Low expression of GFI-1 Gene is associated with Panobinostat-resistance in acute myeloid leukemia through influencing the level of HO-1

Cheng, Bingqing; Tang, Sishi; Zhe, Nana; Ma, Dan; Yu, Kunlin; Wei, Danna; Zhou, Zheng; Lü, Tingting; Wang, Jishi; Fang, Qin

doi:10.1016/j.biopha.2018.02.039

Cited by 12 publications

(9 citation statements)

References 52 publications

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“…Metalloporphyrin are widely used in HO-1-related studies and they have been confirmed with the efficiency against cancers. ZnPPIX was showed to inhibit the proliferation of leukemic cells [95] and suppress the resistance against panobinostat [96]. Treatment with pegylated-ZnPPIX significantly attenuated tumor growth and increased the sensitivity to chemotherapy in human colon cancer SW480 xenograft mouse model [97].…”

Section: Ho-1 Modulators In Cancer Treatmentmentioning

confidence: 99%

A Dual Role of Heme Oxygenase-1 in Cancer Cells

Chiang

Chen

Chang

2018

IJMS

328

249

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Heme oxygenase (HO)-1 is known to metabolize heme into biliverdin/bilirubin, carbon monoxide, and ferrous iron, and it has been suggested to demonstrate cytoprotective effects against various stress-related conditions. HO-1 is commonly regarded as a survival molecule, exerting an important role in cancer progression and its inhibition is considered beneficial in a number of cancers. However, increasing studies have shown a dark side of HO-1, in which HO-1 acts as a critical mediator in ferroptosis induction and plays a causative factor for the progression of several diseases. Ferroptosis is a newly identified iron- and lipid peroxidation-dependent cell death. The critical role of HO-1 in heme metabolism makes it an important candidate to mediate protective or detrimental effects via ferroptosis induction. This review summarizes the current understanding on the regulatory mechanisms of HO-1 in ferroptosis. The amount of cellular iron and reactive oxygen species (ROS) is the determinative momentum for the role of HO-1, in which excessive cellular iron and ROS tend to enforce HO-1 from a protective role to a perpetrator. Despite the dark side that is related to cell death, there is a prospective application of HO-1 to mediate ferroptosis for cancer therapy as a chemotherapeutic strategy against tumors.

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Section: Ho-1 Modulators In Cancer Treatmentmentioning

confidence: 99%

A Dual Role of Heme Oxygenase-1 in Cancer Cells

Chiang

Chen

Chang

2018

IJMS

328

249

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“…Other studies revealed that AML patients with reduced GFI1 expression levels showed increased levels of heme-oxygenase (HO-1; an enzyme involved in heme metabolism), HDAC1, HDAC2, and HDAC3 in correlation with poor prognosis (73). Cells from these patients showed resistance to the induction of apoptosis by Panobinostat, a non-selective pan-HDAC inhibitor (73). A link between GFI1 protein levels and AML development and prognosis was further corroborated by a study in which GFI1 was overexpressed in leukemic cell lines and primary murine cells.…”

Section: Gfi1 Status and Epigenetic Drugs To Treat Amlmentioning

confidence: 99%

Role of GFI1 in Epigenetic Regulation of MDS and AML Pathogenesis: Mechanisms and Therapeutic Implications

Möröy

Khandanpour

2019

Front. Oncol.

