The DNA repair protein O6‐Methylguanine‐DNA methyltransferase (MGMT) is suggested to be associated with resistance to alkylating agents such as Temozolomide which is being used in treatment of ...patients with glioblastoma (GBM). Therefore, we evaluated the associations between MGMT promoter methylation and prognosis of patients with glioblastoma (GBM). Data were extracted from publications in Embase, PubMed, and the Cochrane Library. Data on overall survival (OS), progression‐free survival (PFS), and MGMT methylation status were obtained and 4,097 subjects were enrolled. Data from 34 studies showed that MGMT methylated patients had better OS, compared to GBM unmethylated patients (pooled HRs, 0.494; 95%CI 0.412–0.591; p = 0.001). Meta‐analysis of 10 eligible studies reporting on PFS, demonstrated that MGMT promoter methylation was not significantly associated with better PFS (pooled HRs, 0.653; 95%CI 0.414–1.030; p = 0.067). GBM patients with MGMT methylation were associated with longer overall survival, although this effect was not detected for PFS. Moreover, we performed further analysis in patients underwent a comprehensive imaging evaluation. This data showed a significant association with better OS and PFS, although further studies are warranted to assess the value of emerging marker in prospective setting in patients with glioblastoma as a risk stratification biomarker in clinical management of the patients.
The DNA repair protein O6‐Methylguanine‐DNA methyltransferase (MGMT) is suggested to be associated with resistance to alkylating agents such as Temozolomide which is being used in treatment of patients with glioblastoma (GBM).
Neurotoxicity is a burdensome side effect of platinum‐based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment withdrawal. Peripheral sensory ...neurotoxicity varies from paresthesia in fingers to ataxic gait, which might be transient or irreversible. Because the number of patients being treated with these neurotoxic agents is still increasing, the need for understanding the pathogenesis of this dramatic side effect is critical. Platinum derivatives, such as cisplatin and carboplatin, harm mainly peripheral nerves and dorsal root ganglia neurons, possibly because of progressive DNA‐adduct accumulation and inhibition of DNA repair pathways (e.g., extracellular signal‐regulated kinase 1/2, c‐Jun N‐terminal kinase/stress‐activated protein kinase, and p38 mitogen‐activated protein kinass), which finally mediate apoptosis. Oxaliplatin, with a completely different pharmacokinetic profile, may also alter calcium‐sensitive voltage‐gated sodium channel kinetics through a calcium ion immobilization by oxalate residue as a calcium chelator and cause acute neurotoxicity. Polymorphisms in several genes, such as voltage‐gated sodium channel genes or genes affecting the activity of pivotal metal transporters (e.g., organic cation transporters, organic cation/carnitine transporters, and some metal transporters, such as the copper transporters, and multidrug resistance‐associated proteins), can also influence drug neurotoxicity and treatment response. However, most pharmacogenetics studies need to be elucidated by robust evidence. There are supportive reports about the effectiveness of several neuroprotective agents (e.g., vitamin E, glutathione, amifostine, xaliproden, and venlafaxine), but dose adjustment and/or drug withdrawal seem to be the most frequently used methods in the management of platinum‐induced peripheral neurotoxicity. To develop alternative options in the treatment of platinum‐induced neuropathy, studies on in vitro models and appropriate trials planning should be integrated into the future design of neuroprotective strategies to find the best patient‐oriented solution.
This review summarizes preclinical and clinical evidence of pathogenesis and pathophysiology of platinum‐induced peripheral neurotoxicity, as well as available evidence of neuroprotective and therapeutic strategies. These data may help to develop alternative options in the treatment of platinum‐induced neuropathy, studies on in vitro models, and appropriate trials planning to find the best patient‐oriented solution.
Colorectal cancer (CRC) is one of the most common forms of solid tumors in the world with high rates of mortality and morbidity. Most cases of CRCs are initiated by inactivating mutations in a tumor ...suppressor gene, adenomatous polyposis coli (APC), leading to constitutive activation of the Wnt signaling pathway. This review summarizes the roles of somatic and germline mutations of the APC gene in hereditary as well as sporadic forms of CRC. We also discuss the diagnostic and prognostic value of the APC gene in the pathogenesis of CRC for a better understanding of CRC disease.
•Mutations in a tumor suppressor gene, Adenomatous Polyposis Coli (APC), are critical in colorectal cancer development.•This review summarizes the roles of somatic and germline mutations of the APC gene in CRC initiation and progression.•Therapeutic, diagnostic, and prognostic value of the APC gene mutations will be discussed in the pathogenesis of CRC.
Colorectal‐cancer (CRC) is the third leading cause of death due to cancer, supporting the need for identification of novel anticancer drug to improve the efficacy of current‐therapy. There is growing ...bodies of data showing the antitumor‐activity of curcumin, although it is associated with low absorption. The aim of current study was explored the therapeutic‐potential of novel phytosomal curcumin as well as its application in combination with 5‐Flurouracil (5‐FU) in a mouse‐model of colitis‐associated colon‐cancer. The anti‐proliferative‐activity of phytosomal curcumin was assessed in 2‐ and 3‐dimensional cell‐culture‐models as well as in a mouse‐model of colitis‐associated colon‐cancer. The expression‐levels of CyclinD1, beclin, E‐cadherin, and p‐GSK3a/b were investigated by qRT‐PCR and/or Western‐blotting. We evaluated the anti‐inflammatory of this agent by pathological‐evaluation and disease‐activity‐index (DAI). Moreover, oxidant/antioxidant activity was examined by malondialdehyde (MDA), total‐thiols (T‐SH), superoxide‐dismutase (SOD), and catalase (CAT) activity parameters. Our data showed that phytosomal curcumin and its combination with 5‐FU inhibited cell growth and invasive behavior of CRC cells through modulation of Wnt‐pathway and E‐cadherin. Combination of curcumin with 5‐FU dramatically reduced the tumor‐number and tumor‐size in both distal and middle parts of colon in colitis‐associated colon cancer followed by reduction in DAI. Also, curcumin suppressed the colonic inflammation and notably recovered the increased levels of MDA, decreased thiol level and reduced activity of CAT. We demonstrated the antitumor‐activity of novel form of curcumin in CRC, supporting further investigations on the therapeutic‐potential of this approach in colorectal‐cancer.
