morphinans and Carcinoma--Renal-Cell

Renal cell carcinoma (RCC) is a heterogeneous histological disease and the most common kidney cancer. The mortality rate of RCC remains high despite the improved treatment. Sinomenine is an isoquinoline extracted from Chinese medicinal plant Sinomenium acutum, famous for its ability to suppress several cancer cell types. Our research aimed to explore the anti-cancer potential of sinomenine in RCC. Results showed that sinomenine reduced the viability by reducing sphere-forming ability and enhancing pro-apoptosis effect in ACHN cells in a dose dependent manner. The expression levels of proliferation/apoptosis markers further validated the result. In addition, sinomenine significantly regulated the level of autophagy-related proteins with decreased expression of p62, and increased Beclin1 and LC3 II/LC3 I. Furthermore, phosphatidylinositol-3 kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR), the negatively regulated cell autophagy signaling pathway, was inhibited by sinomenine with decreased membrane translocation of AKT in ACHN cell lines. All in all, our study demonstrated that sinomenine promoted apoptosis in RCC via enhancing autophagy through PI3K/AKT/mTOR pathway.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Kidney Neoplasms; Morphinans; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

New strategies for the treatment of clear-cell renal cell carcinoma (ccRCC) are urgently needed. Recently, accumulating evidence has demonstrated that sinomenine hydrochloride (SH), extracted from the plant sinomenium acutum, has potent anti-cancer activity in multiple human malignant solid tumors. However, the underlying molecular mechanism by which SH treatment exerts its antagonizing tumorigenic effects has not been clearly elucidated. In this study, we showed that SH treatment exerted profound effects on cell growth in ccRCC in a dose- and time-dependent manner in vitro. Furthermore, treatment with SH significantly suppressed the migration, invasiveness and angiogenesis of ccRCC cells in vitro. Mechanistically, we revealed that SH treatment blocked epithelial-mesenchymal transition (EMT) through the downregulation of the expression of the transcription factors Snail1 and Twist in ccRCC cells. Additionally, the depletion of p-Smad2 and p-Smad3 was required for SH treatment to inhibit EMT effectively. Taken together, these findings indicate an anti-cancer role for SH in ccRCC cells and reveal a potential molecular mechanism by which Smad / EMT axis functions in ccRCC, as its hyperactivation has been associated with cell proliferation, migration, invasiveness and angiogenesis in this cancer type. These observations suggest that SH can act as an efficacious adjuvant chemotherapeutic candidate that targets the Smad/EMT axis in patients with ccRCC.

Topics: Carcinoma, Renal Cell; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Drug Delivery Systems; Epithelial-Mesenchymal Transition; Human Umbilical Vein Endothelial Cells; Humans; Kidney Neoplasms; Morphinans; Neoplasm Invasiveness; Neovascularization, Pathologic; Smad Proteins