Treatment and Prevention of Breast Cancer Using Multifunctional Inhibitors of Cholesterol Biosynthesis
Annual rept. 1 Jun 2012-31 May 2013
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Most human breast cancers are hormone responsive, depending on estrogens and progestins for tumor cell proliferation. Initially, hormone-responsive tumors respond to endocrine therapy, however, most human breast tumors develop resistance to currently used endocrine therapeutic protocols. It is therefore essential that we identify additional molecular targets in the signaling pathways that lead to tumor growth if we are to effectively treat and prevent cancers of the breast. It is well-established that breast cancer cells have the capacity to synthesize endogenous cholesterol, the precursor for steroid hormones. Cholesterol biosynthesis by tumor cells therefore potentially contributes towards anti-hormone resistance. Most commonly used cholesterol lowering drugs inhibit HMG CoA-reductase, a key rate-limiting enzyme in the cholesterol biosynthetic pathway these inhibitors are however associated with certain undesirable side effects that limit their use for cancer therapy. Our goal was to identify alternative targets in the pathway leading to the production of cholesterol, which might be regulated with less toxic inhibitors to control the progression of breast disease. Inhibitors of oxidosqualene cyclase OSC, an enzyme down-stream of HMG CoA-reductase, effectively arrested breast cancer cell proliferation. RO0488071 4 -6-Allylmethylaminohexyloxy-4-bromo- 2 -fluorobenzophenone fumarate RO, and an analogue RO0613479, were particularly effective in this regard. Administration of both of these OSC inhibitors to ER positive human breast cancer cells e.g. BT-474, T47-D, MCF-7 cells at a pharmacological dose or at a dose close to the IC50 value for OSC nM range reduced tumor cell viability in vitro. Initial studies show that administration of RO to animals with human breast cancer cell-derived xenografts prevents further in vivo progression of the disease, with no apparent toxicity.
- Medicine and Medical Research