Epigenetic therapy combinations in acute myeloid leukemia: what are the options?

Bewersdorf, Jan Philipp; Shallis, Rory M.; Stahl, Maximilian

doi:10.1177/2040620718816698

Cited by 77 publications

(70 citation statements)

References 153 publications

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“…While these findings require further investigation, it is possible that HDJ2 regulates histone properties. Interestingly, both of the protein synthesis inhibitors (bortezomib and omacetaxine) in our screen were antagonistic to HDJ2 depletion [67]. We confirmed that omacetaxine (protein biosynthesis inhibitor) displayed reduced potency upon inhibition of HDJ2 [42].…”

Section: Discussionsupporting

confidence: 64%

Chemogenomic screening Identifies the Hsp70 Co-chaperone HDJ2 as a Hub for Anticancer Drug Resistance

Nitika

Blackman

Knighton

et al. 2019

Preprint

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24Heat shock protein 70 (Hsp70) is an important molecular chaperone that regulates 25 oncoprotein stability and tumorigenesis. However, attempts to develop anti-chaperone 26 drugs targeting molecules such as Hsp70 have been hampered by toxicity issues. Hsp70 27 is regulated by a suite of co-chaperone molecules that bring "clients" to the primary 28 chaperone for efficient folding. Therefore, rather than targeting Hsp70 itself, here we have 29 examined the feasibility of inhibiting the co-chaperone HDJ2, a member of the J domain 30 protein family, as a novel anticancer strategy. We found HDJ2 to be upregulated in a 31 variety of cancers, suggesting a role in malignancy. To confirm this role, we screened the 32 NIH Approved Oncology collection for chemical-genetic interactions with loss of HDJ2 in 33 cancer. 41 compounds showed strong synergy with HDJ2 loss, whereas 18 dramatically 34 lost potency. Several of these hits were validated using a HDJ2 inhibitor (116-9e) in 35 castration-resistant prostate cancer cell (CRPC) and spheroid models. Taken together, 36 these results confirmed that HDJ2 is a hub for anticancer drug resistance and that HDJ2 37 inhibition may be a potent strategy to sensitize cancer cells to current and future 38 therapeutics. 39 40 41 42 104 Materials and Methods 105 Cell culture. The HAP1 Chronic Myelogenous Leukemia cancer cell line and HDJ2 106 Knockout cell line was purchased from Horizon Discovery and were cultured in Iscove's 107 Modified Eagle Medium (Invitrogen) with 10% fetal bovine serum (Gibco), 100 units/ml 108 penicillin, and 100 μg/ml streptomycin at 5% CO2 and 37° C. The LNCaP cancer cell line 109 was purchased from ATCC and were cultured in RPMI-1640 medium (Invitrogen) with 110 10% fetal bovine serum (FBS, Clontech), 100 units/ml penicillin, and 100 μg/ml 111 streptomycin at 5% CO2 and 37° C. 112 6 Drug Screening. Approved Oncology Drug plates consisting of the most current FDA 113 approved anticancer drugs were obtained from National Cancer Institute (NCI). For 114 experiments delineating the synergy between the loss of HDJ2 and approved anticancer 115 drug, HAP1 cells and HAP1 (HDJ2 KO) cells were plated in growth media at 20% 116 confluency 1 day prior to drug treatment. On Day 1 of treatment, cells were treated with 117 DMSO (control), Approved oncology anticancer drugs at 50 µM for 72 hours. Following 118 drug treatments, Cell Titer-Glo reagent was added directly to the wells according to 119 manufacturer's instructions. The luminescence was measured on Bio-Tek Plate reader. 120 Luminescence reading was normalized to and expressed as a relative percentage of the 121 plate averaged DMSO control. The data shown are the mean and SEM of three 122 independent biological replicates. 123 Combination index (CI) calculations. For IC50 calculations, LNCaP cells were seeded 124 in triplicates in 96-well white bottom Nunc plates in growth media at 20% confluency 1 day 125 prior to initiation of drug treatment. On Day 1 of treatment, cells were treated with DMSO 126 (control) and ten ...

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Section: Discussionsupporting

confidence: 64%

Chemogenomic screening Identifies the Hsp70 Co-chaperone HDJ2 as a Hub for Anticancer Drug Resistance

Nitika

Blackman

Knighton

et al. 2019

Preprint

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“…Epigenetically based combination therapies are recently showing more promising curative results than monotherapies in several cancer types [33,[53][54][55]. The maximum pharmacodynamic effect of a drug, including an HDAC or a DNMT inhibitor, will be limited by the toxicity of the provided dose.…”

Section: Discussionmentioning

confidence: 99%

Adjuvant Epigenetic Therapy of Decitabine and Suberoylanilide Hydroxamic Acid Exerts Anti-Neoplastic Effects in Acute Myeloid Leukemia Cells

Najem

Khawaja

Hodroj

et al. 2019

Cells

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Atypical epigenetic processes including histone acetylation and DNA methylation have been identified as a fundamental theme in hematologic malignancies. Such mechanisms modify gene expression and prompt, in part at least, the initiation and progression of several malignancies including acute myeloid leukemia. In the current study we determined the effects of treating KG-1 and U937 acute myeloid leukemia (AML) cells, in vitro, with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), or with a DNMT inhibitor, decitabine (DAC), or their combination, on cell proliferation, cell cycle progression, apoptosis, and expression of apoptosis-related proteins. Each of SAHA and DAC attenuated cell proliferation and induced cell cycle arrest and apoptotic cell death of KG-1 and U937 cell lines. Besides, their sequential combination improved the obtained anti-neoplastic effect: significant augmentation of growth inhibition and apoptosis induction as compared to cells treated with either drug alone. This effect was featured by the upregulated expression of Bax, cytochrome c1, p21, and cleaved caspases 8, 9, and 3, signifying the activation of both the intrinsic and extrinsic pathways of apoptosis. The sequential combination of SAHA and DAC causes a profound antitumorigenic effect in AML cell lines by inducing the expression of tumor suppressor genes. feature of malignancy. Promoter CpG island hypermethylation of tumor suppressor genes, as mediated by DNA methyltransferase enzymes (DNMTs), is well-reported to associate with a closed chromatin structure and potent transcriptional silencing that inactivates key cellular pathways like DNA damage repair and apoptosis [10,11].The two epigenetic mechanisms are functionally interdependent [12]. DNMTs with several DNA binding factors associate with HDACs to form corepressor complexes that alter chromatin architecture and, subsequently, the transcription of putative target genes [13,14]. Trichostatin A, a histone deacetylase inhibitor, induced DNA demethylation in human cancer cell lines [15], and the use of 5-azacytidine, a demethylating agent, mediated an increase in H4 acetylation [16], therefore providing evidence for an integrated crosstalk between the two epigenetic mechanisms.Dysregulated epigenetic mechanisms are central in the pathogenesis of acute myeloid leukemia (AML), the most common type of acute leukemia in adults with poor prognosis despite induction therapy [17][18][19]. Epigenetic shifts impair the differentiation of myeloid progenitors and promote their uncontrolled clonal proliferation leading to bone marrow failure [20].Unique DNA methylation profiles were reported in AML patient samples. Many genes were found to be differentially hypermethylated and repressed [21,22]. AML blasts also exhibited significant modifications in histone acetylation levels at more than 1000 genomic loci compared with progenitor cells with fundamental promoter regions being hypoacetylated in AML compared with progenitor cells [23].The major role of epigenetics in myeloid leukemogenesi...

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“…Several targeted epigenetic therapies have been explored for AML, for example, hypomethylating agents (HMA), histone deacetylase (HDAC) inhibitors, and IDH1/2 inhibitors. However, as monotherapy these inhibitors do not seem to be effective, and treatment failure is common [250][251][252][253]. To potentiate the efficacy of epigenetic therapy, combination strategies with cytotoxic chemotherapy or other targeted drugs are currently being extensively studied.…”

Section: Pi3k/akt/mtor Inhibitors In Combination With Epigenetic Targmentioning

confidence: 99%

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Darici

Alkhaldi

Horne

et al. 2020

JCM

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Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy characterized by excessive proliferation and accumulation of immature myeloid blasts in the bone marrow. AML has a very poor 5-year survival rate of just 16% in the UK; hence, more efficacious, tolerable, and targeted therapy is required. Persistent leukemia stem cell (LSC) populations underlie patient relapse and development of resistance to therapy. Identification of critical oncogenic signaling pathways in AML LSC may provide new avenues for novel therapeutic strategies. The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathway, is often hyperactivated in AML, required to sustain the oncogenic potential of LSCs. Growing evidence suggests that targeting key components of this pathway may represent an effective treatment to kill AML LSCs. Despite this, accruing significant body of scientific knowledge, PI3K/Akt/mTOR inhibitors have not translated into clinical practice. In this article, we review the laboratory-based evidence of the critical role of PI3K/Akt/mTOR pathway in AML, and outcomes from current clinical studies using PI3K/Akt/mTOR inhibitors. Based on these results, we discuss the putative mechanisms of resistance to PI3K/Akt/mTOR inhibition, offering rationale for potential candidate combination therapies incorporating PI3K/Akt/mTOR inhibitors for precision medicine in AML.

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Epigenetic therapy combinations in acute myeloid leukemia: what are the options?

Cited by 77 publications

References 153 publications

Chemogenomic screening Identifies the Hsp70 Co-chaperone HDJ2 as a Hub for Anticancer Drug Resistance

Chemogenomic screening Identifies the Hsp70 Co-chaperone HDJ2 as a Hub for Anticancer Drug Resistance

Adjuvant Epigenetic Therapy of Decitabine and Suberoylanilide Hydroxamic Acid Exerts Anti-Neoplastic Effects in Acute Myeloid Leukemia Cells

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

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