Oxidosqualene cyclase as a protein target for anticancer therapeutics

A method for determining the pro-apoptotic or anti-proliferative properties of a compound comprising:

• a) contacting a sample of mammalian cancer cells comprising OSC activity with the compound;
• b) measuring the level of any one or more of
• i) a marker of apoptosis and
• ii) one or more of 2,3-(S)-oxidosqualene, lanosterol, and cholesterol in the sample;
• and
• c) comparing the levels of any one or more of (i) and (ii) in the sample contacted with the compound with the levels of any one or more of (i) and (ii) in a control sample,
• wherein the levels of the 2,3-(S)-oxidosqualene and the marker of apoptosis correlate directly with the level of apoptosis and anti-proliferation, and the levels of the lanosterol and cholesterol correlate inversely with the level of apoptosis and anti-proliferation.

A method for identifying an agent that inhibits the proliferation of cancer cells, comprising:

• a) providing a test sample of cancer cells comprising OSC activity;
• b) either:
• i) determining the activity of OSC in the test sample by contacting the sample with a test agent and comparing the level of any one of 2,3-(S)-oxidosqualene, lanosterol, and cholesterol in the test sample with the level of any one of 2,3-(S)-oxidosqualene, lanosterol, and cholesterol in a control sample;
• or
• ii) determining the activity of OSC in the test sample by measuring the level of any one of 2,3-(S)-oxidosqualene, lanosterol, and cholesterol in the sample at a first time point, contacting the sample with a test agent, and measuring the level of any one of 2,3-(S)-oxidosqualene, lanosterol, and cholesterol in the sample at a second time point;
• and
• c) determining whether the test agent is an agent that modulates the intracellular activity of OSC based on either:
• i) a change in level of any one of 2,3-(S)-oxidosqualene, lanosterol, and cholesterol in the test sample compared to the control sample;
• or
• ii) a change in level of any one of 2,3-(S)-oxidosqualene, lanosterol, and cholesterol in the test sample from the first time point to the second time point;
• wherein the level of any one of 2,3-(S)-oxidosqualene, lanosterol, and cholesterol correlates with the level of intracellular OSC activity.

A method for identifying a compound for the treatment of cancer comprising:

• a) providing a test sample of cancer cells;
• b) contacting the test sample with a test compound;
• c) determining the degree of reduction of any one or more of 2,3-(S)-oxidosqualene, lanosterol, and cholesterol;
• d) optionally, determining:
• i) the increase in the level of a marker of apoptosis;
• and
• ii) the decrease in the level of viable cancer cells;
• e) identifying the test compound as a compound that
• i) inhibits the activity of an enzyme in the cholesterol biosynthetic pathway;
• ii) promotes apoptosis in cancer cells;
• or
• iii) kills cancer cells;
• and
• wherein the level of any one of 2,3-(S)-oxidosqualene, lanosterol, and cholesterol correlates with the level of anticancer activity.

A method of preparing a composition comprising a compound for the treatment of cancer, comprising:

• a) providing a test sample of cancer cells;
• b) contacting the test sample with a test compound;
• c) determining the degree of reduction of any of 2,3-(S)-oxidosqualene, lanosterol, and cholesterol;
• d) optionally, determining:
• i) the increase in the level of a marker of apoptosis;
• and
• ii) the decrease in the level of viable cancer cells;
• e) identifying the test compound as a compound that
• i) inhibits the activity of an enzyme in the cholesterol biosynthetic pathway;
• ii) promotes apoptosis in cancer cells;
• or
• iii) kills cancer cells;
• and
• f) admixing the test compound so identified, or a functional analog or homolog of the test compound, with a carrier, thereby preparing the composition.