Understanding Cancer Drug Resistance by Developing and Studying Resistant Cell Line Models

2016 ◽  
Vol 16 (3) ◽  
pp. 226-237 ◽  
Author(s):  
Cristina P.R. Xavier ◽  
Milica Pesic ◽  
M. Helena Vasconcelos
Keyword(s):  
Drug Resistance ◽  
Cell Line ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Cancer Drug ◽  
Cancer Drug Resistance

scholarly journals Misregulation of translation drives prostate cancer drug resistance

2021 ◽  
Author(s):  
Emeline I. J. Lelong ◽  
France Hélène Joncas ◽  
Pauline Adjibade ◽  
Valerie ST.-Sauveur Grenier ◽  
Jean-Philippe Lambert ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Drug Resistance ◽  
Cell Line ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Cancer Drug ◽  
Biological Processes ◽  
Drug Resistant ◽  
Cancer Resistance ◽  
Resistant Cells

ABSTRACTEmerging evidence associates translation factors and regulators to tumorigenesis. Recent advances in our ability to perform global translatome analyses indicate that our understanding of translational changes in cancer resistance is still limited. Here, we characterize global translational changes that occur during the acquisition of prostate cancer (PCa) drug resistance. We generated a patient derived xenograft (PDX) model created from PCa cells to recapitulate key features of resistant PCa progression. From an enzalutamide-sensitive patient derived cell line (VCaP), we generated a castration resistant cell line (VCaPCRPC) and an enzalutamide resistant cell line (VCaPER). We performed Total and polyribosome-bound RNA sequencing and mass spectroscopy from both VCaPCRPC and VCaPER to reveal their respective translatomes. We found that in drug-resistant cells, RNAs associated to ribosomes were enriched for nuclear RNA and DNA binding related biological processes, whereas RNAs that are less associated showed enrichment for processes such as cell membrane and cell-cell junction related biological processes. These results were corroborated by mass spectrometry and suggest that translation is indeed affected during drug resistance. Furthermore, our analysis revealed enrichment of long non-coding RNAs associated to ribosomes, which may suggest aberrant translation or translation of novel peptides that can be considered as new biomarkers. Our findings thus point towards novel therapeutic avenues that may target drug-resistant cells.

Lentivirus-mediated RNA interference reversing the drug-resistance in MDR1 single-factor resistant cell line K562/MDR1

2009 ◽  
Vol 33 (8) ◽  
pp. 1114-1119 ◽  
Author(s):  
Xueshi Ye ◽  
Ting Liu ◽  
Yuping Gong ◽  
Bohui Zheng ◽  
Wentong Meng ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Rna Interference ◽  
Cell Line ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Single Factor

Establishment of Paclitaxel-Resistant Cell Line and the Underlying Mechanism on Drug Resistance

2012 ◽  
pp. 1 ◽  
Author(s):  
Jingjing Zhang ◽  
Jin Zhao ◽  
Wenjing Zhang ◽  
Guanyuan Liu ◽  
Dongmei Yin ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Line ◽  
Underlying Mechanism ◽  
Resistant Cell ◽  
Resistant Cell Line

scholarly journals Cell line-specific network models of ER+ breast cancer identify PI3Kα inhibitor sensitivity factors and drug combinations

2020 ◽  
Author(s):  
Jorge Gómez Tejeda Zañudo ◽  
Pingping Mao ◽  
Clara Alcon ◽  
Kailey J. Kowalski ◽  
Gabriela N. Johnson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Mathematical Models ◽  
Cell Line ◽  
Network Models ◽  
Drug Combinations ◽  
Cancer Drug ◽  
Bh3 Mimetics ◽  
Cancer Drug Resistance ◽  
Sensitivity Factors