The aim of current study is to explore the therapeutic‐potential of novel phytosomal curcumin against colitis‐associated colon‐cancer. Our results demonstrated the anti‐proliferative effects of phytosomal curcumin is mediated by regulating wnt/b‐catenin signaling pathway, suggesting that curcumin either alone or in combination with 5FU can improve clinicopathological features of colon cancer in patients.
The phosphoinositide 3 kinase AKT mammalian target of rapamycin (PI3K-AKTmTOR) signaling pathway is an important in the aetiology of pancreatic cancer (PC) and is frequently activated in PC. It is ...then associated with a poorer prognosis. Aberrant activation of this pathway is involved in cell metabolism and survival, cell cycle progression, regulation of apoptosis, protein synthesis, and genomic instability. Several agents have been developed to target the Akt/PI3K pathways, including PI3K inhibitors, (e.g. LY294002, Wortmannin), PI3K/mTOR inhibitors (e.g. BEZ235), or Akt inhibitors (e.g. perifosine, MK2206), which have been tested alone or in combinations with DNA-targeted agents (e.g., gemcitabine and fluorouracil) in pancreatic ductal adenocarcinoma (PDAC). However, due to their unfavorable pharmaceutical activities, toxicity, and crossover inhibition of other lipid and protein kinases, these compounds have not been used in clinical studies. In this review, we focus on the progress in the development of Akt, PI3K and mTOR inhibitors for clinical applications, together with the need for the development of in PDAC and the need for the identification of predictive biomarkers and combination strategies with less toxicity in counteracting the mechanisms of resistance to the therapy.
The aim of the present review is to give an overview about the role, biosynthesis, and characteristics of Podophyllotoxin (PTOX) as a potential antitumor agent with particular emphasis on key ...biosynthesis processes, function of related enzymes and characterization of genes encoding the enzymes.
Google scholar, PubMed and Scopus were searched for literatures which have studied identification, characterization, fermentation and therapeutic effects of PTOX and published in English language until end of 2016.
PTOX is an important plant-derived natural product, has derivatives such as etoposide and teniposide, which have been used as therapies for cancers and venereal wart. PTOX structure is closely related to the aryltetralin lactone lignans that have antineoplastic and antiviral activities.
Wall. (syn.
) and
L. (Berberidaceae) are the major sources of PTOX. It has been shown that ferulic acid and methylenedioxy substituted cinnamic acid are the enzymes involved in PTOX synthesis. PTOX prevents cell growth via polymerization of tubulin, leading to cell cycle arrest and suppression of the formation of the mitotic-spindles microtubules.
Several investigations have been performed in biosynthesis of PTOX such as cultivation of these plants, though they were unsuccessful. Thus, it is important to find alternative sources to satisfy the pharmaceutical demand for PTOX. Moreover, further preclinical studies are warranted to explore the molecular mechanisms of these agents in treatment of cancer and their possible potential to overcome chemoresistance of tumor cells.
Hepatocellular carcinoma (HCC) is one of the common malignant human tumors with high morbidity worldwide. Aberrant activation of the oncogenic phosphoinositide 3‐kinase/protein kinase B/mammalian ...target of rapamycin (PI3K/AKT/mTOR) signaling is related to clinicopathological features of HCC. Emerging data revealed that microRNAs (miRNAs) have prominent implications for regulating cellular proliferation, differentiation, apoptosis, and metabolism through targeting the PI3K/AKT/mTOR signaling axis. The recognition of the crucial role of miRNAs in hepatocarcinogenesis represents a promising area to identify novel anticancer therapeutics for HCC. The present study summarizes the major findings about the regulatory role of miRNAs in the PI3K/AKT/mTOR pathway in the pathogenesis of HCC.
Emerging data revealed that microRNAs (miRNAs) have prominent implications for regulating cellular proliferation, differentiation, apoptosis, and metabolism through targeting the phosphoinositide 3‐kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling axis. The present study summarizes the major findings about the regulatory role of miRNAs in PI3K/AKT/mTOR pathway in the pathogenesis of hepatocellular carcinoma.
Gold nanoparticles (GNPs), due to their unique physical and chemical properties, including optical properties, are highly regarded and have extensive applications in biomedical. One of the ...applications of gold nanoparticles is detection of chemical and biological material, so that these particles are used in detection of materials based on gold nanoparticles being in aggregate and non- aggregate modes and the change in the color of the nanoparticle solution as a result of this change of mode. In the interaction of gold nanoparticles (Bare nanoparticles or functionalized with different compositions) with analytes, aggregate and non-aggregate mode of nanoparticles changes and finally the change in the color of the solution is seen with naked eye without the need for advanced and costly equipment, indicating the presence or absence of target analytes. This change of mode and the subsequent color change is the basis of colorimetric detection based on gold nanoparticles in detection of various analytes. Various analytes can be detected by this method include ion, nucleic acid, proteins and peptides. In this study, we have reviewed various studies performed based on colorimetric detection using gold nanoparticles in detection of various analytes. According to these studies, simplicity, speed, time and cost savings are of considerable benefits of this method, compared to other detection methods.
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