s-1743 and Prostatic-Neoplasms

Roburic acid (ROB) is a naturally occurred tetracyclic triterpenoid, and the anticancer activity of this compound has not been reported. Docetaxel (DOC) is the first-line chemotherapeutic agent for advanced stage prostate cancer but toxic side effects and drug resistance limit its clinical success. In this study, the potential synergistic anticancer effect and the underlying mechanisms of ROB in combination with DOC on prostate cancer were investigated. The results showed that ROB and DOC in combination synergistically inhibited the growth of prostate cancer cells. The combination also strongly induced apoptosis, and suppressed cell migration, invasion and sphere formation. Mechanistic study showed that the combined effects of ROB and DOC on prostate cancer cells were associated with inhibition of NF-κB activation, down regulation of Bcl-2 and up regulation of Bax. Knockdown of NF-κB by small interfering RNA (siRNA) significantly decreased the combined effect of ROB and DOC. Moreover, we found that esomeprazole (ESOM), a proton pump inhibitor (PPI), strongly enhanced the effectiveness of ROB and DOC on prostate cancer cells in acidic culture medium. Since acidic micro environment is known to impair the efficacy of current anticancer therapies, ESOM combined with ROB and DOC may be an effective approach for improving the treatment of prostate cancer patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Proliferation; Cell Survival; Docetaxel; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Esomeprazole; Humans; Male; Molecular Structure; NF-kappa B; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Structure-Activity Relationship; Tumor Cells, Cultured

Malignant melanomas are characterized by the ability of early metastatic dissemination to regional lymph nodes and the detection of sentinel lymph node metastases serves as an important prognostic parameter. There is clear evidence that melanoma cells and stromal cells of tumor environment can induce lymphangiogenesis, e.g. growth of lymphatic vessels, and this phenomenon is correlated with lymph node metastases. Vascular endothelial growth factor (VEGF) C represents the most potent and well-recognized lymphangiogenic growth factor secreted in tumor milieu by melanoma cells and tumor-associated macrophages, however the mechanism underlying VEGF-C secretion is not completely understood. We demonstrate that an acidic extracellular pH promotes the expression of VEGF-C in A375P melanoma cells and in melanoma cells isolated from a human spontaneous metastatic lesion, through the NF-κB transcription factor. We also demonstrate that esomeprazole, a proton pump inhibitor which requires acidosis to be activated, is able to prevent VEGF-C expression in acidic melanoma cells by interfering with NF-κB activation. Furthermore, we show that esomeprazole abrogates the enhanced VEGF-C expression in tumor cells grown in a acidic medium and stimulated by IL-1β. On the whole, the present study reveals that acidity may be considered a strong promoter of VEGF-C expression in melanoma cells and provides a new pharmacological target to limit the development of tumor lymphangiogenesis.

Topics: Acidosis; Blotting, Western; Breast Neoplasms; Esomeprazole; Female; Fluorescent Antibody Technique; Humans; Hydrogen-Ion Concentration; Immunoenzyme Techniques; Male; Melanoma; NF-kappa B; Prostatic Neoplasms; Proton Pump Inhibitors; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Tumor Cells, Cultured; Vascular Endothelial Growth Factor C