-fed APOE knockout mice (APOE−/− mice) by reducing hepatic SNA. Taken together, this study concludes that senescent cell-secreted netrin-1 mediated SFs outgrowth and infiltration, which contributes to aging-related disorders, suggesting that clearing senescent cells or inhibiting SNA is a promising therapeutic strategy for improving sympathetic nervous system (SNS) hyperactivity-induced aging-related pathologies.

scholarly journals Calreticulin reveals a critical Ca2+ checkpoint in cardiac myofibrillogenesis

2002 ◽  
Vol 158 (1) ◽  
pp. 103-113 ◽  
Author(s):  
Jian Li ◽  
Michel Pucéat ◽  
Carmen Perez-Terzic ◽  
Annabelle Mery ◽  
Kimitoshi Nakamura ◽  
...  
Keyword(s):  
Heart Development ◽  
Molecular Mechanisms ◽  
Es Cells ◽  
Embryonic Stem ◽  
Cardiac Cells ◽  
Embryoid Bodies ◽  
Cell Functions ◽  
Myosin Light Chain 2 ◽  
And Function

Calreticulin (crt) is an ubiquitously expressed and multifunctional Ca2+-binding protein that regulates diverse vital cell functions, including Ca2+ storage in the ER and protein folding. Calreticulin deficiency in mice is lethal in utero due to defects in heart development and function. Herein, we used crt−/− embryonic stem (ES) cells differentiated in vitro into cardiac cells to investigate the molecular mechanisms underlying heart failure of knockout embryos. After 8 d of differentiation, beating areas were prominent in ES-derived wild-type (wt) embryoid bodies (EBs), but not in ES-derived crt−/− EBs, despite normal expression levels of cardiac transcription factors. Crt−/− EBs exhibited a severe decrease in expression and a lack of phosphorylation of ventricular myosin light chain 2 (MLC2v), resulting in an impaired organization of myofibrils. Crt−/− phenotype could be recreated in wt cells by chelating extracellular or cytoplasmic Ca2+ with EGTA or BAPTA, or by inhibiting Ca2+/calmodulin-dependent kinases (CaMKs). An imposed ionomycin-triggered cystolic-free Ca2+ concentration ([Ca2+]c) elevation restored the expression, phosphorylation, and insertion of MLC2v into sarcomeric structures and in turn the myofibrillogenesis. The transcription factor myocyte enhancer factor C2 failed to accumulate into nuclei of crt−/− cardiac cells in the absence of ionomycin-triggered [Ca2+]c increase. We conclude that the absence of calreticulin interferes with myofibril formation. Most importantly, calreticulin deficiency revealed the importance of a Ca2+-dependent checkpoint critical for early events during cardiac myofibrillogenesis.

scholarly journals Procyanidin A1 Alleviates Inflammatory Response induced by LPS through NF-κB, MAPK, and Nrf2/HO-1 Pathways in RAW264.7 cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Shan Han ◽  
Hongwei Gao ◽  
Shaoru Chen ◽  
Qinqin Wang ◽  
Xinxing Li ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Inflammatory Diseases ◽  
Raw264.7 Cells ◽  
Tnf Α ◽  
Intracellular Ros ◽  
Anti Inflammatory ◽  
Cellular Thermal Shift Assay

Abstract Inflammation is a complex physiological process that poses a serious threat to people’s health. However, the potential molecular mechanisms of inflammation are still not clear. Moreover, there is lack of effective anti-inflammatory drugs that meet the clinical requirement. Procyanidin A1 (PCA1) is a monomer component isolated from Procyanidin and shows various pharmacological activities. This study further demonstrated the regulatory role of PCA1 on lipopolysaccharide (LPS)-stimulated inflammatory response and oxidative stress in RAW264.7 cells. Our data showed that PCA1 dramatically attenuated the production of pro-inflammatory cytokines such as NO, iNOS, IL-6, and TNF-α in RAW264.7 cells administrated with LPS. PCA1 blocked IκB-α degradation, inhibited IKKα/β and IκBα phosphorylation, and suppressed nuclear translocation of p65 in RAW264.7 cells induced by LPS. PCA1 also suppressed the phosphorylation of JNK1/2, p38, and ERK1/2 in LPS-stimulated RAW264.7 cells. In addition, PCA1 increased the expression of HO-1, reduced the expression of Keap1, and promoted Nrf2 into the nuclear in LPS-stimulated RAW264.7 cells. Cellular thermal shift assay indicated that PCA1 bond to TLR4. Meanwhile, PCA1 inhibited the production of intracellular ROS and alleviated the depletion of mitochondrial membrane potential in vitro. Collectively, our data indicated that PCA1 exhibited a significant anti-inflammatory effect, suggesting that it is a potential agent for the treatment of inflammatory diseases.

