oxadiazoles and Leukemia--Myeloid--Acute

Acute myeloid leukemia (AML) is a malignant proliferative disease of myeloid hematopoietic origin and cannot be treated appropriately at present. This is due to the fact that leukemia cells are not sensitive to some of the traditional chemotherapy drugs. Or some chemotherapeutic drugs are too toxic to normal cells, affecting their wide clinical application. In this study, we identified BAM15 as a novel mitochondrial uncoupling agent by screening a library of small molecule compounds that inhibit AML cell activity. BAM15 significantly inhibited proliferation and promoted apoptosis in AML cells while at the same time being less cytotoxic to normal cells. The mechanism may be related to the disturbance of the ROS production balance. In vivo investigations revealed that BAM15 effectively suppressed AML progression and prolonged the survival time of mice. In addition, we found that BAM15 can be used in combination with cytarabine to enhance its anti-cancer activity and inhibit the activity of primary cells in AML. Therefore, we identified BAM15 as a potential drug candidate for the treatment of AML.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cytarabine; Diamines; Leukemia, Myeloid, Acute; Mice; Oxadiazoles; Pyrazines; Reactive Oxygen Species

Acute myeloid leukemia (AML) cells are highly dependent on oxidative phosphorylation (OxPhos) for survival, and they continually adapt to fluctuations in nutrient and oxygen availability in the bone marrow (BM) microenvironment. We investigated how the BM microenvironment affects the response to OxPhos inhibition in AML by using a novel complex I OxPhos inhibitor, IACS-010759. Cellular adhesion, growth, and apoptosis assays, along with measurements of expression of mitochondrial DNA and generation of mitochondrial reactive oxygen species indicated that direct interactions with BM stromal cells triggered compensatory activation of mitochondrial respiration and resistance to OxPhos inhibition in AML cells. Mechanistically, inhibition of OxPhos induced transfer of mitochondria derived from mesenchymal stem cells (MSCs) to AML cells via tunneling nanotubes under direct-contact coculture conditions. Inhibition of OxPhos also induced mitochondrial fission and increased functional mitochondria and mitophagy in AML cells. Mitochondrial fission is known to enhance cell migration, so we used electron microscopy to observe mitochondrial transport to the leading edge of protrusions of AML cells migrating toward MSCs. We further demonstrated that cytarabine, a commonly used antileukemia agent, increased mitochondrial transfer of MSCs to AML cells triggered by OxPhos inhibition. Our findings indicate an important role of exogenous mitochondrial trafficking from BM stromal cells to AML cells as well as endogenous mitochondrial fission and mitophagy in the compensatory adaptation of leukemia cells to energetic stress in the BM microenvironment.

Topics: Humans; Leukemia, Myeloid, Acute; Mitochondria; Mitochondrial Dynamics; Oxadiazoles; Oxidative Phosphorylation; Piperidines; Tumor Microenvironment

The polyamine transport system (PTS), hyperactive in cancer cells, can constitute a gate to deliver F14512, a novel spermine epipodophyllotoxin conjugate recently selected for clinical development in AML phase I. We investigated in vitro the high antiproliferative effect of F14512 against 13 leukemia cell lines, and demonstrated a statistically significant correlation with the level of PTS activity, using a novel fluorescent marker F96982. This labelling protocol was then adapted for clinical applications for blood, bone marrow and AML samples with CD45 gating. Within the patient samples, the PTS activity varied significantly in AML cells, as compared to normal lymphocytes. In conclusion, the identification of PTS-positive AML with F98982 probe offers new perspectives to select patients prone to respond to F14512.

Topics: Animals; Antigens, CD34; Biogenic Polyamines; Biological Transport; Cell Line, Tumor; CHO Cells; Cricetinae; Cricetulus; Flow Cytometry; Fluorescent Dyes; Humans; Leukemia, Myeloid, Acute; Oxadiazoles; Podophyllotoxin; Spermine

There has been an ever growing interest in the search for new anti-tumor compounds that do not interact with MDR1-Pgp and MRP1 drug transporters and so circumvent the effect of these proteins conferring multidrug resistance (MDR) and poor prognosis in AML patients. We have investigated the cytotoxic activity of the strong glutathione S-transferase (GST) inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) on AML (HL60) cell lines.. Functional drug efflux studies and cell proliferation assays were performed on both sensitive and MDR AML (HL60) cells after incubation with NBDHEX. Moreover, the mode of cell death (apoptosis vs. necrosis) as well as the correlation between NBDHEX susceptibility and GST activity or Bcl-2 expression was investigated.. NBDHEX is not a substrate of either MDR1-Pgp or MRP1 efflux pumps; in fact, it is not only cytotoxic toward the parental HL60 cell line, but also overcomes the MDR phenotype of its HL60/DNR and HL60/ADR variants.. The data herein reported show that NBDHEX mediates efficient killing of both MDR1-Pgp and MRP1 over-expressing AML cells. Therefore, this drug can potentially be used as an effective agent for treating MDR in AML patients.

Topics: Apoptosis; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Proliferation; Drug Evaluation, Preclinical; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Flow Cytometry; Glutathione; Glutathione Transferase; Humans; Leukemia, Myeloid, Acute; Multidrug Resistance-Associated Proteins; Necrosis; Oxadiazoles; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured