From: The molecular biology and therapeutic potential of Nrf2 in leukemia
Type of leukemia | Type of study | Cell line | Study results | Refs |
---|---|---|---|---|
CML | In vitro | K-562 and KU-812 | Nrf2 gene targets such as HO-1 and NQO1 increased imatinib resistance and decreased apoptosis in CML | [176] |
CML | In vitro | K562/G01 | When Nrf2 expression was inhibited by siRNA, reactive oxygen species (ROS) and the rate of apoptosis in response to imatinib increased, and cell proliferation decreased | [177] |
CML | In vitro | HL60/A(AML) and K562 /G(CML) | Using Triptolide, a natural inhibitor of Nrf2, along with other drugs such as doxorubicin and imatinib, reduced HIF-1a, Nrf2, and drug resistance | [178] |
CML | In vitro and in vivo | K562/A02 and NOD/SCID mice | Wogonin, an Nrf2 inhibitor, reduced Adriamycin resistance by inhibiting the Stat3/NF-κB—signaling | |
CML | In vitro | K562 | Chaetominine disrupted the PI3K/Akt/Nrf2 signaling pathway, inhibited the MRP1-mediated drug efflux pump, induced Bax apoptotic protein, and inhibited anti-apoptotic proteins | [181] |
AML | In vitro | Blood samples from 15 AML patients (PBMC) | Malignant AML stem cells increased NF-κB expression, responsible for high Nrf2 expression | |
AML | In vitro | THP-1, HL60, U937, and AML 193 | In cells resistant to TNF-induced cell death, the Nrf2 pathway is activated | [187] |
AML | In vitro | 17 patients with AML and THP-1, HL60, and U937 | 1) Simultaneous inhibition of HO-1 and NF-κB might be fluent in increasing apoptosis 2) high expression of Nrf2 as a result of NF-κB expression | [91] |
AML | In vitro and in vivo | THP-1, HL-60, U937, and CAMs of chicken eggs | 4f drug-based therapy induces programmed cell death (dependent on mitochondria) by decreasing the level of Nrf2 protein and increasing caspase-3, cleaved poly (ADP-ribose) protein levels, a pro-apoptotic protein. Also, tumor growth was inhibited by 4f in a chick embryo model | [188] |
AML | In vitro | THP-1 and U937 | Several Nrf2 inhibitors were identified, including ATRA, brusatol, and luteolin, which sensitized cells to arsenic trioxide (As2O3), etoposide, and doxorubicin | [189] |
AML | In vitro | HL60, Molm13, THP-1, and U937 | Nrf2 inhibitor, Cytarabine, and Daunorubicin decreased drug resistance in AML | [190] |
AML | In vitro | KG1 | Leukemia stem cells are resistant to apoptosis by activating the PERK/Nrf2 signaling pathway | [191] |
AML | In vitro and in vivo | KG1α, Kasumi-1 and NOD/SCID mice | Disulfiram/copper, which had an inhibitory effect on NF-κB and Nrf2, killed the malignant stem cells in AML | [192] |
AML | In vitro | ALL (REH, MOLT4) AML (MOLM-14) | Inhibition of MAPK/ERK and PI3K/AKT pathways reduced the expression of Nrf2, which was associated with downregulation of target genes, upregulation of ROS, and increased apoptosis | [193] |
AML | In vitro | U937 HL60 | Nrf2 activators in AML cell line U937 prevented the toxicity of calcium (dimethyl fumarate (DMF), tert-butyl hydroquinone, or carnosic acid | |
AML | In vitro | U937, MOLM-13, HL-60, THP1, KG1a | Combination therapy with cytarabine (AraC), DHA, and EPA in AML cell lines increased cell cytotoxicity | [196] |
APL | In vitro | PR9 (U937 cell line with zinc inducible PML/RARa expression) | 1) Nrf2 expression in APL is lower than in AML because some inhibitory mechanisms hinder Nrf2 transcription activity 2) suppressing Nrf2 activity in APL made cells sensitive to treatment with high doses of ascorbate | [199] |
APL | In vitro | NB4 | NF-κB increased Nrf2 expression and leukemia progression | [200] |
CLL | In vitro | Blood samples (PBMC) | The PBMC of patients with CLL had higher levels of Nrf2 than normal blood samples | [203] |
CLL | In vitro | Blood samples (PBMC) | Increased ROR1 expression in CLL cells increases APRIL and BAFF-R expression, leading to the recruitment and accumulation of the p62 protein, which triggers several separate signaling pathways such as Nrf2 | [204] |
ALL | In silico | – | The Nrf2 inhibitory pathway and activation of this factor are disrupted in patients with ALL | [205] |
ALL | In vitro | REH, MOLT-4 | Inhibition of MAPK/ERK and PI3K/AKT pathways reduced Nrf2/NF-κΒ and drug resistance The combination of MAPK/ERK pathway inhibitors plus topoisomerase II inhibitor treatment synergistically increased the production of ROS and caused apoptosis in leukemic cells |