Zalypsis has in vitro activity in acute myeloid blasts and leukemic progenitor cells through the induction of a DNA damage response.

Abstract

BACKGROUND:

Although the majority of patients with acute myeloid leukemia initially respond to conventional chemotherapy, relapse is still the leading cause of death, probably because of the presence of leukemic stem cells that are insensitive to current therapies. We investigated the antileukemic activity and mechanism of action of zalypsis, a novel alkaloid of marine origin.

DESIGN AND METHODS:

The activity of zalypsis was studied in four acute myeloid leukemia cell lines and in freshly isolated blasts taken from patients with acute myeloid leukemia before they started therapy. Zalypsis-induced apoptosis of both malignant and normal cells was measured using flow cytometry techniques. Gene expression profiling and western blot studies were performed to assess the mechanism of action of the alkaloid.

RESULTS:

Zalypsis showed a very potent antileukemic activity in all the cell lines tested and potentiated the effect of conventional antileukemic drugs such as cytarabine, fludarabine and daunorubicin. Interestingly, zalypsis showed remarkable ex vivo potency, including activity against the most immature blast cells (CD34(+) CD38(-) Lin(-)) which include leukemic stem cells. Zalypsis-induced apoptosis was the result of an important deregulation of genes involved in the recognition of double-strand DNA breaks, such as Fanconi anemia genes and BRCA1, but also genes implicated in the repair of double-strand DNA breaks, such as RAD51 and RAD54. These gene findings were confirmed by an increase in several proteins involved in the pathway (pCHK1, pCHK2 and pH2AX).

CONCLUSIONS:

The potent and selective antileukemic effect of zalypsis on DNA damage response mechanisms observed in acute myeloid leukemia cell lines and in patients' samples provides the rationale for the investigation of this compound in clinical trials.

• Authors: Enrique Colado, Teresa Paíno, Patricia Maiso, Enrique M Ocio, Xi Chen, Stela Alvarez-Fernández, Norma C Gutiérrez, Jesús Martín-Sánchez, Juan Flores-Montero, Laura San Segundo, Mercedes Garayoa, Diego Fernández-Lázaro, Maria-Belen Vidriales, Carlos M Galmarini, Pablo Avilés, Carmen Cuevas, Atanasio Pandiella, Jesús F San-Miguel
• Journal: Haematologica (Haematologica) Vol. 96 Issue 5 Pg. 687-95 (May 2011) ISSN: 1592-8721 [Electronic] Italy
• PMID: 21330323 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• BRCA1 Protein
• PM 00104
• Tetrahydroisoquinolines
• Rad51 Recombinase
• Caspases

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• BRCA1 Protein (genetics, metabolism)
• Blotting, Western
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• DNA Breaks, Double-Stranded (drug effects)
• DNA Damage
• Dose-Response Relationship, Drug
• Flow Cytometry
• Gene Expression Profiling
• Gene Expression Regulation, Leukemic (drug effects)
• HL-60 Cells
• Humans
• Leukemia, Myeloid, Acute (genetics, pathology)
• Mitochondria (drug effects, metabolism)
• Oligonucleotide Array Sequence Analysis
• Rad51 Recombinase (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Stem Cells (drug effects, metabolism, pathology)
• Tetrahydroisoquinolines (pharmacology)
• Tumor Cells, Cultured