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How to deal with cancer drug resistance - posted in Research Idea, Design and Collaboration: Anybody has a good idea on how to solve cancer drug resistance issues. Many new drugs are designed to block one or more signal transduction pathways in order to block cancer cell proliferation. But cancer cell can bypass the blocked pathway and survives later in the treatment cycles. Combination or coktail of multiple drugs can have serious side-effects. What other general ideas can provide better...
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Drug resistance remains a great challenge in the treatment of gastric cancer. The goal of this study was to explore the anti-tumor effects and mechanism of cytokine-induced killer (CIK) cell combined with oxaliplatin (L-OHP) in human oxaliplatin-resistant gastric cancer cells. After producing oxaliplatin-resistant gastric cancer cells, cell morphology, growth and doubling time were observed, followed by detection of cell cycle distribution and apoptosis, drug sensitivity (e.g., L-OHP) and expression of P-gp and livin. MTT assay, in vivo pharmacodynamics and pathomorphology experiments were used to detect killing activities of CIK combined with L-OHP. Compared with parental gastric cancer cells, oxaliplatin-resistant gastric cancer cells in S phase were reduced and cell apoptosis rate was increased (P < 0.05), the inhibition rate of 10 chemotherapeutics on oxaliplatin-resistant gastric cancer cells was significantly lower and the expression of P-gp was significantly higher (P < 0.05). However, there was
The dose-limiting toxicity of chemotherapeutics, heterogeneity and drug resistance of cancer cells, and difficulties of targeted delivery to tumors all pose daunting challenges to effective cancer therapy. We report that small interfering RNA (siRNA) duplexes readily penetrate intact bacterially derived minicells previously shown to cause tumor stabilization and regression when packaged with chemotherapeutics. When targeted via antibodies to tumor-cell-surface receptors, minicells can specifically and sequentially deliver to tumor xenografts first siRNAs or short hairpin RNA (shRNA)-encoding plasmids to compromise drug resistance by knocking down a multidrug resistance protein. Subsequent administration of targeted minicells containing cytotoxic drugs eliminate formerly drug-resistant tumors. The two waves of treatment, involving minicells loaded with both types of payload, enable complete survival without toxicity in mice with tumor xenografts, while involving several thousandfold less drug, ...
Drug resistance is a major obstacle in curing ovarian cancer but new research from the Centenary Institute has discovered a treatment that kills ovarian cancer cells in a new way that
The molecular mechanism by which cancer-associated fibroblasts (CAFs) confer chemoresistance in ovarian cancer is poorly understood. The purpose of the present study was to evaluate the roles of CAFs in modulating tumor vasculature, chemoresistance, and disease progression. Here, we found that CAFs upregulated the lipoma-preferred partner (LPP) gene in microvascular endothelial cells (MECs) and that LPP expression levels in intratumoral MECs correlated with survival and chemoresistance in patients with ovarian cancer. Mechanistically, LPP increased focal adhesion and stress fiber formation to promote endothelial cell motility and permeability. siRNA-mediated LPP silencing in ovarian tumor-bearing mice improved paclitaxel delivery to cancer cells by decreasing intratumoral microvessel leakiness. Further studies showed that CAFs regulate endothelial LPP via a calcium-dependent signaling pathway involving microfibrillar-associated protein 5 (MFAP5), focal adhesion kinase (FAK), ERK, and LPP. Thus, ...
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Read up on the latest developments in several important areas of cancer research emerging from the 2019 American Association for Cancer Research annual meeting.
Drug resistance may emerge de novo when beneficial peptides are expressed by bacteria using completely random, noncoding DNA sequences
Hello: We have a drug resistant cell (murine) line that routinely is grown in presence of the drug. When these cell were grown in absence of the drug the phenotype changed to sensible after 90 passages (we compare levels of accumulation of drug in WT and resistant cell, the resistant accumulate less). Can we conclude that there may be single mutation event involved in the generation of resistance and that after 90 passages in absence of selection pressure reverted? Or is it just matter of regulation of expression of genes under that stress? And that in absence of drug everything goes back to normal levels? Is 90 passages too long to restore normal levels of expressions and actually it is a mutation? How to calculate the mutation frequency and number of passages necessary for the expression of a mutation? Thanks for your help! Nancy ...
