A Securinine Derivative as a Novel Treatment for Acute Myeloid Leukemia

Abstract

Acute Myeloid Leukemia (AML) is a rapidly developing cancer of the bone marrow, with a five‐year survival rate of 27.4%. Current methods of treatment are toxic to older patients, creating a need for new treatment options that are more optimal for patient's health. One potential new treatment is with securinine, a natural compound from the Securinega suffruticosa plant that inhibits AML cell growth. Novel securinine derivatives were tested through cell viability assays, and compound 250 was found to exhibit anti‐cancer properties at a higher potency and lower toxicity than the parent drug. 250 was tested in in vivo AML models that exhibited a decrease in the AML burden on the mouse. Further experiments showed that 250 was able to inhibit thioredoxin reductase, an enzyme which maintains redox homeostasis within the cell. This resulted in negatively affecting AML cell metabolism. Nicotinamide add back experiments with 250 treatment allowed the cells to overcome the cytoxicity and decreased the cell death compared to 250 alone. When analyzing various cancers, it was found that AML cell lines had much lower amounts of Thioredoxin reductase compared to solid cancer lines, leading to 250's potent effect on AML cell lines. Future studies may focus on the effect of 250 on p‐38 activation, and p‐38's relevance in 250 mediated AML cell death.Support or Funding InformationThe research was supported by the NIH grant R43CA22870.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.