Potential Anti-Breast-Cancer Drugs Block Cholesterol Synthesis

A novel computer-based modeling system has identified low molecular weight compounds that inhibit growth of breast cancer cells by interacting with a critical enzyme in the cholesterol synthesis pathway.

Investigators at the University of Missouri (Columbia, USA) used their in-house docking software package MDock to search for target molecules of the drug PRIMA-1. PRIMA-1 restores sequence-specific DNA binding and transactivational activity to mutant p53 proteins. Mutations in the p53 tumor suppressor are found in many different neoplastic cells. PRIMA-1 is, therefore, a unique antioncogenic substance, which works as a reactivator of the apoptotic function of mutant p53 via conformational modulation of function-specific epitopes.

MDock identified oxidosqualene cyclase (OSC), which is part of the cholesterol synthetic pathway, as the main target of PRIMA-1. This finding was the basis for further studies to identify other potential drugs that would kill cancer cells by operating on OSC. Results published in the January 19, 2011, online edition of the Journal of Molecular Graphics and Modeling revealed that the experimental drug Ro 48-8071, originally developed as a modulator of cholesterol synthesis, was a potent inhibitor of breast cell growth.

Both PRIMA-1 and Ro 48-8071 significantly reduced the viability of BT-474 and T47-D breast cancer cells relative to normal mammary cells. In addition, like PRIMA-1, Ro 48-8071 resulted in increased binding of p53 to DNA in BT-474 cells (which express mutant p53).

"We had been working with PRIMA-1 for some time, and what we did not quite understand is exactly how it killed tumor cells,” said contributing author Dr. Salman Hyder, professor of biomedical sciences at the University of Missouri. "With the current findings, we think it is possible that one mechanism utilized by PRIMA-1 to kill cancer cells may include shutting down cholesterol synthesis, but we still do not know for certain if that is the case. What we do know is that Ro 48-8071 does stop cholesterol synthesis, and it proved to be just as effective in destroying cancer cells as PRIMA-1, without harming other normal breast cells, which is a big advantage.”

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