Bacteria in tumors make cancer resistant to chemotherapy. Wait, what? That’s right. According to Ravid Straussman at the Weizmann Institute, Gammapro
{loadposition article-preamble} Hi Everyone, Lauren Miller had spectacular success using EFT for her stage 3 cancer. She shares her story (and EFT methods) in this article. Please note that while only one successful EFT session launched this remarkab...
The findings presented here support a model linking Pgrmc1 to cancer progression. Pgrmc1 is overexpressed in breast tumors (Crudden et al., 2005), is induced by chemotherapy (Mallory et al., 2005b), and promotes chemotherapy resistance in breast cancer cells (Crudden et al., 2006). In separate papers, Peluso et al. subsequently showed that Pgrmc1 is overexpressed in ovarian cancer, where it contributes to chemotherapy resistance (Peluso et al., 2008a) and suppresses apoptosis (Peluso et al., 2008b). However, many tumors express Pgrmc1 before chemotherapy, suggesting a function for Pgrmc1 other than drug resistance. Indeed, Pgrmc1 is induced by carcinogens in vivo, suggesting a role in the early stages of tumorigenesis (Selmin et al., 1996). In the present study, we present evidence that Pgrmc1 promotes tumor growth in vivo. We inhibited Pgrmc1 expression by using a sequence-specific shRNA that had been previously characterized in human kidney cells (Hughes et al., 2007) and used two separate in ...
Researchers now able to use a 3D computer model to helps screen millions of chemo drugs, giving researchers a view of the structure of a protein believed played a crucial role in chemotherapy failure.
In cancer chemotherapy, multidrug resistance (MDR) is a major clinical problem which occurs by an influential mechanism and which leads to the failure of cancer chemotherapy and/or a relapse of the cancer. In this study ...
A protein that enables cancer cells to grow, invade tissues and eventually resist chemotherapy and has lethal consequences for patients was found by researchers.
Active drug efflux by the adenosine triphosphate-binding cassette (ABC) transporter ABCG2 is one of the common mechanisms causing multiple drug resistance in various human cancers. In the intrinsic drug resistance of hepatocellular carcinoma (HCC), the role of ABCG2 is closely associated with side population (SP), a minor subset of cancer stem-like cells with unique capacity to extrude lipophilic dye Hoechst 33342 and many chemotherapeutic agents. In this study, we showed that ABCG2 was intrinsically expressed in a subgroup of HCC tissues and its expression pattern significantly influenced the levels of drug efflux from HCC cell lines. In MHCC-97L HCC cell line with intrinsic ABCG2 expression, we confirmed the importance of SP cells to the drug efflux-related chemotherapy resistance and found that the SP analysis provided an efficient method to evaluate the functional activity of ABCG2 transporter. In this cell line, we discovered that the SP proportion was modulated by the treatments of Akt ...
