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A Securinine Derivative as a Novel Treatment for Acute Myeloid Leukemia
Author(s) -
Oldford Natasha R.,
Karunanithi Sheela,
Liu Ruifu,
Hou Youngchun,
Stetson Lindsay,
Roe Anne,
Lee Grace,
Goyco Juan Valentin,
Moreton Stephen,
Wald David
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.lb224
Subject(s) - myeloid leukemia , thioredoxin reductase , cancer research , leukemia , cytotoxicity , cell culture , in vivo , cancer , pharmacology , cell growth , bone marrow , programmed cell death , myeloid , chemistry , thioredoxin , medicine , enzyme , biology , biochemistry , in vitro , immunology , apoptosis , microbiology and biotechnology , genetics
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 Information The 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 .