High-throughput drug screening reveals Pyrvinium pamoate as effective candidate against pediatric MLL-rearranged acute myeloid leukemia

Wander, Priscilla; Arentsen-Peters, Susan T.C.J.M.; Pinhanҫos, Sandra S.; Koopmans, Bianca; Dolman, M. Emmy M.; Ariese, Hendrikus C R; Bos, Frank L.; Castro, Patricia Garrido; Jones, Luke; Schneider, Pauline; Navarro, Míriam Guillén; Molenaar, Jan J.; Rios, Anne C.; Zwaan, C. Michel; Stam, Ronald W.

doi:10.1016/j.tranon.2021.101048

Cited by 10 publications

(9 citation statements)

References 32 publications

(31 reference statements)

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“…Several anti-cancer mechanisms of pyrvinium have been reported in solid tumors, including the regulation of multiple signaling pathways (such as β-catenin, AKT, STAT3, and Hedgehog signaling) which support cell proliferation and survival, and the regulation of cellular response signaling (such as autophagy and UPR), which is observed in several solid tumor malignancies [ 13 ]; however, reports of the role of pyrvinium in myeloid leukemia are limited [ 12 , 39 ]. Harada et al reported that pyrvinium could inhibit ATP production, STAT3 phosphorylation, and human erythroleukemia (HEL 92.1.7) cell proliferation, but did not have this activity in corresponding cells without mitochondrial DNA [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Deciphering the Role of Pyrvinium Pamoate in the Generation of Integrated Stress Response and Modulation of Mitochondrial Function in Myeloid Leukemia Cells through Transcriptome Analysis

Tseng

et al. 2021

Biomedicines

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Pyrvinium pamoate, a widely-used anthelmintic agent, reportedly exhibits significant anti-tumor effects in several cancers. However, the efficacy and mechanisms of pyrvinium against myeloid leukemia remain unclear. The growth inhibitory effects of pyrvinium were tested in human AML cell lines. Transcriptome analysis of Molm13 myeloid leukemia cells suggested that pyrvinium pamoate could trigger an unfolded protein response (UPR)-like pathway, including responses to extracellular stimulus [p-value = 2.78 × 10−6] and to endoplasmic reticulum stress [p-value = 8.67 × 10−7], as well as elicit metabolic reprogramming, including sulfur compound catabolic processes [p-value = 2.58 × 10−8], and responses to a redox state [p-value = 5.80 × 10−5]; on the other hand, it could elicit a pyrvinium blunted protein folding function, including protein folding [p-value = 2.10 × 10−8] and an ATP metabolic process [p-value = 3.95 × 10−4]. Subsequently, pyrvinium was verified to induce an integrated stress response (ISR), demonstrated by activation of the eIF2α-ATF4 pathway and inhibition of mTORC1 signaling, in a dose- and time-dependent manner. Additionally, pyrvinium could co-localize with mitochondria and then decrease the mitochondrial basal oxidative consumption rate, ultimately dysregulating the mitochondrial function. Similar effects were observed in cabozantinib-resistant Molm13-XR cell lines. Furthermore, pyrvinium treatment retarded Molm13 and Molm13-XR xenograft tumor growth. Thus, we concluded that pyrvinium exerts anti-tumor activity, at least, via the modulation of the mitochondrial function and by triggering ISR.

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Section: Discussionmentioning

confidence: 99%

Deciphering the Role of Pyrvinium Pamoate in the Generation of Integrated Stress Response and Modulation of Mitochondrial Function in Myeloid Leukemia Cells through Transcriptome Analysis

Tseng

et al. 2021

Biomedicines

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“…With a different approach using a high-throughput drug library screening methodology, more than 4,000 compounds were screened at various final concentrations on two primary AML patient samples with MLL-AF9 translocation aiming to identify drugs that can achieve inhibition of more than 50% leukemic cell viability. Pyrvinium was the highest-ranked hit at the highest dose tested and achieved elimination of the leukemic cells in both samples, while affecting the viability of non-leukemic bone marrow control samples by 50% ( Wander et al, 2021 ). Pyrvinium is an FDA approved anthelmintic drug used in the clinic for the treatment of pinworms in humans ( Beck et al, 1959 ).…”

Section: Using In Silico Tools and Drug Screens To Identify Novel Drugs With Anti-leukemic Therapeutic Potentialmentioning

confidence: 99%

“…Although the authors did not investigate in detail the mechanism of the anti-leukemia activity of pyrvinium in the MLL samples, they showed lack of β -catenin protein in MLL- rearranged AML cells and, at the same time, mitochondrial localization of the drug in the MLL cells. Therefore, they speculate that pyrvinium might cause mitochondrial respiration impairment in leukemia cells with MLL translocations ( Wander et al, 2021 ).…”

Section: Using In Silico Tools and Drug Screens To Identify Novel Drugs With Anti-leukemic Therapeutic Potentialmentioning

confidence: 99%

Drug Repurposing for Targeting Acute Leukemia With KMT2A (MLL)—Gene Rearrangements

Tsakaneli

Williams

2021

Front. Pharmacol.

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The treatment failure rates of acute leukemia with rearrangements of the Mixed Lineage Leukemia (MLL) gene highlight the need for novel therapeutic approaches. Taking into consideration the limitations of the current therapies and the advantages of novel strategies for drug discovery, drug repurposing offers valuable opportunities to identify treatments and develop therapeutic approaches quickly and effectively for acute leukemia with MLL-rearrangements. These approaches are complimentary to de novo drug discovery and have taken advantage of increased knowledge of the mechanistic basis of MLL-fusion protein complex function as well as refined drug repurposing screens. Despite the vast number of different leukemia associated MLL-rearrangements, the existence of common core oncogenic pathways holds the promise that many such therapies will be broadly applicable to MLL-rearranged leukemia as a whole.

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Section: Introductionmentioning

confidence: 99%

“…Based on genetic mutations and speci c chromosomal rearrangements, the World Health Organization (WHO) divides AML with recurrent genetic abnormalities into 11 subgroups [2]. The mixedlineage leukemia (MLL) gene rearrangements is one of the most common chromosomal abnormalities in AML [3,4].The MLL gene at 11q23 has many partner genes, of which over 80 have been identi ed [5]. Among them, the SEPTIN6 (SEPT6) gene located at Xq24 involving in the formation of MLL arrangement t(X;11)(q22-24;q23) is extremely rare in AML [6], a limited number of cases have been documented in literatures.…”

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confidence: 99%

MLL-SEPT6 Positive Acute Myeloid Leukemia Patients Often Co-occur With NRAS Mutations?

Chen

2021

Preprint

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BackgroundThe MLL-SEPT6 fusion gene is a relatively rare genetic event in leukemia. Its clinical characteristics, prognosis, especially the profile of co-occurring gene mutations remain unclear. MethodsWe retrospectively analyzed four rare leukemia cases carrying MLL-SEPT6 in our hospital from laboratory examination, diagnosis, treatment and prognosis, and provided a comprehensive and detailed description on clinical profile of MLL-SEPT6-positive AML patients in the literature. ResultsAll the four patients were diagnosed with acute myeloid leukemia (AML) and harbored X chromosome and 11 chromosome rearrangements. Three of four cases occurred NRAS mutation while the rest one with congenital AML did not. Of the four cases, one developed drug-resistant, one suffered relapse after bone marrow transplantation (BMT) and one died. Combined with other cases reported in literatures, we found that of all patients diagnosed with AML, 90.9% were children (≤ 9 years old) and 54.5% were infants (≤1 year old). The survival time between infant group (≤1 year old) and pediatric group (>1 and <18 years old), patients that received BMT and that received chemotherapy alone did not show significant differences (P>0.05). ConclusionsMLL-SEPT6 was more commonly observed in pediatric AML patients, some of which may co-occur with NRAS mutations. The prognosis was inconclusive and may not be related to age or BMT. More information needs to be accumulated and summarized from additional cases to confirm the underlying connection between NRAS mutations and MLL-SEPT6 in order to better understand the profile in MLL-SEPT6-positive AML.

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High-throughput drug screening reveals Pyrvinium pamoate as effective candidate against pediatric MLL-rearranged acute myeloid leukemia

Abstract: Highlights Drug library screening identified pyrvinium to be effective against MLL -rearranged AML. Pyrvinium targets the mitochondria of MLL -rearranged AML cells. Pyrvinium does not antagonize with standard chemotherapy in MLL -rearranged AML.

Cited by 10 publications

References 32 publications

Deciphering the Role of Pyrvinium Pamoate in the Generation of Integrated Stress Response and Modulation of Mitochondrial Function in Myeloid Leukemia Cells through Transcriptome Analysis

Deciphering the Role of Pyrvinium Pamoate in the Generation of Integrated Stress Response and Modulation of Mitochondrial Function in Myeloid Leukemia Cells through Transcriptome Analysis

Drug Repurposing for Targeting Acute Leukemia With KMT2A (MLL)—Gene Rearrangements

MLL-SEPT6 Positive Acute Myeloid Leukemia Patients Often Co-occur With NRAS Mutations?

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