Therapy resistance can arise within tumor cells because of genetic or phenotypic changes (intrinsic resistance), or it can be the result of an interaction with the tumor microenvironment (extrinsic resistance). Exosomes are membranous vesicles 40 to 100 nm in diameter constitutively released by almost all cell types, and mediate cell-to-cell communication by transferring mRNAs, miRNAs, DNAs and proteins causing extrinsic therapy resistance. They transfer therapy resistance by anti-apoptotic signalling, increased DNA-repair or delivering ABC transporters to drug sensitive cells. As functional mediators of tumor-stroma interaction and of epithelial to mesenchymal transition, exosomes also promote environment-mediated therapy resistance. Exosomes may be used in anticancer therapy exploiting their delivery function. They may effectively transfer anticancer drugs or RNAs in the context of gene therapy reducing immune stimulatory effects of these drugs and hydrophilic qualities facilitating crossing of cell
The estrogen receptor (ER) is expressed in approximately 70% of the breast carcinomas. In general, for these patients anti-hormonal therapy is the therapy of first choice. Despite good responses in 50-60% of the patients, unfortunately all patients develop (acquired) resistance. Patients with acquired anti-hormonal resistance can be subdivided into three different groups: (1) patients that have lost ER-expression (~25%), (2) patients with preserved ER-expression (~55%) and (3) patients with enhanced ER-expression (~30%). Several studies suggest different treatment strategies for these three different ER-phenotypes in antihormonal resistant breast cancer. In patients with acquired anti-hormonal resistance, ~30% of the patients still respond to hormone-additive therapy with estrogens. In vitro studies have shown estrogen-induced apoptosis in long-treated estrogen deprived cells (simulating aromatase inhibitor resistance). It is suggested that this estrogen-hypersensitivity is accompanied by ...
For decades, natural products represent a significant source of diverse and unique bioactive lead compounds in drug discovery field. In Clinical oncology, complete tumors remission is hampered by the development of drug-resistance. Therefore, development of cytotoxic agents that may overcome drug resistance is urgently needed. Here, the natural benzophenanthridine alkaloid sanguinarine has been studied for its cytotoxic activity against multidrug resistance (MDR) cancer cells. We investigated the role of the ATP-binding cassette (ABC) transporters BCRP/ABCG2, P-glycoprotein/ABCB1 and its close relative ABCB5 in drug resistance. Further drug resistance mechanisms analyzed in this study were the tumor suppressor TP53 and the epidermal growth factor receptor (EGFR). Multidrug resistant cells overexpressing BCRP, ABCB5 and mutated ∆EGFR were not cross-resistant towards sanguinarine. Interestingly, P-gp overexpressing cells were hypersensitive to sanguinarine. Doxorubicin uptake assay carried by flow
Defining the molecular transcriptomic profile for predicting the clinical outcome of anthracycline resistant breast cancers. Defining metastases in relation with the primary tumor. BREAST-OMICS
Two recent in vitro studies conducted in the U.S. and Europe raise a provocative question: Can FDA-approved human immunodeficiency virus (HIV) drugs be used to treat chemoresistant ovarian cancer? Both studies were based upon the fact that HIV patients taking antiretroviral inhibitors have a lower incidence of infection-associated malignancies. Based upon that fact, the researchers…
Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of only 9%. Acquired drug resistance is a major factor that limits the effectiveness of chemotherapy. Exosomes, secreted
Italian and German scientists have designed peptides to target the protein-protein interface of a key enzyme in DNA synthesis crucial for cancer growth. The peptides act by a novel inhibitory mechanism and curb cancer cell growth in drug resistant ovarian cancer cells. The interdisciplinary research project was led by the University of Modena and Reggio Emilia (UNIMORE) and the Heidelberg Institute for Theoretical Studies (HITS).
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This cisplatin-resistant cell line has been developed by chronic exposure of the parent cisplatin-sensitive A2780 cell line (ECACC No. 93112519) to increasing concentrations of cisplatin. A2780cis is cross-resistant to melphalan, adriamycin and irradiation. An increased ability to repair DNA damage as well as cytogenetic abnormalities has been observed. In order to retain resistance cisplatinum has to be added to the media every 2-3 passages. In addition to this matched pair of drug-sensitive/resistant cell lines an adriamycin-resistant cell line, A2780adr (ECACC No. 93112520), has been isolated from the same parental line A2780 ...
