Perhexiline is used to inhibit degradation of lipids for energy production, and thereby to promote more oxygen-efficient utilization of glucose as an energy source in chronic ischemic cardiomyopathy. We hypothesized that perhexiline might be able to cause similar response in prostate cancer cells.
These data suggest that perhexiline could have potential in limiting the proliferation of prostate cancer cells, but one of the challenges in utilizing perhexiline in clinical setting are ‘poor-metabolizers’, patients who have altered activity of CYP2D6 (cytochrome P450 family 2 subfamily D member 6) [26]. This problem can be overcome by dose-reduction and/or genetic testing [27]. The dose-limitation challenge motivated us to evaluate whether combinatorial treatment with perhexiline and anti-androgens would allow dose reduction. For these experiments, we selected a low dose of perhexiline (5 μM), which on its own led to prominent increase in intracellular lipid content but only modestly inhibited proliferation (Figure (Figure5A5A and and5B).5B). Interestingly, combinatorial treatment of LNCaP cells with perhexiline and either Abiraterone or Enzalutamide (MDV-3100) almost completely blocked proliferation (Figure (Figure5E5E).
Taken together, these data suggest that a novel AR target gene, ECI2, supports aberrant metabolic homeostasis of prostate cancer cells. Inhibition of lipid degradation either by knocking down this enzyme or by a small molecule inhibitor leads to metabolic stress and activation of the cell death response.
