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The related miRNAs involved in doxorubicin resistance or sensitivity of various cancers: an update

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Abstract

Doxorubicin (DOX) is an effective chemotherapy agent against a wide variety of tumors. However, intrinsic or acquired resistance diminishes the sensitivity of cancer cells to DOX, which leads to a cancer relapse and treatment failure. Resolutions to this challenge includes identification of the molecular pathways underlying DOX sensitivity/resistance and the development of innovative techniques to boost DOX sensitivity. DOX is classified as a Topoisomerase II poison, which is cytotoxic to rapidly dividing tumor cells. Molecular mechanisms responsible for DOX resistance include effective DNA repair and resumption of cell proliferation, deregulated development of cancer stem cell and epithelial to mesenchymal transition, and modulation of programmed cell death. MicroRNAs (miRNAs) have been shown to potentiate the reversal of DOX resistance as they have gene-specific regulatory functions in DOX-responsive molecular pathways. Identifying the dysregulation patterns of miRNAs for specific tumors following treatment with DOX facilitates the development of novel combination therapies, such as nanoparticles harboring miRNA or miRNA inhibitors to eventually prevent DOX-induced chemoresistance. In this article, we summarize recent findings on the role of miRNAs underlying DOX sensitivity/resistance molecular pathways. Also, we provide latest strategies for utilizing deregulated miRNA patterns as biomarkers or miRNAs as tools to overcome chemoresistance and enhance patient’s response to DOX treatment.

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Availability of data and materials

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Abbreviations

DOX:

Doxorubicin, Adriamycin

TOP2:

Topoisomerase II

DDR:

DNA damage response

CSC:

Cancer stem cell

EMT:

Epithelial to mesenchymal transition

miRNAs:

MicroRNAs

WHO:

World Health Organization

MDR:

Multidrug resistance

DSBs:

DNA double-strand breaks

PARP1:

Poly ADP-ribose polymerase1

HDAC1:

Histone deacetylase1

BMI1:

B-lymphoma Moloney murine leukemia virus insertion region-1 protein

FANCF:

Fanconi anemia complementation group F

CDIs:

Cyclin-dependent kinase inhibitors

CDKs:

Cyclin-dependent kinases

PANK1:

Panto-therate kinase-1

AURKA:

Aurora kinase A

PI3K:

Phosphoinositide-3 kinase

mTOR:

Mechanistic target of rapamycin

MAPK:

Mitogen-activated protein kinase

VEGFA:

Vascular endothelial growth factor A

FGF2:

Fibroblast growth factor2

TAC:

Docetaxol, doxorubicin plus cisplatin

PKB:

Protein kinase B

CML:

Chronic myeloid leukemia

PTEN:

Phosphatase and tensin homolog

AML:

Acute myeloid leukemia

KRAS:

Kirstin rat sarcoma viral oncogene protein

MAPK7:

Mitogen-activated protein kinase7

MEKK1:

MAP/ERK kinase kinase1

RUNX2:

Runt related transcription factor 2

TFAP4:

Transcription factor activated enhancer-binding proten4

NAMPT:

Nicotinamide phosphoribosyltransferase

PPIA:

Peptidyl poly-isomerase A

ROS:

Reactive oxygen species

Bcl-2:

B-cell lymphoma-2

Bcl-2 Like1:

Apoptotic Bcl-2 members including Bcl2L1

NTSR1:

Glioblastoma neurotensin receptor 1

MCL1:

Myeloid leukemia 1

DISC:

Death-inducing signaling complex

cFLIP:

Cellular FLICE-like inhibitory

SIRT1:

Silent information regulator 1

BIM:

Bcl-2 interacting mediator

BLID:

BH3-like –motif-containing protein

FOX:

Forkedhead box

FOXO1:

FOX class O1

FOXP2:

FOX class P2

FOXO3:

FOX class O3

FADD:

Fas-associated death domain

ULK1:

Unc51-like autophagy-activating kinase

ATGs:

Autophagy-related genes

LAPTM4B:

Lysosomal protein transmembrane 4 beta

ATG16L1:

Autophagy related 16-like-1

HMGN5:

High-mobility group nucleosome domain 5

HMGB1:

High-mobility group box1

P-glycoprotein:

P-gp

MDR1:

Multidrug resistance protein1

CAR:

Constitutive androstane receptor

ZNRD1:

Zink ribbon domain-containing

MRP1:

Multidrug resistance-associated protein1

SPIN1:

Spindlin1

Wnt:

Wingless

p-β-catenin:

Phospho-β-catenin

NEAT1:

Nuclear enriched abundant transcript1

Sox7:

Sex-determining region Y-box7

PKD1:

Protein kinase D1

GSK3:

Glycogen synthase kinase 3

YB1:

Factor Y box-binding protein 1

PD-L1:

Programmed cell death ligand 1

TWIST1:

Twist-related protein 1

ZEB1/2:

Zinc finger E-box-binding homeobox ½

eIF5A2:

Eukaryotic translational initiation factor 5 A2

STMN1:

Statmin1

OPN:

Osteopontin

MDR:

Multidrug resistance

USP9X:

Ubiquitin specific peptidase 9 X-linked

NLS:

Nuclear localization signal

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Acknowledgements

We would like to express our gratitude to personnel of medical genetic lab at dep. of Medical Genetics.

Funding

This study was supported by Molecular Medicine Research Center (Grant No. 64694) of Tabriz University of Medical Sciences, Tabriz, Iran.

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Authors and Affiliations

  1. Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran

    Zahra Torki

  2. Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Zahra Torki, Davood Ghavi, Yazdan Rahmati, Dara Rahmanpour & Mohammad Reza Alivand

  3. Department of Photo Healing and Regeneration, Medical Laser Research Center, Yara Institute, Academic Center for Education, Culture, and Research (ACECR), Tehran, Iran

    Majid Pornour

  4. Department of Surgery, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Solmaz Hashemi

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  1. Zahra Torki
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  2. Davood Ghavi
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  4. Yazdan Rahmati
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  5. Dara Rahmanpour
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Contributions

ZT designed the study. MRA and ZT wrote the first draft of the manuscript. MP revised the manuscript for important intellectual content. SH, YR and DR contributed in gathering the data. MP and MRA supervised the study. All authors read and approved the final version of the manuscript.

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Correspondence to Majid Pornour or Mohammad Reza Alivand.

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This study was approved by the Ethics Committee of Tabriz University of Medical Sciences, Tabriz, Iran with Ethics code IR.TBZMED.VCR.REC.1398.466.

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Torki, Z., Ghavi, D., Hashemi, S. et al. The related miRNAs involved in doxorubicin resistance or sensitivity of various cancers: an update. Cancer Chemother Pharmacol 88, 771–793 (2021). https://doi.org/10.1007/s00280-021-04337-8

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