scholarly journals Enhanced Protein Damage Clearance Induces Broad Drug Resistance in Multitype of Cancers Revealed by an Evolution Drug‐Resistant Model and Genome‐Wide siRNA Screening

2020 ◽  
Vol 7 (23) ◽  
pp. 2001914
Author(s):  
Fangyuan Shao ◽  
Xueying Lyu ◽  
Kai Miao ◽  
Lisi Xie ◽  
Haitao Wang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Protein Damage ◽  
Drug Resistant ◽  
Genome Wide ◽  
Sirna Screening

scholarly journals Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations

2016 ◽  
Author(s):  
Jonathan S. Brammeld ◽  
Mia Petljak ◽  
Inigo Martincorena ◽  
Steven P. Williams ◽  
Luz Garcia Alonso ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Point Mutations ◽  
Gene Mutations ◽  
Resistance Mechanisms ◽  
Chemical Mutagenesis ◽  
Specific Gene ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Genome Wide

AbstractDrug resistance is an almost inevitable consequence of cancer therapy and ultimately proves fatal for the majority of patients. In many cases this is the consequence of specific gene mutations that have the potential to be targeted to re-sensitize the tumor. The ability to uniformly saturate the genome with point mutations without chromosome or nucleotide sequence context bias would open the door to identify all putative drug resistance mutations in cancer models. Here we describe such a method for elucidating drug resistance mechanisms using genome-wide chemical mutagenesis allied to next-generation sequencing. We show that chemically mutagenizing the genome of cancer cells dramatically increases the number of drug-resistant clones and allows the detection of both known and novel drug resistance mutations. We have developed an efficient computational process that allows for the rapid identification of involved pathways and druggable targets. Such a priori knowledge would greatly empower serial monitoring strategies for drug resistance in the clinic as well as the development of trials for drug resistant patients.

Harnessing Gene Expression Profiles for the Identification of Drug Resistance Genes in Pediatric AML

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 283-283
Author(s):  
Costa Bachas ◽  
Gerrit Jan Schuurhuis ◽  
C. Michel Zwaan ◽  
Marry M. van den Heuvel-Eibrink ◽  
Monique L. Den Boer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Ex Vivo ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Drug Resistant ◽  
Genome Wide ◽  
Pediatric Aml ◽  
Upstream Regulators ◽  
Gene Expression Levels

Abstract Abstract 283 The vast majority of pediatric AML patients (>90%) achieve complete remission, however 30–40% relapse and face a dismal prognosis. Current therapy is insufficient as drug resistant cells survive chemotherapy; novel strategies are needed to overcome chemoresistance and improve outcome. The molecular basis underlying drug resistance in AML cells remains largely unknown. Based on the hypothesis that drug resistance in AML patients is largely due to intrinsic properties of leukemic blasts, we here correlated ex-vivo drug resistance data of primary patient samples to genome wide microarray gene expression profiles of AML blasts from diagnosis samples. Peripheral blood or bone marrow samples of 73 pediatric AML patients were enriched for leukemic blasts (median 89% blasts). Ex-vivo drug resistance towards cytarabine (ara-C, N=73), daunorubicin (DNR, N=69), etoposide (VP16, N=39) and cladribine (CDA, N=59) was assayed using the 4 days colorimetric MTT assay; median LC50 values are shown in Table 1. Genome wide expression profiling on the enriched samples was performed using the Affymetrix HGU 133 plus 2 platform (Balgobind et al, Hematologica, 2011). Spearman's rank correlation analyses were used to correlate gene expression levels to the LC50 values, nominal p-values < 0.001 were considered significant. The number of significant probe sets for each drug is shown in Table 1. The strongest correlation of ex-vivo drug resistance and gene expression was found for VP16 (r2 ranged from −0.78 to 0.69 with p values ranging from 1×10−4 to 2×10−7 for the above mentioned 656 probes). The figure illustrates the correlation of ex-vivo DNR resistance with gene expression levels. We performed Gene Ontology (GO) enrichment analysis and Ingenuity Pathway Analysis (IPA) using expression values of the probe sets that were associated with ex-vivo resistance for each drug to gain insight in the possible cellular pathways involved. Chromatin remodeling, epigenetic regulation of gene expression and methyltransferase activity were among the top GO categories for ara-C resistance. For example, a high expression of MLL2, MLL4, ASXL1, and CARM1 was associated with high ara-C LC50 values. For DNR, GO and IPA indicated a role for response to growth factor stimuli and mitochondrial response to oxidative stress; examples of individual genes are shown in the Figure below. For VP16, a low expression of genes that are implicated in cell cycle, DNA replication and DNA damage response was associated with increased resistance. This included DNA polymerases, genes in BRCA1 signaling as well as the target of VP16, topoisomerase 2α. Upstream regulators that contribute to the gene expression profiles that were associated with ex-vivo drug resistance according to IPA are shown in Table 2. Interestingly, for DNR, VP16 and CDA the expression profiles in part explained by regulation via CD40L, a gene that has been associated with drug resistance in lymphatic leukemias. Targeted therapeutics are being developed to interfere in the CD40L mediated anti-apoptotic signaling and thus may offer alternative treatment options in drug resistant AML. Hence, we present novel data in which diagnosis samples of a relatively large group of pediatric AML patients were used to identify gene expression profiles that are associated with cellular drug resistance. These data may pave the way to the identification of genes that contribute to drug resistance, e.g. CD40L. Moreover, our findings may enhance the development of personalized treatment strategies by sensitizing patients to conventional chemotherapeutic drugs. Table 1. Summary of ex-vivo drug resistance of primary AML blasts and its correlation with genome wide gene expression data Drug LC50 significant probe sets Ara-C .360 (.182-.616) 113 DNR .172 (.093-.250) 465 VP16 2.65 (1.84-6.70) 656 CDA .020 (.004-.027) 269 LC50 = lethal concentration needed to kill 50% of the cells depicted as median ug/mL(p25-p75). Table 2. Summary of pathway analysis of gene expression that correlated with ex-vivo drug sensitivity Drug top 3 upstream regulators p range upstream regulators Ara-C IL5 2.40×10−02 DNR CD40L, IRF8, OSCAR 7.4×10−4 to 4.4×10−5 VP16 CD40L, BRCA1, ACAT1 3.2×10−2 to 9.6×10−3 CDA CD40L, ASB2,IL10RB 1.15×10−2 to 8.3×10−4 Upstream regulators are ranked according to p-value. Disclosures: No relevant conflicts of interest to declare.

