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The Protective Effect of DAS and DADS Against Doxorubicin Induced Toxicity
Author(s) -
Taylor LaShaundra,
Miles Jana,
Webster Camille,
Hudson Alicia,
Soliman Karam,
FloresRozas Hernan,
DarlingReed Selina
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.lb21
Subject(s) - doxorubicin , mutant , reactive oxygen species , chemistry , cancer research , cardiotoxicity , pharmacology , biology , toxicity , gene , biochemistry , chemotherapy , genetics , organic chemistry
Purpose Cancer survival rates are increasing but the mechanisms involved in the adverse effects of cancer therapy such as doxorubicin are still being investigated along with treatment for these effects. Doxorubicin, an established chemotherapeutic agent used for various cancers, has limited use due to cardiotoxicity. The objective of this study, is to determine how garlic constituents, Diallyl sulfide (DAS) and Diallyl disulfide (DADS) may decrease the adverse effects of doxorubicin exposure. With a S. cerevisiae deletion library, a genome wide screen was conducted to detect mutants sensitive to doxorubicin exposure. A mutant deleted for the gene enconding for Mac1 , a copper sensing transcription factor, was found to be highly sensitive. In S. cerevisiae the MAC1 gene is activated upon copper deficiency, resulting in the induction of copper transporters. Other doxorubicin sensitive strains included the sod1 mutant and its copper chaperone ccs1 mutant, both of which are associated with MAC1 . The sensitivity of the mutant strains to doxorubicin, was in part due to the drug's capacity to generate reactive oxygen species (ROS). To test if garlic constituents, DAS and DADS could reduce the sensitivity of the mutants to ROS, the viability of the sensitive yeast strains were determined by exposing them to doxorubicin in the presence or absence of DAS and DADS. Methods Yeast survival assays were completed to determine the sensitivity of wt, mac1, ccs1 , and sod1 strains to doxorubicin, menadione and etoposide, co‐treated with DAS and DADS. Statistical significance was set at p<0.05. Results mac1 shows sensitivity to doxorubicin and etoposide but not menadione. Menadione contains a quinone ring like doxorubicin, and acts through the induction of reactive oxygen species. Etoposide, a chemotherapeutic agent acts only through inhibition of DNA topoisomerase II. The sensitivity of mac1 to both etoposide and doxorubicin, shows that doxorubicin's sensitivity to mac1 is through its action on topoisomerase II. Unlike DAS, DADS was able to decrease the sensitivity of mac1 to doxorubicin and etoposide. Menadione has greater toxicity to ccs1 and sod1 than doxorubicin and etoposide, with DAS and DADS both increasing the survival of all chemicals to ccs1 and sod1 . Conclusion Garlic constituents, das and dads may decrease the adverse effects of doxorubicin exposure, improving the quality of life of patients expose to doxorubicin. Support or Funding Information Research supported by National Institutes of Health (NIH) under Award Number G12MD007582 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .