Securinine, a myeloid differentiation agent with therapeutic potential for AML.

Abstract

As the defining feature of Acute Myeloid Leukemia (AML) is a maturation arrest, a highly desirable therapeutic strategy is to induce leukemic cell maturation. This therapeutic strategy has the potential of avoiding the significant side effects that occur with the traditional AML therapeutics. We identified a natural compound securinine, as a leukemia differentiation-inducing agent. Securinine is a plant-derived alkaloid that has previously been used clinically as a therapeutic for primarily neurological related diseases. Securinine induces monocytic differentiation of a wide range of myeloid leukemia cell lines as well as primary leukemic patient samples. Securinine's clinical potential for AML can be seen from its ability to induce significant growth arrest in cell lines and patient samples as well as its activity in significantly impairing the growth of AML tumors in nude mice. In addition, securinine can synergize with currently employed agents such as ATRA and decitabine to induce differentiation. This study has revealed securinine induces differentiation through the activation of DNA damage signaling. Securinine is a promising new monocytic differentiation inducing agent for AML that has seen previous clinical use for non-related disorders.

• Authors: Kalpana Gupta, Amitabha Chakrabarti, Sonia Rana, Ritu Ramdeo, Bryan L Roth, Munna L Agarwal, William Tse, Mukesh K Agarwal, David N Wald
• Journal: PloS one (PLoS One) Vol. 6 Issue 6 Pg. e21203 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21731671 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Azepines
• Cyclin-Dependent Kinase Inhibitor p21
• Heterocyclic Compounds, 4 or More Rings
• Heterocyclic Compounds, Bridged-Ring
• Lactones
• Piperidines
• Receptors, GABA
• securinine

Topics

• Animals
• Azepines (chemistry, pharmacology, therapeutic use, toxicity)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• DNA Damage
• HL-60 Cells
• Heterocyclic Compounds, 4 or More Rings (chemistry, pharmacology, therapeutic use, toxicity)
• Heterocyclic Compounds, Bridged-Ring
• Humans
• Lactones (chemistry, pharmacology, therapeutic use, toxicity)
• Leukemia, Myeloid, Acute (drug therapy, pathology)
• Mice
• Mice, Nude
• Monocytes (drug effects, pathology)
• Myeloid Cells (drug effects, pathology)
• Piperidines (chemistry, pharmacology, therapeutic use, toxicity)
• Receptors, GABA (metabolism)
• Reproducibility of Results
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays