High affinity and covalent-binding microtubule stabilizing agents show activity in chemotherapy-resistant acute myeloid leukemia cells Journal Article

Authors: Pera, B.; Calvo-Vidal, M. N.; Ambati, S.; Jordi, M.; Kahn, A.; Díaz, J. F.; Fang, W.; Altmann, K. H.; Cerchietti, L.; Moore, M. A. S.
Article Title: High affinity and covalent-binding microtubule stabilizing agents show activity in chemotherapy-resistant acute myeloid leukemia cells
Abstract: Treatment failure in acute myeloid leukemia (AML) is frequently due to the persistence of a cell population resistant to chemotherapy through different mechanisms, in which drug efflux via ATP-binding cassette (ABC) proteins, specifically P-glycoprotein, is one of the most recognized. However, disappointing results from clinical trials employing inhibitors for these transporters have demonstrated the need to adopt different strategies. We hypothesized that microtubule targeting compounds presenting high affinity or covalent binding could overcome the effect of ABC transporters. We therefore evaluated the activity of the high-affinity paclitaxel analog CTX-40 as well as the covalent binder zampanolide (ZMP) in AML cells. Both molecules were active in chemosensitive as well as in chemoresistant cell lines overexpressing P-glycoprotein. Moreover, ZMP or CTX-40 in combination with daunorubicin showed synergistic killing without increased in vitro hematopoietic toxicity. In a primary AML sample, we further demonstrated that ZMP and CTX-40 are active in progenitor and differentiated leukemia cell populations. In sum, our data indicate that high affinity and covalent-binding anti-microtubule agents are active in AML cells otherwise chemotherapy resistant. © 2015 Elsevier Ireland Ltd.
Keywords: cancer chemotherapy; controlled study; unclassified drug; human cell; drug potentiation; nonhuman; paclitaxel; chemotherapy; cytarabine; antineoplastic agent; binding affinity; cell proliferation; animal cell; mouse; cell cycle; apoptosis; caspase 3; in vitro study; chemosensitivity; vinblastine; cancer resistance; cancer inhibition; leukemia cell; abc transporter; daunorubicin; acute myeloblastic leukemia; cell cycle arrest; real time polymerase chain reaction; hematopoietic stem cell; drug cytotoxicity; microtubules; p-glycoprotein; resistance; colony forming unit; paclitaxel derivative; caspase 7; acute myeloid leukemia (aml); multidrug resistance protein; human; priority journal; article; ctx 40; microtubule stabilizing agent; zampanolide
Journal Title: Cancer Letters
Volume: 368
Issue: 1
ISSN: 0304-3835
Publisher: Elsevier Ireland Ltd.  
Date Published: 2015-11-01
Start Page: 97
End Page: 104
Language: English
DOI: 10.1016/j.canlet.2015.07.038
PROVIDER: scopus
PUBMED: 26277539
PMCID: PMC5019175
Notes: Export Date: 2 October 2015 -- Source: Scopus
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MSK Authors
  1. Alissa Rachel Kahn
    8 Kahn
  2. Srikanth Reddy Ambati
    27 Ambati
  3. Malcolm A S Moore
    428 Moore