Role of NF-E2 related factor 2 (Nrf2) on chemotherapy resistance in acute myeloid leukemia (AML) and the effect of pharmacological inhibition of Nrf2

PloS One
Sreeja KarathedathPoonkuzhali Balasubramanian

Abstract

Cytarabine (Ara-C) and Daunorubicin (Dnr) forms the backbone of acute myeloid leukemia (AML) therapy. Drug resistance and toxic side effects pose a major threat to treatment success and hence alternate less toxic therapies are warranted. NF-E2 related factor-2 (Nrf2), a master regulator of antioxidant response is implicated in chemoresistance in solid tumors. However, little is known about the role of Nrf2 in AML chemoresistance and the effect of pharmacological inhibitor brusatol in modulating this resistance. Primary AML samples with high ex-vivo IC50 to Ara-C, ATO, Dnr had significantly high NRF2 RNA expression. Gene-specific knockdown of NRF2 improved sensitivity to these drugs in resistant AML cell lines by decreasing the expression of downstream antioxidant targets of Nrf2 by compromising the cell's ability to scavenge the ROS. Treatment with brusatol, a pharmacological inhibitor of Nrf2, improved sensitivity to Ara-C, ATO, and Dnr and reduced colony formation capacity. AML cell lines stably overexpressing NRF2 showed increased resistance to ATO, Dnr and Ara-C and increased expression of downstream targets. This study demonstrates that Nrf2 could be an ideal druggable target in AML, more so to the drugs that function thro...Continue Reading

References

Apr 2, 2005·Nature Reviews. Cancer·Michael DeanSusan Bates
Jan 10, 2006·Methods in Enzymology·Danyelle M TownsendKenneth D Tew
Jul 28, 2009·Annals of Oncology : Official Journal of the European Society for Medical Oncology·D PulteH Brenner
Mar 10, 2010·Journal of Surgical Oncology·Tsuyoshi TakahashiHiromi Wada
Jan 6, 2011·Proceedings of the National Academy of Sciences of the United States of America·Dongmei RenDonna D Zhang
Oct 5, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Roland B WalterElihu H Estey
Feb 14, 2012·BMC Cancer·Naoyuki HanadaYasuo Saijo
Jul 14, 2012·Cancer Cell·Yoichiro MitsuishiHozumi Motohashi
Nov 2, 2013·Asian Pacific Journal of Cancer Prevention : APJCP·Xiu-Feng HuXiao-Shan Feng
Oct 23, 2014·Journal of Cancer Prevention·Jae Hong NoYong Sang Song
Oct 24, 2014·Cancer Research·Shasha TaoDonna D Zhang
Dec 4, 2015·Nature·Sheroy MinocherhomjiIan D Hickson

❮ Previous
Next ❯

Citations

Jan 10, 2019·Journal of Cellular Physiology·Le Xuan Truong NguyenVinod Pullarkat
Jan 30, 2020·Cell Death and Differentiation·Elsa Sanchez-LopezMichael Karin
Feb 29, 2020·Antioxidants·Emiliano PanieriLuciano Saso
Jun 30, 2018·International Journal of Hematology·Hisashi Takei, Susumu S Kobayashi
May 18, 2019·Oxidative Medicine and Cellular Longevity·Emiliano Panieri, Luciano Saso
Jul 1, 2020·Expert Opinion on Investigational Drugs·Toshihisa Satta, Steven Grant
Jan 7, 2021·Antioxidants & Redox Signaling·Emiliano Panieri, Luciano Saso
Feb 12, 2021·Phytotherapy Research : PTR·Marjan TalebiSaeed Samarghandian
Feb 24, 2021·Pharmaceutical Research·William D Hedrich, Hongbing Wang
Mar 24, 2021·Archives of Pharmacal Research·Bo-Hyun ChoiMi-Kyoung Kwak
Aug 2, 2017·Biochemical and Biophysical Research Communications·Fuxing DongRuiqin Yao
Apr 4, 2021·Antioxidants·Giuseppina BarreraStefania Pizzimenti
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Pelin Telkoparan-AkillilarLuciano Saso
Apr 24, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Abbas Pirpour TazehkandNasser Samadi

❮ Previous
Next ❯

Methods Mentioned

BETA
ubiquitination
flowcytometry
density gradient centrifugation
PCR
transfection
flow cytometry

Software Mentioned

GraphPad Prism
flowJO
ComboSyn
Digital Darkroom
Compusyn
BD Accuri C6
KC

Related Concepts

Related Feeds

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease with approximately 20,000 cases per year in the United States. AML also accounts for 15-20% of all childhood acute leukemias, while it is responsible for more than half of the leukemic deaths in these patients. Here is the latest research on this disease.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

AML: Role of LSD1 by CRISPR (Keystone)

Find the latest rersearrch on the ability of CRISPR-Cas9 mutagenesis to profile the interactions between lysine-specific histone demethylase 1 (LSD1) and chemical inhibitors in the context of acute myeloid leukemia (AML) here.

Blood And Marrow Transplantation

The use of hematopoietic stem cell transplantation or blood and marrow transplantation (bmt) is on the increase worldwide. BMT is used to replace damaged or destroyed bone marrow with healthy bone marrow stem cells. Here is the latest research on bone and marrow transplantation.