High affinity and covalent-binding microtubule stabilizing agents show activity in chemotherapy-resistant acute myeloid leukemia cells.
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.
Department of Medicine, Weill Cornel Medical College, 1300 York Avenue, New York, NY 10065, United States.
Benet
B
Pera
Department of Medicine, Weill Cornel Medical College, 1300 York Avenue, New York, NY 10065, United States.
M Nieves
MN
Calvo-Vidal
Department of Cell Biology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
Srikanth
S
Ambati
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zürich, HCI H405, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.
Michel
M
Jordi
Department of Cell Biology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
Alissa
A
Kahn
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
J Fernando
JF
Díaz
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nan Wei Road, Beijing 100050, China.
Weishuo
W
Fang
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zürich, HCI H405, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.
Karl-Heinz
KH
Altmann
Department of Medicine, Weill Cornel Medical College, 1300 York Avenue, New York, NY 10065, United States. Electronic address: lec2010@med.cornell.edu.
Leandro
L
Cerchietti
Department of Cell Biology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
Malcolm A S
MAS
Moore
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003630:Daunorubicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D018942:Macrolides / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000633:toxicity; D013997:Time Factors; D050257:Tubulin Modulators / Q000494:pharmacology* / Q000633:toxicity
D018942:Macrolides; D050257:Tubulin Modulators; C444900:zampanolide; D017239:Paclitaxel; D003630:Daunorubicin
Acute myeloid leukemia (AML); Chemotherapy; Microtubules; P-glycoprotein; Resistance