Distinct Effect Of Aldehydes In Anthracycline Cytotoxicity In S. Cerevisiae

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAAnthracyclines constitute drugs of choice as single agents or in combination therapy in cancers that are refractory to other therapies, such as triple negative breast cancer, commonly observed in African-American women (AA) and is characterized for lacking biomarkers for targeted therapy, and for being aggressive and carrying bad prognoses. Anthracyclines effectiveness is dose-dependent, which increases the risk of side-effects and eventually the development of drug resistance. In S. cerevisiae, mutants of HOM6 display hypersensitivity to doxorubicin by inactivation of the homoserine dehydrogenase. We hypothesized that the L-aspartate-semialdehyde accumulating at this step, sensitizes the cells to anthracyclines. We confirmed this by inactivating HOM3, a prior step in the threonine biosynthesis pathway which prevents the accumulation of the L-aspartate-semialdehyde, rescuing the hom6 strain. To expand our knowledge of the relationship between aldehydes and anthracyclines, we sought to identify other aldehydes that can enhance the toxic effects of doxorubicin. We exposed S. cerevisiae to aldehydes (acetaldehyde, formaldehyde and glutaraldehyde) alone and combined with doxorubicin, cisplatin and menadione. Combination of formaldehyde (2 mM) and doxorubicin was most effective at reducing cell survival by between 31 to 39-fold (in wild type cells) relative to doxorubicin and formaldehyde alone. This effect was dose-dependent on doxorubicin. Co-treatment with formaldehyde and doxorubicin also showed increased toxicity in anthracycline-resistant strains siz1 and msh2. Combination of formaldehyde (2 mM) and menadione (60 mM) reduced cell survival by between 1- to 1.5-fold in wild type cells. Combination of acetaldehyde (2 mM) and menadione (60 mM) reduced cell survival by between 1.6- to 2.2-fold in wild type cells. Wild type cells treated with the combination of cisplatin (80 μM) and acetaldehyde (2 mM) or glutaraldehyde (2 mM) showed a reduced cell survival by between 0.4- to 3.12-fold with the combination of cisplatin and glutaraldehyde being the more cytotoxic of the two. Acetaldehyde, formaldehyde and glutaraldehyde show enhanced toxicity of wild type cells when combined with cytotoxic drugs. The potential use of a combination of aldehydes and cytotoxic drugs could potentially lead to applications intended to enhance anthracycline-based therapy.Citation Format: Jana S. Miles, Tryphon K. Mazu, Hernan Flores-Rozas. Effect of aldehydes in anthracycline cytotoxicity in S. cerevisiae. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2545. doi:10.1158/1538-7445.AM2015-2545