A Novel Three Small Molecule Inhibitor Combination Therapy For Prostate Cancer

Background/Aim: Prostate cancer is common in elderly men. Single treatment options are inadequate for effective therapy. In this study, three small-molecule inhibitors targeting three different pathways related to stemness were combined to obtain an effective antiproliferative effect on prostate cancer cell lines. These small molecules and their corresponding target were: KJ-Pyr-9 as an inhibitor of MYC proto-oncogene bHLH transcription factor (MYC); pyrvinium pamoate as an inhibitor of WNT; and glasdegib as an inhibitor of Sonic Hedgehog (SHH), which induces stem cell properties of cells.

Materials and Methods: Firstly, the half-maximal inhibitory concentration (IC₅₀) and IC₂₅ doses of each drug against the PC-3 cell line and dose optimization for combination of all three drugs were determined. PNT1A cells were used as a healthy control. 3D culture and scratch assays were applied to test efficiency of combined drug treatment.

Results: According to 2D culture results, the combination was synergistic in PC-3 while its effect was minimal in PNT1A. The combined treatment diminished both viability and size of 3D spheroids of PC-3 and LNCaP cells. In addition, the combined treatment reduced the migratory potential of PC-3 and LNCaP cells.

Conclusion: The combined treatment proposed in this study is novel and promising in overcoming drug resistance and side-effects of single agents and may herald a new era in the treatment paradigm for prostate cancer.