Cholesterol biosynthesis inhibitor RO 48-8071 suppresses growth of TNBC in vivo and in vitro
Author(s): Yayun Liang, Matthew T Cook, Salman M. Hyder
Treating TNBC patients is difficult because tumors lack traditional ER, PR and Her-2-neu and targeted therapy approaches are therefore ineffective. The main purpose of this report is to identify alternatives that could be targeted using agents to control TNBC progression without being toxic to the patient. With this in mind, we considered inhibition of the cholesterol biosynthesis pathway as a possible target and conducted studies, both in vitro and in vivo to examine the effectiveness of such a strategy. RO 48-8071 ([4’-[6-(Allylmethylamino)hexyloxy]-4-bromo- 2’-fluorobenzophenone fumarate]; RO), a small-molecule inhibitor of oxidosqualene cyclase (OSC, a key enzyme in cholesterol biosynthesis), potently reduced the viability of MDA-MB-231 and BT-20 TNBC cells, as well as a cell line that expresses Her-2-neu but not ER or PR. Exposure of TNBC cells in vitro to pharmacological levels of RO (24 to 48 h), or a dose close to the IC50 for OSC (nM) for a week, reduced cell viability significantly. Importantly normal mammary cells were unaffected by RO. FACS analysis showed that RO induced apoptosis of TNBC cells. BT-20 tumor xenografts were generated in nude mice to determine whether RO is effective in reducing TNBC cells in vivo. Administration of RO to mice prevented tumor growth, with no apparent toxicity. Examination of crosssections of RO-treated tumor tissues showed that RO induced TUNEL expression (apoptosis) and suppressed the angiogenic markers VEGF and CD-31. In conclusion, RO is a potent inhibitor of TNBC cell proliferation. The anti-tumor properties of RO appear to be due to induction of apoptosis and suppression of angiogenesis.