Anti-tumor Effects of Penfluridol through Dysregulation of Cholesterol Homeostasis

Background: Psychiatric patients appear to be at lower risk of cancer. Some antipsychotic drugs might haveinhibitory effects on tumor growth, including penfluridol, a strong agent. To test this, we conducted a studyto determine whether penfluridol exerts cytotoxic effects on tumor cells and, if so, to explore its anti-tumormechanisms.
Methods: Growth inhibition of mouse cancer cell lines by penfluridol was determined using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Cytotoxic activity was determined byclonogenic cell survival and trypan blue assays. Animal tumor models of these cancer cells were established andto evaluate penfluridol for its anti-tumor efficacy in vivo. Unesterified cholesterol in cancer cells was examined byfilipin staining. Serum total cholesterol and tumor total cholesterol were detected using the cholesterol oxidase/paminophenazone(CHOD-PAP) method.
Results: Penfluridol inhibited the proliferation of B16 melanoma (B16/F10), LL/2 lung carcinoma (LL/2), CT26 colon carcinoma (CT26) and 4T1 breast cancer (4T1) cells in vitro. Invivo penfluridol was particularly effective at inhibiting LL/2 lung tumor growth, and obviously prolonged thesurvival time of mice bearing LL/2 lung tumors implanted subcutaneously. Accumulated unesterified cholesterolwas found in all of the cancer cells treated with penfluridol, and this effect was most evident in LL/2, 4T1 andCT26 cells. No significant difference in serum cholesterol levels was found between the normal saline-treatedmice and the penfluridol-treated mice. However, a dose-dependent decrease of total cholesterol in tumor tissueswas observed in penfluridol-treated mice, which was most evident in B16/F10-, LL/2-, and 4T1-tumor-bearingmice.
Conclusion: Our results suggested that penfluridol is not only cytotoxic to cancer cells in vitro but canalso inhibit tumor growth in vivo. Dysregulation of cholesterol homeostasis by penfluridol may be involved inits anti-tumor mechanisms.