Abstract
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.
Highlights
Our analysis indicates that B. monnieri extracts increase mutation frequency but not chromosomal instability in yeast deleted for RAD1
The ability of B. monnieri extracts to induce an apoptosis-like effect in yeast deleted for RAD1 [19] as well as apoptosis in some cancer cells lines [29,30,31] suggested an impact on DNA integrity
These results are consistent with a connection between DNA damage but not chromosome instability and exposure to B. monnieri extracts
Summary
We speculated that one or more of these compounds was responsible for promoting an apoptosis-like event and limiting growth in yeast deleted for RAD1 [19]. These bioactive compounds from B. monnieri may have potential as drug candidates for the treatment of ERCC4 deficient colorectal cancer. We investigate the molecular mechanisms that promote the apoptosislike event following exposure to B. monnieri extract, using the yeast model for ERCC4 deficient colorectal cancer. Analysis of major constituents from B. monnieri indicates that bacopasaponin C is the bioactive compound responsible for preferentially limiting the growth of RAD1 deleted yeast. C, and perhaps other bioactive compounds from B. monnieri, promotes disruption of the vacuole leading to induction of an apoptosis-like event facilitated by leakage of vacuolar components
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