Chemical-Genetic Interactions of Bacopa monnieri Constituents in Cells Deficient for the DNA Repair Endonuclease RAD1 Appear Linked to Vacuolar Disruption

Molecules

Chananya Huangteerakul¹  HsuMon Aung¹  Thitipa Thosapornvichai¹  LaranT. Jensen¹  AmornratNaranuntarat Jensen²  Kornkanok Ingkaninan³  Suchada Sukrong⁴  Marisa Duangkaew⁵ 

[1] Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences and Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok 65000, Thailand;Research Unit of DNA Barcoding of Thai Medicinal Plants, Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10400, Thailand;Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;

关键词: Bacopa monnieri;    colorectal cancer;    synthetic lethality;    chemical genetics;    yeast;    bacopasaponin C;   

DOI  :  10.3390/molecules26051207

来源: DOAJ

【 摘 要 】

Colorectal cancer is a common cancer worldwide and reduced expression of the DNA repair endonuclease XPF (xeroderma pigmentosum complementation group F) is associated with colorectal cancer. Bacopa monnieri extracts were previously found to exhibit chemical-genetic synthetic lethal effects in a Saccharomyces cerevisiae model of colorectal cancer lacking Rad1p, a structural and functional homologue of human XPF. However, the mechanisms for B. monnieri extracts to limit proliferation and promote an apoptosis-like event in RAD1 deleted yeast was not elucidated. Our current analysis has revealed that B. monnieri extracts have the capacity to promote mutations in rad1∆ cells. In addition, the effects of B. monnieri extracts on rad1∆ yeast is linked to disruption of the vacuole, similar to the mammalian lysosome. The absence of RAD1 in yeast sensitizes cells to the effects of vacuole disruption and the release of proteases. The combined effect of increased DNA mutations and release of vacuolar contents appears to induce an apoptosis-like event that is dependent on the meta-caspase Yca1p. The toxicity of B. monnieri extracts is linked to sterol content, suggesting saponins may be involved in limiting the proliferation of yeast cells. Analysis of major constituents from B. monnieri identified a chemical-genetic interaction between bacopasaponin C and rad1∆ yeast. Bacopasaponin C may have potential as a drug candidate or serve as a model for the development of analogs for the treatment of colorectal cancer.

【 授权许可】

Unknown