Osimertinib binds tightly to a protein, epidermal growth factor receptor (EGFR), which is overexpressed in many tumours.. EGFR is involved in a pathway that signals for cell proliferation, and so is a target for drugs. Blocking the action of EGFR (inhibiting it) can switch it off, and so is a good way to treat the disease.. Osimertinib is an effective anticancer drug that works in this way. It is used to treat non-small-cell lung cancer (NSCLC), in cases where the cancer cells have a particular (T790M) mutant form of EGFR.. It is a so-called third-generation EGFR inhibitor, which was approved as a cancer treatment in 2017. Osimertinib is a covalent inhibitor: as such, it binds irreversibly to EGFR by forming a chemical bond with it.. Although patients generally respond well to osimertinib, most acquire drug resistance within one year of treatment, so the drug stops working.. Drug resistance arises because the EGFR protein mutates, so that the drug binds less tightly.. One such mutation, called ...
Chemoresistant tumor cells pose a threat to the efficacy of treatment and severely worsen the prognosis for the treated animal due to relapse. Understanding the mechanism of resistance is the first step leading to circumvention of the resistance and development of more efficient therapies. The chemotherapeutic doxorubicin was used to ... read more treat canine MelT4 melanoma, and POS and HMPOS osteosarcoma cells. The survival of cells was determined by cell count as well as MTT essay, and the mRNA of surviving cells isolated. PCR and electrophoresis were used to visualize the presence of mRNA coding for drug efflux pumps MDR, ABCB5 and ABCG2 as well as transcription factors NANOG, Oct-4 and SOX-2. The presence of cell surface marker CD-133 was also determined. Western Blots were performed for ABCB5 and ABCG2 to determine eventual translation of the results on an mRNA level to a protein level. A non-treated cell population equal to the surviving population was used as reference in all ...
Model of tumor cell resistance to antineoplastic therapy through angiopoietin-like protein 2 (ANGPTL2) expression. Tumor cell-secreted ANGPTL2 induces spleen ty
The Ras/MEK/ERK and PI3K/Akt/mTor pathways play a central role in the regulation of normal cell growth, division and differentiation. Dysregulation of these signaling pathways driven by oncogenic mutations/activation leading to elevated kinase activity has been demonstrated in many human cancers. Strong evidence suggests the existence of a feedback loop with crosstalk between these two signaling cascades leading to redundancy in survival pathways. Consequently, monotherapy targeting a single cascade may be insufficient to induce tumor cell death due to drug resistance mechanisms. Initial biological results are presented from a series of novel small molecule kinase inhibitors specifically designed to simultaneously target both MEK1 and PI3K. Structural analogs of the ATP-competitive PI3K inhibitor ZSTK474 and the ATP-noncompetitive class of MEK inhibitors PD0325901, respectively, were covalently combined to provide single compound dual inhibitors. Inhibitors showed potent MEK1 inhibition (0.015 , ...
Health, ...German researchers have identified an unexpected molecular marker that...Triple-negative breast cancers --which do not express the genes for es...At the IMPAKT Breast Cancer Conference in Brussels PhD student Caroli...The researchers undertook their study in three steps. First they condu...,Gene,expression,predicts,chemotherapy,sensitivity,,of,triple-negative,breast,cancer,medicine,medical news today,latest medical news,medical newsletters,current medical news,latest medicine news
Background: Among several chemotherapeutic agents, 5-Fluorouracil (5-FU) has been widely used as a key drug in adjuvant chemotherapy for gastric cancer. However, no reliable marker, which predicts the response to 5-FU in an adjuvant setting, has been identified. Hypoxia-induced drug resistance, via up-regulation of hypoxia-inducible factor (HIF) -1α, is a major obstacle in the development of effective cancer therapy. Despite the numerous investigations, few clinical studies have so far assessed the relationship between the HIF-1α expression and the chemo-resistance of gastric cancer patients in an adjuvant setting.. Objective: To determine whether the expression of HIF-1α predicts the relapse of gastric cancer patients who underwent curative surgery followed by adjuvant 5-FU chemotherapy.. Materials and Methods: Two HIF-1α knockdown gastric cancer cell lines were established in order to clarify the role of HIF-1α in chemo-resistance against 5-FU. The sensitivity to 5-FU was evaluated by MTT ...
The development of targeted therapies has provided new options for the personalized management of patients with advanced solid tumors. mAbs directed against the EGFR, such as cetuximab and panitumumab, have emerged as important therapeutic agents in the treatment of metastatic colorectal cancer patients. However, their use is substantially limited by intrinsic and acquired cancer cell resistance. Several hypotheses have been developed to explain why resistant cancer cell arises and how it is possible to overcome it. One possibility is cancer intrinsic genetic heterogeneity, which could be more prominent in the metastatic setting (28, 29). Heterogeneous genetic alterations in genes involved in the EGFR pathways have been hypothesized to play a role in resistance to anti-EGFR drugs in colorectal cancer, including activating mutations in KRAS, NRAS, B-RAF, and PIK3CA, and loss of expression of PTEN (13). The overall scenario is complicated by presence of additional genetic mechanisms able to ...
TY - JOUR. T1 - Molecular determinants of chemotherapy resistance in ovarian cancer. AU - Cooley, Megan. AU - Fang, Pingping. AU - Fang, Fang. AU - Nephew, Kenneth. AU - Chien, Jeremy. PY - 2015/11/1. Y1 - 2015/11/1. KW - cancer genomics. KW - chemotherapy. KW - functional genomics. KW - heterogeneity. KW - intra-tumor. KW - ovarian cancer. KW - resistance. UR - http://www.scopus.com/inward/record.url?scp=84947967812&partnerID=8YFLogxK. UR - http://www.scopus.com/inward/citedby.url?scp=84947967812&partnerID=8YFLogxK. U2 - 10.2217/pgs.15.130. DO - 10.2217/pgs.15.130. M3 - Article. C2 - 26554863. AN - SCOPUS:84947967812. VL - 16. SP - 1763. EP - 1767. JO - Pharmacogenomics. JF - Pharmacogenomics. SN - 1462-2416. IS - 16. ER - ...
New research using mathematical models of different types of cancer-including melanoma, pancreatic, and colorectal-to determine the evolutionary dynamics of lesions in response to treatment is revealing why and how cancer cells resist targeted therapies. The study by Ivana Bozic, PhD, from the Department of Mathematics at Harvard University, and colleagues was published online in eLife.. Study Details. The investigators, a team of mathematicians and oncologists from a variety of academic centers, designed a mathematical model to predict the effects of combination targeted therapies on tumors based on data obtained from 20 melanoma patients receiving vemurafenib (Zelboraf). They then applied their model to an independent set of pancreatic, colorectal, and melanoma cancer patients with metastatic disease. Their findings showed that when dual therapy is used, most patients experience longer-term disease control as long as there were no single cell mutations that caused cross-resistance to both ...
Background] Most NSCLC patients harboring activating EGFR mutations benefit from treatment with EGFR-TKIs, but the final clinical efficacy of EGFR-TKIs varies because of development of tumor resistant to EGFR-TKIs. Multiple kinase-targeted 2nd generation TKIs such as afatinib have been developed to overcome drug resistance to the 1st generation TKIs. Afatinib is an irreversible multitargeted TKI targeting EGFR including T790M, HER2 and HER4. To develop further personalized therapeutics and drug resistance modifiers, we should understand the molecular based mechanism of drug resistance to 2nd as well as 3rd generation TKIs. In our present study, we present a novel finding that acquisition of cancer stem-like cells properties accompanying with activation of residual Src family kinase (SFK)/focal adhesion kinase (FAK) is responsible for the survival of afatinib-resistant lung cancer cells when expression of targeted EGFR, HER2 and HER4 is abraded.. [Materials and methods] We have established ...
They will use the funds to develop software tools for designing and testing site-specific CRISPR systems that target drug resistance mechanisms in cancer cells.
Affiliation (Current):東北大学,農学研究科,教授, Research Field:Applied microbiology,Biological Sciences,Science and Engineering,Applied molecular and cellular biology,応用微生物学・応用生物化学, Keywords:糸状菌,転写因子,トランスポーター,シグナル伝達,麹菌,菌類,発現制御,アミラーゼ生産,ヒスチジンキナーゼ,転写制御因子, # of Research Projects:19, # of Research Products:127, Ongoing Project:Elucidation of drug resistance mechanisms in filamentous fungi by functional analyses of transcription factors
PerProGlio Project aims to identify individual parameters that determine recurrence and therapy resistance in Glioblastoma (GBM) with possible therapeutic implications.
The drug resistant cell line MOR/0.2R has been derived from the parent line, MOR, by continuous exposure to increasing concentrations of doxorubicin (also known as adriamycin). MOR/0.2R accumulate lower levels of doxorubicin than the parent line and have been shown to overexpress multi drug resistance associated protein (MRP). Expression of a 190kDa membrane protein associated with the degree of drug-resistance has been indicated. Cells grow as easily detaching aggregates ...
The expanding spectrum of both established and candidate oncogenic driver mutations identified in non-small-cell lung cancer (NSCLC), coupled with the increasing number of clinically available signal transduction pathway inhibitors targeting these driver mutations, offers a tremendous opportunity to enhance patient outcomes. Despite these molecular advances, advanced-stage NSCLC remains largely incurable due to therapeutic resistance. In this Review, we discuss alterations in the targeted oncogene (on-target resistance) and in other downstream and parallel pathways (off-target resistance) leading to resistance to targeted therapies in NSCLC, and we provide an overview of the current understanding of the bidirectional interactions with the tumour microenvironment that promote therapeutic resistance. We highlight common mechanistic themes underpinning resistance to targeted therapies that are shared by NSCLC subtypes, including those with oncogenic alterations in epidermal growth factor ...
Our observations identify NM23-H1 as the archetype of a metastasis suppressor gene acting as repressor of the early stages of the invasive program in primary tumors. We propose that NM23-H1 functions as a barrier against the conversion of in situ carcinoma into invasive carcinoma. Our data support the notion that NM23-H1 silencing induces an invasive phenotype linked to partial EMT associated with the β-catenin nuclear translocation and upregulation of TCF/LEF-1-mediated transcription, a molecular signature of the Wnt pathway (32). EMT is a major switch to exacerbate the metastatic behavior by generating migratory and invasive signals, as well as anticancer drug resistance phenotypes (33). We found that NM23-H1 is reduced at the invasive front of human primary tumors concomitantly with reduced membrane-bound E-cadherin, further supporting the biological significance of our experimental data. Collectively, our data identify NM23-H1 as a critical regulator of E-cadherin-mediated intercellular ...
During the third situation, we were unable to make a definitive determination. Other cases with acquired mutations of uncertain significance integrated two cancers with ,-catenin mutations, the two of which occurred concomitantly with the EGFR T790M mutation. Fifteen posttreatment biopsies did not reveal any new mutations as assessed from the SNaPshot assay, nor MET or EGFR amplification. Two sufferers on this group had inadequate posttreatment tissue for EGFR and MET gene copy amount analyses. Between the 15 individuals without having an recognized genetic resistance mechanism, only 2 patients had stopped EGFR TKI treatment for more than two weeks in the time of biopsy. Each of the drug-resistant tumor specimens underwent routine pathological analyses, and in some instances, sizeable alterations from the predominant histology of the resistant tumors have been observed. To our surprise, 5 patients were found to have a diagnosis of smaller cell lung cancer inside their drug-resistant tumor ...
The failure of chemotherapeutic drugs in treatment of various cancers is attributed to the acquisition of drug resistance. However, the migration mechanisms of drug-resistant cancer cells remain incom...
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This proposal outlines a 5 year program designed to develop the principal investigator into an independent translational researcher and investigate the role of...
Colorectal cancer is the third most common cancer among men and women. It is a major clinical problem worldwide, considering a high number of positive-diagnosed patients and death rate among them....