scholarly journals Enhanced Expression of IGFBP-3 Reduces Radiosensitivity and Is Associated with Poor Prognosis in Oral Squamous Cell Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 494
Author(s):  
Junki Sakata ◽  
Akiyuki Hirosue ◽  
Ryoji Yoshida ◽  
Yuichiro Matsuoka ◽  
Kenta Kawahara ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Molecular Mechanisms ◽  
Immunohistochemical Analysis ◽  
Cell Functions ◽  
Potential Biomarker ◽  
Igfbp 3

Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) modulates various cell functions through IGF-dependent or independent mechanisms. However, its biological roles in the radiosensitivity of oral squamous cell carcinoma (OSCC) remain largely unknown. The purpose of this study was to determine the clinical significance and molecular mechanisms of the association between IGFBP-3 and OSCC radiosensitivity. We performed an immunohistochemical analysis of IGFBP-3 in 52 OSCC specimens from patients treated with preoperative chemoradiotherapy and surgery (phase II study). Associations between IGFBP-3 expression and clinicopathological features were also evaluated. In addition, we examined the effects of IGFBP-3 on post-X-ray irradiation radiosensitivity and DNA damage in vitro. High IGFBP-3 expression was significantly correlated with poor chemoradiotherapy responses and prognosis. With IGFBP-3 knockdown, irradiated OSCC cells exhibited significantly higher radiosensitivity compared with that of control cells. Moreover, IGFBP-3 depletion in OSCC cells reduced phosphorylation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which is required for DNA double-strand break repair during non-homologous end joining. These findings indicate that IGFBP-3 may have a significant role in regulating DNA repair and is be a potential biomarker for predicting clinical response to radiotherapy and prognosis in OSCC.

scholarly journals Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): Effects of raloxifene, on Endoglin and ALK1 expression in endothelial cells

2010 ◽  
Vol 103 (03) ◽  
pp. 441-451 ◽  
Author(s):  
Virginia Albiñana ◽  
Maria Bernabeu-Herrero ◽  
Roberto Zarrabeitia ◽  
Carmelo Bernabeu ◽  
Luisa Botella
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Estrogen Therapy ◽  
Clinical Manifestations ◽  
Transforming Growth Factor Β ◽  
Therapeutic Effects ◽  
Hereditary Haemorrhagic Telangiectasia ◽  
Cell Functions

SummaryHereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is an autosomal dominant vascular disease. The clinical manifestations are epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations. There are two predominant types of HHT caused by mutations in Endoglin (ENG) and activin receptor-like kinase 1 (ALK1) (ACVRL1) genes, HHT1 and HHT2, respectively. No cure for HHT has been found and there is a current need to find new effective drug treatments for the disease. Some patients show severe epistaxis which interferes with their quality of life. We report preliminary results obtained with Raloxifene to treat epistaxis in postmenopausal HHT women diagnosed with osteoporosis. We tried to unravel the molecular mechanisms involved in the therapeutic effects of raloxifene. ENG and ACVRL1 genes code for proteins involved in the transforming growth factor β pathway and it is widely accepted that haploinsufficiency is the origin for the pathogenicity of HHT. Therefore, identification of drugs able to increase the expression of those genes is essential to propose new therapies for HHT. In vitro results show that raloxifene increases the protein and mRNA expression of ENG and ALK1 in cultured endothelial cells. Raloxifene also stimulates the promoter activity of these genes, suggesting a transcriptional regulation of ENG and ALK1. Furthermore, Raloxifene improved endothelial cell functions like tubulogenesis and migration in agreement with the reported functional roles of Endoglin and ALK1. Our pilot study provides a further hint that oral administration of raloxifene may be beneficial for epistaxis treatment in HHT menopausal women. The molecular mechanisms of raloxifene involve counteracting the haploin-sufficiency of ENG and ALK1.

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