Candida auris and Nosocomial Infection

2020 ◽  
Vol 21 (4) ◽  
pp. 365-373 ◽  
Author(s):  
Sweety Dahiya ◽  
Anil K. Chhillar ◽  
Namita Sharma ◽  
Pooja Choudhary ◽  
Aruna Punia ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Pathogenic Fungus ◽  
Control Measures ◽  
Whole Genome Sequence ◽  
Whole Genome ◽  
Drug Resistant ◽  
Candida Auris ◽  
Preventive Control ◽  
Identification Techniques ◽  
Sensitivity Profile

The existence of the multi-drug resistant (MDR) pathogenic fungus, Candida auris came to light in 2009. This particular organism is capable of causing nosocomial infections in immunecompromised persons. This pathogen is associated with consistent candidemia with high mortality rate and presents a serious global health threat. Whole genome sequence (WGS) investigation detected powerful phylogeographic Candida auris genotypes which are specialized to particular geological areas indicating dissemination of particular genotype among provinces. Furthermore, this organism frequently exhibits multidrug-resistance and displays an unusual sensitivity profile. Identification techniques that are commercialized to test Candida auris often show inconsistent results and this misidentification leads to treatment failure which complicates the management of candidiasis. Till date, Candida auris has been progressively recorded from several countries and therefore its preventive control measures are paramount to interrupt its transmission. In this review, we discussed prevalence, biology, drug-resistance phenomena, virulence factors and management of Candida auris infections.

Fanconi Anemia DNA Repair Pathway as a New Mechanism to Exploit Cancer Drug Resistance

2020 ◽  
Vol 20 (9) ◽  
pp. 779-787
Author(s):  
Kajal Ghosal ◽  
Christian Agatemor ◽  
Richard I. Han ◽  
Amy T. Ku ◽  
Sabu Thomas ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Cancer Drugs ◽  
Repair Pathway ◽  
Cancer Drug Resistance ◽  
Anti Cancer ◽  
Cancerous Cells

Chemotherapy employs anti-cancer drugs to stop the growth of cancerous cells, but one common obstacle to the success is the development of chemoresistance, which leads to failure of the previously effective anti-cancer drugs. Resistance arises from different mechanistic pathways, and in this critical review, we focus on the Fanconi Anemia (FA) pathway in chemoresistance. This pathway has yet to be intensively researched by mainstream cancer researchers. This review aims to inspire a new thrust toward the contribution of the FA pathway to drug resistance in cancer. We believe an indepth understanding of this pathway will open new frontiers to effectively treat drug-resistant cancer.