Durable control of invasive solid tumors necessitates identifying therapeutic resistance mechanisms and effective drug combinations. A promising approach to tackle the cancer drug resistance problem is to build mechanistic mathematical models of the signaling network of cancer cells, and explicitly model the dynamics of information flow through this network under distinct genetic conditions and in response to perturbations. In this work, we used a network-based mathematical model to identify sensitivity factors and drug combinations for the PI3K&alpha inhibitor alpelisib, which was recently approved for ER+ PIK3CA mutant breast cancer. We experimentally validated the model-predicted efficacious combination of alpelisib and BH3 mimetics (e.g. MCL1 inhibitors) in ER+ breast cancer cell lines. We also experimentally validated the reduced sensitivity to alpelisib caused by FOXO3 knockdown, which is a novel potential resistance mechanism. Our experimental results showed cell line-specific sensitivity to the combination of alpelisib and BH3 mimetics, which was driven by the choice of BH3 mimetics. We find that cell lines were sensitive to the addition of either MCL1 inhibitor s63845 alone or in combination with BCL-XL/BCL-2 inhibitor navitoclax, and that the need for the combination of both BH3 mimetics was predicted by the expression of BCL-XL. Based on these results, we developed cell line-specific network models that are able to recapitulate the observed differential response to alpelisib and BH3 mimetics, and also incorporate the most recent knowledge on resistance and response to PI3K&alpha inhibitors. Overall, we present an approach for the development, experimental testing, and refining of mathematical models, which we apply to the context of PI3K&alpha inhibitor drug resistance in breast cancer. Our approach predicted and validated PI3K&alpha inhibitor sensitivity factors (FOXO3 knockdown) and drug combinations (BH3 mimetics), and illustrates that network-based mathematical models can contribute to overcoming the challenge of cancer drug resistance.

scholarly journals Generating Paclitaxel-Resistant in Cervical Cancer HeLa Cell Line

2020 ◽  
Vol 11 (2) ◽  
pp. 90
Author(s):  
Muhammad Hasan Bashari ◽  
Fachreza Aryo Damara ◽  
Isna Nisrina Hardani ◽  
Gita Widya Pradini ◽  
Tenny Putri ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Line ◽  
Hela Cells ◽  
Molecular Mechanisms ◽  
Inhibitory Concentration ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Resistant Cells

Cervical cancer is one of the most leading causes of women death. Currently, paclitaxel is still one of the main therapeutic regimens for cervical cancer patients. However, some patients developed to be paclitaxel-resistant. Hence, studies to find out the novel strategies to resolve this problem are important. Generating resistant cancer cell lines can be utilized as the potent tool to evaluate the efficacy of any therapeutic agent toward cancer drug-resistant problems. Current studies describing the methods to establish chemoresistance are lacking. Moreover, study in Indonesia conducting chemoresistance in cell line is limited. This study was aimed to elaborate the characteristics of HeLa cells during generation of paclitaxel-resistant cervical cancer cells. The parental HeLa cells were exposed to an escalating concentration of paclitaxel for a long time period. Subsequently, cells were divided into two groups for the evaluation of resistance characteristics. The values of inhibitory concentration 50 (IC50) and inhibitory concentration 90 (IC90) were analyzed using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. Our data showed that the longer exposing periods of paclitaxel, the higher IC50 and IC90 values of HeLa cells are. IC90 of paclitaxel in HeLa Pac RB was increased from 69 pM, 440 pM, 2,561 pM and 10,337 pM on 0th, 1st, 2nd, 3rd and 4th months, respectively. Interestingly, the resistant cells were recovered to be paclitaxel-sensitive when they were not being continuously exposed to paclitaxel. In addition, the paclitaxel resistant cells become less sensitive against 5-FU but not doxorubicin, cisplatin and etoposide. We were able to generate cervical cancer HeLa paclitaxel-resistant cell line. These cell line could potentially be utilized for further studies in order to understand the molecular mechanisms of drug resistance in cervical cancer and as a tool for cancer drug discovery.Keywords: cervical cancer, drug resistant cell line, paclitaxel resistant cells, stepwise escalating concentration.

