Repositioning “old” drugs for new causes: identifying new inhibitors of prostate cancer cell migration and invasion

Abstract

The majority of prostate cancer (PCa) deaths occur due to the metastatic spread of tumor cells to distant organs. Currently, there is a lack of effective therapies once tumor cells have spread outside the prostate. It is therefore imperative to rapidly develop therapeutics to inhibit the metastatic spread of tumor cells. Gain of cell motility and invasive properties is the first step of metastasis and by inhibiting motility one can potentially inhibit metastasis. Using the drug repositioning strategy, we developed a cell-based multi-parameter primary screening assay to identify drugs that inhibit the migratory and invasive properties of metastatic PC-3 PCa cells. Following the completion of the primary screening assay, 33 drugs were identified from an FDA approved drug library that either inhibited migration or were cytotoxic to the PC-3 cells. Based on the data obtained from the subsequent validation studies, mitoxantrone hydrochloride, simvastatin, fluvastatin and vandetanib were identified as strong candidates that can inhibit both the migration and invasion of PC-3 cells without significantly affecting cell viability. By employing the drug repositioning strategy instead of a de novo drug discovery and development strategy, the identified drug candidates have the potential to be rapidly translated into the clinic for the management of men with aggressive forms of PCa.

Novel Analytical Platform For Robust Identification of Cell Migration Inhibitors

“…The main advantage of our approach is its simplicity in scoring both of cell migration and cell death within a single assay. This is consistent with the recent focus of pharmaceutical industry to take into account polypharmacologic effects 10 , and current interest in drug repurposing 7,11,12 . Recent studies began to adopt the standard wound healing assay for screening multi-phenotypic responses of compounds with polypharmacologic effects 13 .…”

“…Recent studies began to adopt the standard wound healing assay for screening multi-phenotypic responses of compounds with polypharmacologic effects 13 . Other studies tried to investigate the effect of compounds or natural extract by integrating results from two independent phenotypic assays including both cell viability assay and wound healing assay 7,8,14,15 . However, such previous studies still required the primary screening to eliminate false positive compound with cytotoxic effect.…”

“…Prior studies have tried to suppress influence of cell growth on wound closure by pre-treating cells with Mitomycin C (MMC) or growing cells in low serum condition prior to drug treatment [4][5][6] . Cytotoxicity associated with most anti-cancer drugs is another confounding phenotype, which can cause an apparent delay in wound closure 2,7 . Because of such complexity, some drug candidates were mistakenly interpreted as cell migration inhibitors, although they were later found to be cytotoxic drugs in different cell lines or other treatment conditions 2 .…”

Suppression of STIM1 inhibits the migration and invasion of human prostate cancer cells and is associated with PI3K/Akt signaling inactivation

“…Only ~33% of men presented with metastatic tumors live beyond 5 years. Although prostate cancer treatment has achieved numerous breakthroughs in the last decade, effective therapies to prevent prostate cancer metastasis to other parts of body are still lacking ( 3 ). Therefore, novel approaches are urgently needed for the prevention and treatment of the metastasis of prostate carcinoma.…”

Live-single-cell phenotypic cancer biomarkers-future role in precision oncology?

“… 57 For example, assessment of cell migration has been employed to screen FDA-approved drugs for effective treatment of metastatic prostate cancer. 58 The screen was based on the phenotype of cell migration and invasion and depended on assessing the behavior of living prostate cancer cells lines exposed to tested drugs vs. vehicle controls. 58 Within this same concept, a multi-phenotype assay measuring all live-cell biomarkers outlined in Table 1 could be a potentially powerful tool for compound discovery and FDA approved drug library screening for prostate and other solid tumors.…”