Antitumour activity of a potent MEK inhibitor RDEA119/BAY 869766 combined with rapamycin in human orthotopic primary pancreatic cancer xenografts

<p>Abstract</p> <p>Background</p> <p>Combining MEK inhibitors with other signalling pathway inhibitors or conventional cytotoxic drugs represents a promising new strategy against cancer. RDEA119/BAY 869766 is a highly potent and selective MEK1/2 inhibitor undergoing phase I human clinical trials. The effects of RDEA119/BAY 869766 as a single agent and in combination with rapamycin were studied in 3 early passage primary pancreatic cancer xenografts, OCIP19, 21, and 23, grown orthotopically.</p> <p>Methods</p> <p>Anti-cancer effects were determined in separate groups following chronic drug exposure. Effects on cell cycle and downstream signalling were examined by flow cytometry and western blot, respectively. Plasma RDEA119 concentrations were measured to monitor the drug accumulation <it>in vivo</it>.</p> <p>Results</p> <p>RDEA119/BAY 869766 alone or in combination with rapamycin showed significant growth inhibition in all the 3 models, with a significant decrease in the percentage of cells in S-phase, accompanied by a large decrease in bromodeoxyuridine labelling and cell cycle arrest predominantly in G1. The S6 ribosomal protein was inhibited to a greater extent with combination treatment in all the three models. Blood plasma pharmacokinetic analyses indicated that RDEA119 levels achieved <it>in vivo </it>are similar to those that produce target inhibition and cell cycle arrest <it>in vitro</it>.</p> <p>Conclusions</p> <p>Agents targeting the ERK and mTOR pathway have anticancer activity in primary xenografts, and these results support testing this combination in pancreatic cancer patients.</p

The Bmi-1/NF-kappa B/VEGF story: another hint for proteasome involvement in glioma angiogenesis?

Angiogenesis is an essential process for sustaining tumor growth, particularly in cancer cell types with rapid proliferation, including malignant glioma. Bmi-1 is a transcriptional regulator of the polycomb group involved in repression of gene expression by altering the state of chromatin at specific promoters. Bmi-1 overexpression was previously implicated in glioma tumorigenesis, proliferation, self-renewal, apoptotic resistance and invasiveness. In a recent study, Jiang et al. (PLoS One 8:e55527, 2013) have revealed the involvement of Bmi-1/NF-kappa B/VEGF pathway in promoting glioma cell-mediated tubule formation and migration of endothelial cells and neovascularization both in vitro and in vivo. NF-kappa B inhibition reversed these effects, supporting a role for Bmi-1 in glioma angiogenesis. Given the intimate association of Bmi-1 and NF-kappa B with the ubiquitin-proteasome system, a better understanding of protein turnover in angiogenic signaling, discussed here, provides novel implications for anti-angiogenic treatment strategies in gliomas

Penetration of anticancer drugs through tumour tissue as a function of cellular packing density and interstitial fluid pressure and its modification by bortezomib

<p>Abstract</p> <p>Background</p> <p>Limited penetration of anticancer drugs in solid tumours is a probable cause of drug resistance. Our previous results indicate that drug penetration depends on cellular packing density and adhesion between cancer cells.</p> <p>Methods</p> <p>We used epithelioid and round cell variants of the HCT-8 human colon carcinoma cell lines to generate tightly and loosely packed xenografts in nude mice. We measured packing density and interstitial fluid pressure (IFP) and studied the penetration of anti-cancer drugs through multilayered cell cultures (MCC) derived from epithelioid HCT-8 variants, and the distribution of doxorubicin in xenografts with and without pre-treatment with bortezomib.</p> <p>Results</p> <p>We show lower packing density in xenografts established from round cell than epithelioid cell lines, with lower IFP in xenografts. There was better distribution of doxorubicin in xenografts grown from round cell variants, consistent with previous data in MCC. Bortezomib pre-treatment reduced cellular packing density, improved penetration, and enhanced cytotoxcity of several anticancer drugs in MCC derived from epithelioid cell lines. Pre-treatment of xenografts with bortezomib enhanced the distribution of doxorubicin within them.</p> <p>Conclusions</p> <p>Our results provide a rationale for further investigation of agents that enhance the distribution of chemotherapeutic drugs in combination with conventional chemotherapy in solid tumours.</p