Mycobacterial DNA Replication as a Target for Antituberculosis Drug Discovery

2017 ◽  
Vol 17 (19) ◽  
pp. 2129-2142 ◽  
Author(s):  
Renata Płocinska ◽  
Malgorzata Korycka-Machala ◽  
Przemyslaw Plocinski ◽  
Jaroslaw Dziadek
Keyword(s):  
Drug Resistance ◽  
Dna Replication ◽  
Drug Targets ◽  
Rapid Development ◽  
New Drugs ◽  
Drug Resistant ◽  
Antituberculosis Drug ◽  
Nucleotide Synthesis ◽  
Antituberculosis Therapy ◽  
Optimal Drug

Background: Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, is a leading infectious disease organism, causing millions of deaths each year. This serious pathogen has been greatly spread worldwide and recent years have observed an increase in the number of multi-drug resistant and totally drug resistant M. tuberculosis strains (WHO report, 2014). The danger of tuberculosis becoming an incurable disease has emphasized the need for the discovery of a new generation of antimicrobial agents. The development of novel alternative medical strategies, new drugs and the search for optimal drug targets are top priority areas of tuberculosis research. Factors: Key characteristics of mycobacteria include: slow growth, the ability to transform into a metabolically silent - latent state, intrinsic drug resistance and the relatively rapid development of acquired drug resistance. These factors make finding an ideal antituberculosis drug enormously challenging, even if it is designed to treat drug sensitive tuberculosis strains. A vast majority of canonical antibiotics including antituberculosis agents target bacterial cell wall biosynthesis or DNA/RNA processing. Novel therapeutic approaches are being tested to target mycobacterial cell division, twocomponent regulatory factors, lipid synthesis and the transition between the latent and actively growing states. Discussion and Conclusion: This review discusses the choice of cellular targets for an antituberculosis therapy, describes putative drug targets evaluated in the recent literature and summarizes potential candidates under clinical and pre-clinical development. We focus on the key cellular process of DNA replication, as a prominent target for future antituberculosis therapy. We describe two main pathways: the biosynthesis of nucleic acids precursors – the nucleotides, and the synthesis of DNA molecules. We summarize data regarding replication associated proteins that are critical for nucleotide synthesis, initiation, unwinding and elongation of the DNA during the replication process. They are pivotal processes required for successful multiplication of the bacterial cells and hence they are extensively investigated for the development of antituberculosis drugs. Finally, we summarize the most potent inhibitors of DNA synthesis and provide an up to date report on their status in the clinical trials.

Silencing PEX26 as an Unconventional Mode to Kill Drug-Resistant Cancer Cells and Forestall Drug Resistance

Autophagy ◽  
2021 ◽  
Author(s):  
Michael S. Dahabieh ◽  
Fan Huang ◽  
Christophe Goncalves ◽  
Raúl Ernesto Flores González ◽  
Sathyen Prabhu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Drug Resistant

scholarly journals pH-activated, mitochondria-targeted, and redox-responsive delivery of paclitaxel nanomicelles to overcome drug resistance and suppress metastasis in lung cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
He Wang ◽  
Wenwen Shi ◽  
Danning Zeng ◽  
Qiudi Huang ◽  
Jiacui Xie ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Disulfide Bonds ◽  
Cancer Metastasis ◽  
Mitochondrial Outer Membrane ◽  
Drug Resistant ◽  
Redox Responsive ◽  
Dimethylmaleic Anhydride ◽  
Extended Circulation ◽  
Mitochondria Targeting

Abstract Background Mitochondria play a role in the occurrence, development, drug resistance, metastasis, and other functions of cancer and thus are a drug target. An acid-activated mitochondria-targeting drug nanocarrier with redox-responsive function was constructed in the present study. However, whether this vector can precisely delivery paclitaxel (PTX) to enhance therapeutic efficacy in drug-resistant lung cancer is unknown. Results Acid-cleavable dimethylmaleic anhydride (DA) was used to modify pluronic P85-conjugated mitochondria-targeting triphenylphosphonium (TPP) using disulfide bonds as intermediate linkers (DA-P85-SS-TPP and DA-P-SS-T). The constructed nanocarriers demonstrated enhanced cellular uptake and selective mitochondrial targeting at extracellular pH characteristic for a tumor (6.5) and were characterized by extended circulation in the blood. TPP promoted the targeting of the DA-P-SS-T/PTX nanomicelles to the mitochondrial outer membrane to decrease the membrane potential and ATP level, resulting in inhibition of P-glycoprotein and suppression of drug resistance and cancer metastasis. PTX was also rapidly released in the presence of high glutathione (GSH) levels and directly diffused into the mitochondria, resulting in apoptosis of drug-resistant lung cancer cells. Conclusions These promising results indicated that acid-activated mitochondria-targeting and redox-responsive nanomicelles potentially represent a significant advancement in cancer treatment. Graphic Abstarct

scholarly journals Analysis of drug resistance and mutation profiles in Mycobacterium tuberculosis isolates in a surveillance site in Beijing, China

