Abstract 4784
Background
Doxorubicin is an anthracycline antibiotic that acts as a DNA intercalating agent, inhibiting the topoisomerase II and inducing the apoptotic cell death, mainly due to the accumulation of double-strand DNA breaks (DSB). This research aims to identify in what way the abnormalities in microRNA (miRNA) expression profile in cancer cells can confer them the resistance to doxorubicin.
Methods
MiRNA targets within gene transcripts were predicted in silico using the TargetScan software.
Results
Binding sites for miRNAs miR-21, miR-96, miR-183 and miR-365, which are usually upregulated in cancer cells, were revealed in transcript of TOP2A gene encoding topoisomerase II-alpha. Transcripts of proapoptotic genes BID, BCL2L11 (BIM), BMF, BAX, BAK1, PMAIP1 (NOXA), and BBC3 (PUMA) as well as transcripts of tumor suppressor genes TP53 and PTEN carry targets for at least one of hyperexpressed miRNAs miR-19, miR-21, miR-23, miR-27, miR-29, miR-155, miR-181, miR-221/222 and miR-375. Downregulation of anti-onco-miRNAs let-7, miR-22, miR-34, miR-101, miR-125, miR-140, miR-143, miR-199, miR-200, miR-203, miR-204 and miR-205 allows overexpression of antiapoptotic genes BCL2, BCL2L1 (Bcl-XL), MCL1 and AKT1. In the same way, downregulation of the anti-onco-miRNAs can lead to overexpression of ABCA1/4/12, ABCB1 (MDR1), ABCB6, ABCC1 (MRP1) and ABCC3/5/8/11 genes encoding the ATP binding cassette (ABC) transporters. Moreover, multiple targets for the both up- and downregulated miRNAs were found in transcripts of XRCC5/6, PRKDC, LIG4, DCLRE1C, NHEJ1 (XLF), RAD50/51/51B/51D/52/54B/54L, MRE11A, NBN (NBS1), GEN1, ATM and ATR genes encoding the key elements of non-homologous end joining and homologous recombination pathways.
Conclusions
Obviously, in case of doxorubicin administration, strategy of early tumors consists in strengthening of miR-21 expression with the purpose to silence TOP2A gene and escape from immediate apoptotic death. Advanced tumors with more profound abnormalities in miRNA signature overexpress antiapoptotic genes as well as genes responsible for DSB repair and drug efflux and, therefore, can do without the TOP2A silencing.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Palladin Institute of Biochemistry of the National Academy of Sciences of Ukraine.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
2791 - Efficacy of weekly paclitaxel-bevacizumab combination in advanced non squamous non-small cell lung cancer (NSCLC) : a retrospective multicentric study.
Presenter: Geoffroy Bilger
Session: Poster Display session 1
Resources:
Abstract
2916 - Post progression survival for patients treated with docetaxel/nintedanib in the SENECA trial
Presenter: Enrica Capelletto
Session: Poster Display session 1
Resources:
Abstract
1427 - Final results of randomized phase II trial of metronomic vs weekly oral vinorelbine (OV) as first-line chemotherapy (CT) in advanced NSCLC patients unfit to platinum-based CT (P-CT): Tempo-Lung EudraCT Number: 2014-003859-61
Presenter: Dariusz Kowalski
Session: Poster Display session 1
Resources:
Abstract
3789 - Pioglitazone and clarithromycin combined with metronomic low-dose chemotherapy versus nivolumab in patients with advanced non–small-cell lung cancer treated in 2nd-line and beyond: Outcomes from a randomized phase II trial (ModuLung)
Presenter: Daniel Heudobler
Session: Poster Display session 1
Resources:
Abstract
1519 - Predicting Chemotherapy Toxicity in Elderly Patients with Advanced Non-small Cell Lung Cancer: A Prospective Multicenter Study of the National Hospital Organization in Japan
Presenter: Masaki Kanazu
Session: Poster Display session 1
Resources:
Abstract
1874 - A prospective phase II trial of carboplatin (CBDCA) and nab-paclitaxel (nabPTX) for advanced non-small cell lung cancer (NSCLC) with interstitial lung disease (ILD)
Presenter: Toshiyuki Harada
Session: Poster Display session 1
Resources:
Abstract
3819 - Weekly Epirubicin as palliative treatment in elderly patients with malignant pleural mesothelioma.
Presenter: Paola Candido
Session: Poster Display session 1
Resources:
Abstract
3390 - Survival Prolongation by Rationale INnovative Genomics (SPRING): An international WIN Consortium phase I study exploring safety and efficacy of avelumab, palbociclib, and axitinib in advanced non-small cell lung cancer (NSCLC) with integrated genomic and transcriptomic correlates.
Presenter: Benjamin Solomon
Session: Poster Display session 1
Resources:
Abstract
5069 - Preliminary results from phase 1b study of spartalizumab plus chemotherapy for advanced non-small cell lung cancer (NSCLC)
Presenter: Armando Santoro
Session: Poster Display session 1
Resources:
Abstract
2041 - Efficacy results of selective AXL inhibitor bemcentinib with pembrolizumab following chemo in patients with NSCLC
Presenter: Jose Trigo Perez
Session: Poster Display session 1
Resources:
Abstract