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Growth factor independence 1 (GFI1) is a DNA binding zinc finger protein, which can mediate transcriptional repression mainly by recruiting histone-modifying enzymes to its target genes. GFI1 plays important roles in hematopoiesis, in particular by regulating both the function of hematopoietic stem- and precursor cells and differentiation along myeloid and lymphoid lineages. In recent years, a number of publications have provided evidence that GFI1 is involved in the pathogenesis of acute myeloid leukemia (AML), its proposed precursor, myelodysplastic syndrome (MDS), and possibly also in the progression from MDS to AML. For instance, expression levels of the GFI1 gene correlate with patient survival and treatment response in both AML and MDS and can influence disease progression and maintenance in experimental animal models. Also, a non-synonymous single nucleotide polymorphism (SNP) of GFI1, GFI1 -36N, which encodes a variant GFI1 protein with a decreased efficiency to act as a transcriptional repressor, was found to be a prognostic factor for the development of AML and MDS. Both the GFI1 -36N variant as well as reduced expression of the GFI1 gene lead to genome-wide epigenetic changes at sites where GFI1 occupies target gene promoters and enhancers. These epigenetic changes alter the response of leukemic cells to epigenetic drugs such as HDAC- or HAT inhibitors, indicating that GFI1 expression levels and genetic variants of GFI1 are of clinical relevance. Based on these and other findings, specific therapeutic approaches have been proposed to treat AML by targeting some of the epigenetic changes that occur as a consequence of GFI1 expression. Here, we will review the well-known role of Gfi1 as a transcription factor and describe the more recently discovered functions of GFI1 that are independent of DNA binding and how these might affect disease progression and the choice of epigenetic drugs for therapeutic regimens of AML and MDS.

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“…Still, attention should be paid to pAkt along with its down-stream target pRaptor, both of which were up-regulated by SFN after long-term exposure. Long-term administration of the HDAC inhibitors panobinostat or valproic acid has been shown to induce resistance triggered by Akt reactivation [37,38]. Speculatively, an elevation of Akt phosphorylation in the presence of SFN indicates early signs of resistance.…”

Section: Discussionmentioning

confidence: 99%

Chronic Sulforaphane Administration Inhibits Resistance to the mTOR-Inhibitor Everolimus in Bladder Cancer Cells

Justin

Rutz

Maxeiner

et al. 2020

IJMS

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Progressive bladder cancer growth is associated with abnormal activation of the mammalian target of the rapamycin (mTOR) pathway, but treatment with an mTOR inhibitor has not been as effective as expected. Rather, resistance develops under chronic drug use, prompting many patients to lower their relapse risk by turning to natural, plant-derived products. The present study was designed to evaluate whether the natural compound, sulforaphane (SFN), combined with the mTOR inhibitor everolimus, could block the growth and proliferation of bladder cancer cells in the short- and long-term. The bladder cancer cell lines RT112, UMUC3, and TCCSUP were exposed short- (24 h) or long-term (8 weeks) to everolimus (0.5 nM) or SFN (2.5 µM) alone or in combination. Cell growth, proliferation, apoptosis, cell cycle progression, and cell cycle regulating proteins were evaluated. siRNA blockade was used to investigate the functional impact of the proteins. Short-term application of SFN and/or everolimus resulted in significant tumor growth suppression, with additive inhibition on clonogenic tumor growth. Long-term everolimus treatment resulted in resistance development characterized by continued growth, and was associated with elevated Akt-mTOR signaling and cyclin-dependent kinase (CDK)1 phosphorylation and down-regulation of p19 and p27. In contrast, SFN alone or SFN+everolimus reduced cell growth and proliferation. Akt and Rictor signaling remained low, and p19 and p27 expressions were high under combined drug treatment. Long-term exposure to SFN+everolimus also induced acetylation of the H3 and H4 histones. Phosphorylation of CDK1 was diminished, whereby down-regulation of CDK1 and its binding partner, Cyclin B, inhibited tumor growth. In conclusion, the addition of SFN to the long-term everolimus application inhibits resistance development in bladder cancer cells in vitro. Therefore, sulforaphane may hold potential for treating bladder carcinoma in patients with resistance to an mTOR inhibitor.

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Low expression of GFI-1 Gene is associated with Panobinostat-resistance in acute myeloid leukemia through influencing the level of HO-1

Cited by 12 publications

References 52 publications

A Dual Role of Heme Oxygenase-1 in Cancer Cells

A Dual Role of Heme Oxygenase-1 in Cancer Cells

Role of GFI1 in Epigenetic Regulation of MDS and AML Pathogenesis: Mechanisms and Therapeutic Implications

Chronic Sulforaphane Administration Inhibits Resistance to the mTOR-Inhibitor Everolimus in Bladder Cancer Cells

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