2021 ◽  
Vol 49 (1) ◽  
pp. 030006052098493
Author(s):  
Jie Zhang ◽  
Yixuan Ren ◽  
Liping Pan ◽  
Junli Yi ◽  
Tong Guan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Drug Testing ◽  
Multidrug Resistant ◽  
High Rate ◽  
Drug Resistant ◽  
Surveillance Site ◽  
Mdr Tb ◽  
Previously Treated Patients ◽  
Beijing China

Objective This study analyzed drug resistance and mutations profiles in Mycobacterium tuberculosis isolates in a surveillance site in Huairou District, Beijing, China. Methods The proportion method was used to assess drug resistance profiles for four first-line and seven second-line anti-tuberculosis (TB) drugs. Molecular line probe assays were used for the rapid detection of resistance to rifampicin (RIF) and isoniazid (INH). Results Among 235 strains of M. tuberculosis, 79 (33.6%) isolates were resistant to one or more drugs. The isolates included 18 monoresistant (7.7%), 19 polyresistant (8.1%), 28 RIF-resistant (11.9%), 24 multidrug-resistant (MDR) (10.2%), 7 pre-extensively drug-resistant (XDR, 3.0%), and 2 XDR strains (0.9%). A higher rate of MDR-TB was detected among previously treated patients than among patients with newly diagnosed TB (34.5% vs. 6.8%). The majority (62.5%) of RIF-resistant isolates exhibited a mutation at S531L in the DNA-dependent RNA polymerase gene. Meanwhile, 62.9% of INH-resistant isolates carried a mutation at S315T1 in the katG gene. Conclusion Our results confirmed the high rate of drug-resistant TB, especially MDR-TB, in Huairou District, Beijing, China. Therefore, detailed drug testing is crucial in the evaluation of MDR-TB treatment.

scholarly journals SMAD1 as a biomarker and potential therapeutic target in drug-resistant multiple myeloma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jian Wu ◽  
Min Zhang ◽  
Omar Faruq ◽  
Eldad Zacksenhaus ◽  
Wenming Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Therapeutic Target ◽  
Biological Activities ◽  
Xenograft Model ◽  
Myeloma Cell ◽  
Soft Agar ◽  
Drug Resistant ◽  
Migration Assay

Abstract Background SMAD1, a central mediator in TGF-β signaling, is involved in a broad range of biological activities including cell growth, apoptosis, development and immune response, and is implicated in diverse type of malignancies. Whether SMAD1 plays an important role in multiple myeloma (MM) pathogenesis and can serve as a therapeutic target are largely unknown. Methods Myeloma cell lines and primary MM samples were used. Cell culture, cytotoxicity and apoptosis assay, siRNA transfection, Western blot, RT-PCR, Soft-agar colony formation, and migration assay, Chromatin immunoprecipitation (Chip), animal xenograft model studies and statistical analysis were applied in this study. Results We demonstrate that SMAD1 is highly expressed in myeloma cells of MM patients with advanced stages or relapsed disease, and is associated with significantly shorter progression-free and overall survivals. Mechanistically, we show that SMAD1 is required for TGFβ-mediated proliferation in MM via an ID1/p21/p27 pathway. TGF-β also enhanced TNFα-Induced protein 8 (TNFAIP8) expression and inhibited apoptosis through SMAD1-mediated induction of NF-κB1. Accordingly, depletion of SMAD1 led to downregulation of NF-κB1 and TNFAIP8, resulting in caspase-8-induced apoptosis. In turn, inhibition of NF-κB1 suppressed SMAD1 and ID1 expression uncovering an autoregulatory loop. Dorsomorphin (DM), a SMAD1 inhibitor, exerted a dose-dependent cytotoxic effect on drug-resistant MM cells with minimal cytotoxicity to normal hematopoietic cells, and further synergized with the proteasomal-inhibitor bortezomib to effectively kill drug-resistant MM cells in vitro and in a myeloma xenograft model. Conclusions This study identifies SMAD1 regulation of NF-κB1/TNFAIP8 and ID1-p21/p27 as critical axes of MM drug resistance and provides a potentially new therapeutic strategy to treat drug resistance MM through targeted inhibition of SMAD1.

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