Assessing the Anticancer Potential of ONC201 and ONC206 Imipridones on Human Prostate Cancer Using 2D and 3D Cell Models

Abstract

Background: Prostate cancer (PC) is the second most commonly diagnosed cancer and the fifth leading cause of cancer-related deaths among men worldwide. Although many therapeutic approaches have been used to manage PC, the disease often develops resistance and progresses into an aggressive and lethal state, known as metastatic castration-resistant prostate cancer (mCRPC). Therefore, defining new targets and elucidating novel therapeutics for treating and managing PC are of utmost priority. Imipridones represent a novel class of anti-cancer compounds that showed promising results in several cancer types. ONC201, the first-in-class clinical imipridone, showed to have anticancer effects in PC. ONC206, an analog derivative of ONC201, possesses enhanced nanomolar potency against several cancers. However, there are no published studies assessing the anti-cancer activity of ONC206 in PC. With ONC206 being more potent than ONC201, it might be able to target the tumors that have acquired therapy resistance mechanisms.

Objective: The aim of this study is to investigate the anti-cancer potential of ONC206, in comparison to ONC201, on human PC using two-dimensional (2D) and three-dimensional (3D) in vitro cell models.

Methods: ONC201 and ONC206 drugs were tested on two PC cell lines (DU145 and PC3) using several in vitro assays. MTT assay was performed to evaluate the cytotoxic effect of a wide range of concentrations of ONC201 and ONC206 on PC cells. Trypan blue exclusion assay was then used to assess the effect of both drugs on cellular viability. In addition, cell migration ability was investigated using the “wound-healing” scratch assay. Furthermore, the 3D sphere-forming assay was applied to examine the effect of both drugs in targeting the enriched population of PC stem/progenitor cells.

Results: Our MTT data showed that ONC206 exerts a more potent cytotoxic effect on the DU145 and PC3 cell lines compared to ONC201, in a time and dose-dependent manner. These results were confirmed through the trypan-blue viability assay. Similarly, ONC206 displayed a more significant attenuation in the migration ability of PC cells in comparison to ONC201. Importantly, these results were validated in a 3D culture system with the sphere-forming assay, where both imipridones decreased the size and the sphere forming ability of prostatospheres. ONC206 was also more potent than ONC201 in targeting the subpopulation of prostate cancer stem cells.

Conclusion: Imipridones represent a novel therapeutic approach for the management of cancer. Our data shows that ONC206, the analog derivative of ONC201, shows more potent anti-cancer effects on PC cells at nanomolar concentrations, paving the way for new effective therapeutics and better clinical management of PC.