Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis.

Mammalian target of rapamycin (mTOR) inhibitors curtail cap-dependent translation. However, they can also induce post-translational modifications of proteins. We assessed both effects to understand the mechanism by which mTOR inhibitors like rapamycin sensitize multiple myeloma cells to dexamethasone-induced apoptosis.

VHL expression in renal cell carcinoma sensitizes to bortezomib (PS-341) through an NF-kappaB-dependent mechanism.

In renal cell carcinomas (RCC), NF-kappaB blockade is required for maximal bortezomib-induced apoptosis, and expression of the von Hippel-Lindau (VHL) tumor suppressor protein downregulates NF-kappaB. Thus, we hypothesized that expression of wild-type (wt) VHL sensitizes RCC cells to bortezomib by reducing constitutive NF-kappaB activity. Using isogenic paired cell lines with and without expression of wtVHL, we have confirmed that VHL expression reduces constitutive NF-kappaB activity.

Maximal apoptosis of renal cell carcinoma by the proteasome inhibitor bortezomib is nuclear factor-kappaB dependent.

Advanced renal cell carcinoma (RCC) is resistant to cytotoxic chemotherapy, and immunotherapy has modest activity. Proteasome inhibitors represent a novel class of anticancer agents that have activity across a wide spectrum of tumor types. We investigated the efficacy of the proteasome inhibitor bortezomib (VELCADE, formerly known as PS-341) in RCC and found that bortezomib potently induces apoptosis of RCC cell lines.

Drug interactions between the proteasome inhibitor bortezomib and cytotoxic chemotherapy, tumor necrosis factor (TNF) alpha, and TNF-related apoptosis-inducing ligand in prostate cancer.

Purpose: Proteasome inhibition has been shown to be an effective anticancer therapy in many tumor models, including prostate cancer. We sought to identify drug interactions between the proteasome inhibitor bortezomib and other apoptotic stimuli, including cytotoxic chemotherapy and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In addition, we wanted to gain insight into the role of nuclear factor kappaB inhibition as a mediator of bortezomib cytotoxic effects.

Role of the AKT kinase in expansion of multiple myeloma clones: effects on cytokine-dependent proliferative and survival responses.

IL-6 is an established growth factor for multiple myeloma tumor cells, stimulating proliferative and survival responses. Recent work indicates that IL-6 can activate the AKT kinase in myeloma cells. Thus, to test a potential role for AKT in IL-6-induced cellular responses, we transfected myeloma cell lines with an active 'E40K' or dominant negative'PH AKT construct using an adenoviral vector.