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High affinity and covalent-binding microtubule stabilizing agents show activity in chemotherapy-resistant acute

Benet Pera1, M Nieves Calvo-Vidal1, Srikanth Ambati2

  • 1Department of Medicine, Weill Cornel Medical College, 1300 York Avenue, New York, NY 10065, United States.

Cancer Letters
|August 17, 2015
PubMed

Insights

New anti-microtubule agents, paclitaxel analog CTX-40 and zampanolide (ZMP), show promise against chemotherapy-resistant acute myeloid leukemia (AML) by overcoming drug efflux mechanisms. These compounds are effective in AML cells, including those overexpressing P-glycoprotein.

Area of Science:

  • Oncology
  • Pharmacology
  • Cell Biology

Background:

  • Treatment failure in acute myeloid leukemia (AML) is often linked to chemotherapy-resistant cells.
  • Drug efflux via ATP-binding cassette (ABC) proteins, particularly P-glycoprotein, is a key resistance mechanism.
  • Previous clinical trials with ABC transporter inhibitors have yielded disappointing results, necessitating novel strategies.

Purpose of the Study:

  • To investigate if microtubule-targeting compounds with high-affinity or covalent binding can overcome ABC transporter-mediated drug resistance in AML.
  • To evaluate the activity of paclitaxel analog CTX-40 and zampanolide (ZMP) in AML cells, including chemoresistant models.

Main Methods:

  • Assessed the activity of CTX-40 and ZMP in chemosensitive and P-glycoprotein-overexpressing chemoresistant AML cell lines.
  • Evaluated the synergistic effects of ZMP or CTX-40 in combination with daunorubicin.
  • Tested the efficacy of ZMP and CTX-40 in a primary AML sample, assessing activity across different leukemia cell populations.

Main Results:

  • Both CTX-40 and ZMP demonstrated activity in both chemosensitive and chemoresistant AML cell lines overexpressing P-glycoprotein.
  • Combinations of ZMP or CTX-40 with daunorubicin exhibited synergistic cytotoxicity without increasing in vitro hematopoietic toxicity.
  • ZMP and CTX-40 were found to be active against both progenitor and differentiated leukemia cell populations in a primary AML sample.

Conclusions:

  • High-affinity and covalent-binding anti-microtubule agents are effective against AML cells that are otherwise resistant to chemotherapy.
  • CTX-40 and ZMP represent promising therapeutic candidates for overcoming chemotherapy resistance in AML, potentially by circumventing P-glycoprotein-mediated efflux.
Keywords:
Acute myeloid leukemia (AML)ChemotherapyMicrotubulesP-glycoproteinResistance

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