Synergistic Effect of Endogenous and Exogenous Aldehydes on Doxorubicin Toxicity in Yeast.

Synergistic Effect of Endogenous and Exogenous Aldehydes on Doxorubicin Toxicity in Yeast. Biomed Res Int. 2018;2018:4938189 Authors: Miles JS, Sojourner SJ, Whitmore AM, Freeny D, Darling-Reed S, Flores-Rozas H Abstract Anthracyclines are frequently used to treat many cancers including triple negative breast cancer, which is commonly observed in African-American women (AA), and tend to be more aggressive, carry worse prognoses, and are harder to manage because they lack molecular targets. Although effective, anthracyclines use can be limited by serious side effects and eventually the development of drug resistance. In S. cerevisiae, mutants of HOM6 display hypersensitivity to doxorubicin. HOM6 is required for synthesis of threonine and interruption of the pathway leads to accumulation of the threonine intermediate L-aspartate-semialdehyde. This intermediate may synergize with doxorubicin to kill the cell. In fact, deleting HOM3 in the first step, preventing the pathway to reach the HOM6 step, rescues the sensitivity of the hom6 strain to doxorubicin. Using several S. cerevisiae strains (wild type, hom6, hom3, hom3hom6, ydj1, siz1, and msh2), we determined their sensitivity to aldehydes and to their combination with doxorubicin, cisplatin, and etoposide. Combination of formaldehyde and doxorubicin was most effective at reducing cell survival by 31-fold-39-fold (in wild type cells) relative to doxorubicin and formaldehyde alone. This ...
Source: Biomed Res - Category: Research Authors: Tags: Biomed Res Int Source Type: research