Dataset Information

Mitochondrial proteome of human leuekmia.

ABSTRACT: Proteome characterization of isolated mitochondria samples prepared from three commonly used acute leukemia cell lines (HL-60, KG-1, MV-4-11). Data were compared to isolated mitochondria prepared from peripheral blood mononuclear cells (PBMC), isolated from healthy human subjects.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Kelsey Fisher-Wellman

PROVIDER: PXD020715 | JPOST Repository | Tue Aug 04 00:00:00 BST 2020

REPOSITORIES: jPOST

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Publications

Intrinsic OXPHOS limitations underlie cellular bioenergetics in leukemia.

Nelson Margaret Am MA McLaughlin Kelsey L KL Hagen James T JT Coalson Hannah S HS Schmidt Cameron C Kassai Miki M Kew Kimberly A KA McClung Joseph M JM Neufer P Darrell PD Brophy Patricia P Vohra Nasreen A NA Liles Darla D Cabot Myles C MC Fisher-Wellman Kelsey H KH

eLife 20210616

Currently there is great interest in targeting mitochondrial oxidative phosphorylation (OXPHOS) in cancer. However, notwithstanding the targeting of mutant dehydrogenases, nearly all hopeful 'mito-therapeutics' cannot discriminate cancerous from non-cancerous OXPHOS and thus suffer from a limited therapeutic index. Using acute myeloid leukemia (AML) as a model, herein, we leveraged an in-house diagnostic biochemical workflow to identify 'actionable' bioenergetic vulnerabilities intrinsic to canc ...[more]

PMID: 34132194

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Project description:Aplidin (plitidepsin) is a novel antitumor agent isolated from the Mediterranean tunicate Aplidium albicans. Aplidin has shown impressive in vitro and in vivo activity against various cancer cell lines. Based on the results from several laboratories Aplidin has recently been granted orphan drug designation for the treatment of acute lymphoblastic leukemia (ALL) and Multiple Myeloma (MM) by the European Commision and Food and Drug Administration. Aplidin has selective cytotoxicity in vitro towards leukemia cells as compared to hematopoeitic progenitors and lacks cross-resistance with other known cytotoxic drugs with the exception of gemcitabine (Leukemia, 2003, Bresters, Broekhuizen). Here, a systematic study of drug combinations with Aplidin, for possible use in hematological malignancies was undertaken. The combination of cytarabine (AraC) and Aplidin was found to be synergistic in three cell lines tested: CCRF-CEM, a human T-cell lymphoblastic leukemia cell line, K562, a acute mylelogenous leukemia cell line and SKI-DLCL, a human Diffuse Large Cell Lymphoma cell line. The combination was further tested in the CCRF-CEM and the SKI-DLCL xenograft model in SCID mice. In an attempt to understand the basis of Aplidin action (alone and in combination) on leukemia and lymphoma cells in vitro and in vivo, gene expression profiling was carried out. Results indicate that multiple cellular pathways are effected by treatment with Aplidine including MAPK signaling, WNT signaling, cell cycle and ATP synthesis. Additionally we have found that that cells lacking functional mitochondria are resistant to Aplidin. Mitochondrial membrane potential and reactive oxygen spicies production was increased following Aplidin treatment but the overall synthesis of ATP was decreased. Addition of AraC to Aplidin resulted in depolarization of mitochondrial membrane and even further increase of ROS production. AraC alone did not affect the cellular ATP pool thus significantly potentiating Aplidin induced apoptosis. Our studies suggest that cancer cell mitochondria may be a target of Aplidin. Based on these studies, a phase I study of the combination of Aplidin and AraC is planned for the treatment of patients with relapsed leukemia. Overall design. Overall goal of the experiment was to obtain molecular insight into the mechanism of action of Aplidin alone as well as its combination with AraC. SKI-DLCL cells were treated in vitro with IC50 doses for Aplidin, AraC or Aplidin+AraC combination. Each samples was done in biological triplicates. Total number of samples was 12. Alternatively, SKI-DLCL cells were injected into scid mice and when the tumor was pulpable animals were given a single dose of Aplidin 1mg/kg and AraC 50mg/kg in combination. On day eight after drugs administration tumors were harvested and total RNA was isolated. No replicates are available. Data was validated using semi-quantitative RT-PCR

Dataset Information

Mitochondrial proteome of human leuekmia.

Publications

Intrinsic OXPHOS limitations underlie cellular bioenergetics in leukemia.

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