jib-04 and Prostatic-Neoplasms

siRNAs hold a great potential for cancer therapy, however, poor stability in body fluids and low cellular uptake limit their use in the clinic. To enhance the bioavailability of siRNAs in tumors, novel, safe, and effective carriers are needed.. Here, we developed cationic solid lipid nanoparticles (cSLNs) to carry siRNAs targeting EphA2 receptor tyrosine kinase (siEphA2), which is overexpressed in many solid tumors including prostate cancer. Using DDAB cationic lipid instead of DOTMA reduced nanoparticle size and enhanced both cellular uptake and gene silencing in prostate cancer cells. DDAB-cSLN showed better cellular uptake efficiency with similar silencing compared to commercial transfection reagent (Dharmafect 2). After verifying the efficacy of siEphA2-loaded nanoparticles, we further evaluated a potential combination with a histone lysine demethylase inhibitor, JIB-04. Silencing EphA2 by siEphA2-loaded DDAB-cSLN did not affect the viability (2D or 3D culture), migration, nor clonogenicity of PC-3 cells alone. However, upon co-administration with JIB-04, there was a decrease in cellular responses. Furthermore, JIB-04 decreased EphA2 expression, and thus, silencing by siEphA2-loaded nanoparticles was further increased with co-treatment.. We have successfully developed a novel siRNA-loaded lipid nanoparticle for targeting EphA2. Moreover, preliminary results of the effects of JIB-04, alone and in combination with siEphA2, on prostate cancer cells and prostate cancer tumor spheroids were presented for the first time. Our delivery system provides high transfection efficiency and shows great promise for targeting other genes and cancer types in further in vitro and in vivo studies.

Topics: Aminopyridines; Cations; Cell Line, Tumor; Cell Survival; Gene Silencing; Histone Demethylases; Humans; Hydrazones; Lipids; Male; Nanoparticles; Particle Size; Prostate; Prostatic Neoplasms; Receptor, EphA2; RNA, Small Interfering; Transfection

JIB‑04 is a structurally unique small molecule, known to exhibit anticancer activity and to inhibit the growth of human lung cancer and prostate cancer cell lines. However, the anticancer effect of JIB‑04 against human hepatic carcinoma, and its underlying mechanisms, are still unclear. In the present study, MHCC97H and HepG2 cells were employed to investigate the anticancer effects of JIB‑04 on cell viability and apoptosis. Annexin V/PI staining, a CCK‑8 assay and western blot analysis demonstrated that JIB‑04 induced apoptosis in MHCC97H and HepG2 cells, which was evidenced by the expression of proapoptotic and apoptotic proteins including p53, Bak, Bax, caspase‑3 and caspase‑9. Subsequently, the expression trends of Bcl‑2 and p53 were reversed after co‑treatment with pifithrin‑α (PFT‑α, a p53 inhibitor). The results revealed that JIB‑04 suppressed the cell viability of MHCC97H and HepG2 cells in a concentration‑dependent manner. Meanwhile, it was also demonstrated that JIB‑04 effectively triggered MHCC97H and HepG2 cell apoptosis by downregulating Bcl‑2/Bax expression, and upregulating proapoptotic and apoptotic protein expression via the p53/Bcl2/caspase signaling pathway. JIB‑04 had effects on the inhibition of cell viability and the induction of apoptosis in MHCC97H and HepG2 cells. The underlying mechanism of action of JIB‑04 was associated with the p53/Bcl‑2/caspase signaling pathway. Our findings provide a foundation for understanding the anticancer effect of JIB‑04 on MHCC97H and HepG2 cells, and suggested that JIB‑04 may be a promising therapeutic agent in human liver cancer.

Topics: Aminopyridines; Caspases; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Hydrazones; Lung Neoplasms; Male; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Tumor Suppressor Protein p53