betadex and Carcinoma--Renal-Cell

Tumor targeting small molecular inhibitors are the most popular treatments for many malignant diseases, including cancer. However, the lower clinical response and drug resistance still limit their clinical efficacies. HGFK1, the first kringle domain of hepatocyte growth factor, has been defined as a potent anti-angiogenic factor. Here, we aimed to develop and identify novel nanoparticles-PH1/pHGFK1 as potential therapeutic agents for the treatment of renal cell carcinoma (RCC).. We produced a novel cationic polymer-PH1 and investigated the anti-tumor activity of PH1/pHGFK1 nanoparticle alone and its combination therapy with sorafenib in RCC cell line xenografted mice model. Then, we figured out its molecular mechanisms in human RCC cell lines in vitro.. We firstly demonstrated that intravenous injection of PH1/pHGFK1 nanoparticles significantly inhibited tumor growth and prolonged the survival time of tumor-bearing mice, as well as synergistically enhanced anti-tumor activities of sorafenib. Furthermore, we elucidated that recombinant HGFK1 improved sorafenib-induced cell apoptosis and arrested cell cycle. In addition, HGFK1 could also decrease sorafenib-induced autophagy and stemness via blockading NF-κB signaling pathway in RCC both in vitro and in vivo.. HGFK1 could inhibit tumor growth, synergistically enhance anti-tumor activities of sorafenib and reverse its drug resistance evolution in RCC. Our results provide rational basis for clinical application of sorafenib and HGFK1 combination therapy in RCC patients.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; beta-Cyclodextrins; Carcinoma, Renal Cell; Cell Cycle; Cell Movement; Cell Proliferation; Drug Synergism; Female; Folic Acid; Hepatocyte Growth Factor; Humans; Kidney Neoplasms; Kringles; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplastic Stem Cells; Polyethylene Glycols; Polyethyleneimine; Sorafenib; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

A monoclonal antibody, NR-2 MAb, against one of the rat renal cell tumor-associated antigens was developed. NR-2 MAb belonged to IgM class and recognized a polypeptide of 81,000 daltons designated as NR-2 antigen, which is of non-glycoprotein nature with a pI of 4.6. NR-2 MAb was employed to probe the histogenesis of renal cell tumors in rats treated with N-ethyl-N-hydroxyethylnitrosamine followed by trisodium nitrilotriacetate monohydrate. Immunohistochemical analysis indicated that NR-2 antigen was expressed in simple hyperplasia, adenomatous hyperplasia and renal cell tumors. Both clear cells and basophilic cells of the simple hyperplasia showed equally strong positive reactions with NR-2 MAb, whereas the vacuolated epithelium was negative. Furthermore, the proximal tubules in nontumorous areas also expressed NR-2 antigen, suggesting that the hyperplastic lesions which eventually lead to renal cell tumors may derive from epithelia of proximal tubules and not directly from vacuolated epithelium. Such NR-2 antigen-positive epithelia of proximal tubules seem to be initiated cells. NR-2 MAb also cross-reacted with preneoplastic liver lesions.

Topics: Animals; Antibodies, Monoclonal; Antigens, Neoplasm; beta-Cyclodextrins; Biomarkers, Tumor; Carcinoma, Renal Cell; Cyclodextrins; Hyperplasia; Kidney Neoplasms; Liver; Male; Molecular Weight; Neoplasm Proteins; Rats; Rats, Inbred Strains