Evidence for Feedback Regulation Following Cholesterol Lowering Therapy in a Prostate Cancer Xenograft Model

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Epidemiologic data suggest cholesterol-lowering drugs may slow prostate cancer progression but not incidence.
• The effect of combination cholesterol-lowering therapy on prostate cancer is unclear.

Purpose of the Study:

• To investigate the effects of simvastatin and ezetimibe, alone or in combination, on prostate cancer growth in vivo.

Main Methods:

• LAPC-4 prostate cancer xenografts were established in nude mice on a high-cholesterol diet.
• Mice were treated with simvastatin, ezetimibe, or combination therapy, and tumor volume was monitored.
• Serum and tumor cholesterol levels, and low-density lipoprotein receptor mRNA expression were analyzed.

Main Results:

• Simvastatin reduced prostate cancer cell proliferation in vitro; ezetimibe had no effect.
• Neither simvastatin nor ezetimibe alone affected tumor growth in vivo.
• Combination therapy accelerated tumor growth, increased tumor cholesterol, and induced low-density lipoprotein receptor mRNA.

Conclusions:

• Systemic cholesterol reduction did not slow tumor growth.
• Prostate tumors may develop resistance to cholesterol-lowering therapy via low-density lipoprotein receptor induction.
• Combination therapy may promote prostate cancer growth through this mechanism.