Nicardipine is a putative EED inhibitor and has high selectivity and potency against chemoresistant prostate cancer in preclinical models.

BACKGROUND: It is imperative to develop novel therapeutics to overcome chemoresistance, a significant obstacle in the clinical management of prostate cancer (PCa) and other cancers. METHODS: A phenotypic screen was performed to identify novel inhibitors of chemoresistant PCa cells. The mechanism of action of potential candidate(s) was investigated using in silico docking, and molecular and cellular assays in chemoresistant PCa cells. The in vivo efficacy was evaluated in mouse xenograft models of chemoresistant PCa. RESULTS: Nicardipine exhibited high selectivity and potency against chemoresistant PCa cells via inducing apoptosis and cell cycle arrest. Computational, molecular, and cellular studies identified nicardipine as a putative inhibitor of embryonic ectoderm development (EED) protein, and the results are consistent with a proposed mechanism of action that nicardipine destabilised enhancer of zeste homologue 2 (EZH2) and inhibited key components of noncanonical EZH2 signalling, including transducer and activator of transcription 3, S-phase kinase-associated protein 2, ATP binding cassette B1, and survivin. As a monotherapy, nicardipine effectively inhibited the skeletal growth of chemoresistant C4-2B-TaxR tumours. As a combination regimen, nicardipine synergistically enhanced the in vivo efficacy of docetaxel against C4-2 xenografts. CONCLUSION: Our findings provided the first preclinical evidence supporting nicardipine as a novel EED inhibitor that has the potential to be promptly tested in PCa patients to overcome chemoresistance and improve clinical outcomes.

A surface-modified sperm sorting device with long-term stability.

Microfluidic devices fabricated from poly (dime- thylsiloxane) (PDMS) offer the ability to improve our biological and medical capabilities. Although PDMS offers a range of intriguing benefits for biomedical applications, the intrinsically hydrophobic nature of PDMS may impede with the tremendous potential of these devices. Here, we describe a PDMS-based sperm sorting device, which has been surface-modified via graft-co-polymerization of poly(ethylene glycol) methyl ether methacrylate to create a moderately hydrophilic and non-fouling surface. This process involves the exposure of PDMS to UV/ozone, which activates the PDMS surface to bond to the substrate and, at the same time, initiates the graft-co-polymerization from the PDMS surface. In this study, we confirmed long-term stability of surface-modified PDMS for up to 56 days based on Fourier transformation infrared spectroscopy (FTIR), contact angle measurements, and protein adsorption studies. Moreover, the applicability of our method to PDMS-based sperm sorting devices was demonstrated by successfully sorting human sperm.