Screening of 129 FDA approved anti-cancer drugs in colorectal cancer cell lines resistant to oxaliplatin or irinotecan (SN38).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 642-642 ◽  
Author(s):  
Jan Stenvang ◽  
Christine Hjorth Andreassen ◽  
Nils Brünner
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Cell Viability ◽  
Cell Line ◽  
Cell Lines ◽  
Resistant Cell ◽  
Cancer Drug ◽  
Cancer Drugs ◽  
Drug Candidates ◽  
Anti Cancer

642 Background: In metastatic colorectal cancer (mCRC) only 3 cytotoxic drugs (oxaliplatin, irinotecan and fluorouracil (5-FU)) are approved and the first and second line response rates are about 50% and 10-15%, respectively. Thus, new treatment options are needed. Novel anti-cancer drug candidates are primarily tested in an environment of drug resistance and the majority of novel drug candidates fail during clinical development. Therefore, “repurposing” of drugs has emerged as a promising strategy to apply established drugs in novel indications. The aim of this project was to screen established anti-cancer drugs to identify candidates for testing in mCRC patients relapsing on standard therapy. Methods: We applied 3 parental (drug sensitive) CRC cell lines (HCT116, HT29 and LoVo) and for each cell line also an oxaliplatin and irinotecan (SN38) resistant cell line. We obtained 129 FDA approved anti-cancer drugs from the Developmental Therapeutics Program (DTP) at the National Cancer Institute (NCI) ( https://dtp.cancer.gov/ ). The parental HT29 cell line and the drug resistant sublines HT29-SN38 and HT29-OXPT were exposed to 3 concentrations of each of the anti-cancer drugs. The effect on cell viability was analyzed by MTT assays. Nine of the drugs were analyzed for effect in the LoVo and HCT116 and the SN38- and oxaliplatin-resistant derived cell lines. Results: None of the drugs caused evident differential response between the resistant and sensitive cells or between the SN38 and oxaliplatin resistant cells. The screening confirmed the resistance as the cells displayed resistance to drugs in the same class as the one they were made resistant to. Of the drugs, 45 decreased cell viability in the HT29 parental and oxaliplatin- or SN-38 resistant cell lines. Nine drugs were tested in all nine CRC cell lines and eight decrease cell viability in the nine cell lines. These included drugs in different classes such as epigenetic drugs, antibiotics, mitotic inhibitors and targeted therapies. Conclusions: This study revealed several possible new “repurposing” drugs for CRC therapy, by showing that 45 FDA-approved anti-cancer drugs decrease cell viability in CRC cell lines with acquired drug resistance.

scholarly journals The Significance of MicroRNAs Expression in Regulation of Extracellular Matrix and Other Drug Resistant Genes in Drug Resistant Ovarian Cancer Cell Lines

2020 ◽  
Vol 21 (7) ◽  
pp. 2619 ◽  
Author(s):  
Dominika Kazmierczak ◽  
Karol Jopek ◽  
Karolina Sterzynska ◽  
Barbara Ginter-Matuszewska ◽  
Michal Nowicki ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Extracellular Matrix ◽  
Drug Resistance ◽  
Cell Line ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Drug Resistant ◽  
Resistant Genes

Ovarian cancer rates the highest mortality among all gynecological malignancies. The main reason for high mortality is the development of drug resistance. It can be related to increased expression of drug transporters and increased expression of extracellular matrix (ECM) proteins. Our foremost aim was to exhibit alterations in the miRNA expression levels in cisplatin (CIS), paclitaxel (PAC), doxorubicin (DOX), and topotecan (TOP)—resistant variants of the W1 sensitive ovarian cancer cell line—using miRNA microarray. The second goal was to identify miRNAs responsible for the regulation of drug-resistant genes. According to our observation, alterations in the expression of 40 miRNAs were present. We could observe that, in at least one drug-resistant cell line, the expression of 21 miRNAs was upregulated and that of 19 miRNAs was downregulated. We identified target genes for 22 miRNAs. Target analysis showed that miRNA regulates key genes responsible for drug resistance. Among others, we observed regulation of the ATP-binding cassette subfamily B member 1 gene (ABCB1) in the paclitaxel-resistant cell line by miR-363 and regulation of the collagen type III alpha 1 chain gene (COL3A1) in the topotekan-resistant cell line by miR-29a.

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