ABSTRACT
As a main treatment of prostate cancer, castration therapy has been widely applied in the clinic. However, the therapeutic strategy for hormone-independent prostate cancer (HIPC) was not satisfied. Gemcitabine is an important chemotherapeutic agent that has been approved for the treatment of numerous human solid tumors, including HIPC, whereas the gemcitabine resistance has become a serious problem in clinical chemotherapy. In the present study, the mechanisms of resistance to gemcitabine were investigated in HIPC cell lines. The results demonstrated that the autophagy markers were induced significantly in HIPC cells subsequent to gemcitabine treatment. Meanwhile, administration of gemcitabine to HIPC cells increased the expression of high mobility group box1 (HMGB1). Furthermore, the gemcitabine-induced autophagy response was attenuated in stable HIPC cells harboring HMGB1 shRNA. Notably, the HIPC cells stably transfected with HMGB1 shRNA or treated with autophagy inhibitors were more sensitive to gemcitabine compared with the control group. These data suggested that inhibition of HMGB1 increased the sensitivity to gemcitabine by decreasing autophagy response in HIPC cells. Overall, the present findings demonstrate a new mechanism for the resistance to gemcitabine in HIPC cell lines.
ABSTRACT
Androgen receptor (AR) plays a crucial role in the development and progression of prostate cancer (PCa). PCa patients typically receive androgen deprivation therapy; nonetheless, these patients eventually develop castration and radiation resistance. We hypothesized that we could further improve radiotherapeutic efficacy of hormone-independent PCa (HIPC) by silencing AR. In this study, nanoparticle (NP) AR-shRNA was formulated using folate-targeted H1 nanopolymer. We demonstrated that NP AR-shRNA enhances PCa radiosensitivity as indicated by the inhibition of cell growth, increased apoptosis, and increased cell cycle arrest in AR-dependent HIPC in vitro. The radiosensitizing effect of NP AR-shRNA could be validated in vivo, as NP AR-shRNA significantly suppressed tumor growth and prolonged the survival of HIPC tumor-bearing mice. Analysis at the molecular level revealed that NP AR-shRNA inhibits DNA damage repair signaling pathways. Our study supports further investigation of NP AR-shRNA for the improvement of radiotherapy efficacy in HIPC.
Subject(s)
Androgen Receptor Antagonists/therapeutic use , Folic Acid/chemistry , Nanoparticles/chemistry , Prostatic Neoplasms/radiotherapy , RNA, Small Interfering/therapeutic use , Radiation-Sensitizing Agents/therapeutic use , Animals , Cell Line, Tumor , Humans , Male , Mice , Mice, Nude , Radiation Tolerance , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVE: To employ PEG-PCL diblock copolymers to prepare DTX-loaded polymeric micelles (PEG-PCL-DTX micelles, DTX-PMs) which addressed the issue of DTX's drug loading capacity, encapsulation efficiency and in vitro release. We also studied its effectiveness for the cytotoxicity on prostate cancer. METHODS: The polymeric micelles were screened by its shape using transmission electron microscope and were also characterized in terms of particle size, Zeta potential, drug loading efficiency, in vitro release and cytotoxicity by using laser particle size analyzer and HPLC. Cytotoxicity against LNCap-C4-2B prostate cancer cells of the DTX-PMs and commercial product of Duopafei® were evaluated by MTT assay. RESULTS: The average particle size and Zeta potential of DTX-PMs were found to be 25.1 nm and 0.64 mV. The micelles' drug loading and encapsulation efficiency were 8.72% and 98.1%, respectively. Cytotoxicity assay showed that DTX-PMs exerted significant anti-proliferation activity on LNCap-C4-2B prostate cancer cells. CONCLUSION: Slightly soluable DTX successfully formulated into the PEG-PCL micells, exhibiting small partical size and good stability. Delayed release in vitro and maintained quite a constant concentration in plasma for a long period, which was favorable for its clinic application. In conclusion, DTX-PMs developed here sufficiently solubilized DTX and increase the concentration of DTX in aqueous phase, offering a sustained in vitro release and effective cytotoxicity on LNCap-C4-2B prostate cancer.
