The proteasome inhibitor bortezomib acts differently in combination with p53 gene transfer or cytotoxic chemotherapy on NSCLC cells

Abstract

In this report, the effects of a combined treatment with the proteasome inhibitor bortezomib and either a recombinant adenoassociated virus type 2 (rAAV-2)-mediated p53 gene transfer or chemotherapeutic agents, docetaxel and pemetrexed, were tested on p53 positive and p53negative non-small cell lung cancer (NSCLC) cell lines. The combination of bortezomib and rAAV-p53 led to a significant synergistic inhibition of cell growth between 62-82% depending on the p53 status of the cell line and drug concentration. Surviving cells of the combined treatment showed a significant reduced ability to form colonies. Enhanced cell toxicity was associated with a 5.3-14.4-fold increase of the apoptotic rate and intracellular p53 level up to 50.4% following vectormediated p53 restoration and bortezomib treatment. In contrast, an antagonistic effect on tumor cell growth and colony formation was observed for the combination of bortezomib and docetaxel or pemetrexed as a reduction of cell growth between 31 and 48% was found in comparison to 50% using the single agents. Lower cytotoxic effects were associated with significantly reduced apoptosis and an increase of clonogenic growth. The observed antagonistic effects between bortezomib and docetaxel or pemetrexed might influence clinical trials using these compounds. Conversely, p53 restoration and bortezomib treatment led to enhanced, synergistic tumor cell toxicity.

A randomized phase II study of bortezomib and pemetrexed, in combination or alone, in patients with previously treated advanced non-small-cell lung cancer

“…Neukirchen et al demonstrated a significant reduction in growth inhibition and apoptosis when bortezomib and docetaxel or pemetrexed were administered simultaneously. This indicates antagonism between these combinations, possibly due to bortezomib-mediated G2/M arrest preventing cells from entering the stage of the cell cycle at which docetaxel or pemetrexed have cytotoxic activity [40]. Conversely, Gordon et al showed that, bortezomib increases the cytotoxicity of pemetrexed in malignant pleural mesothelioma cell lines in a concentration-dependent manner when administered prior to pemetrexed [41].…”

“…Recent preclinical data have shown that bortezomib and pemetrexed in combination can be both antagonistic [40] and synergistic [41]. Neukirchen et al demonstrated a significant reduction in growth inhibition and apoptosis when bortezomib and docetaxel or pemetrexed were administered simultaneously.…”

Accumulation of GAS5 in exosomes is a marker of apoptosis induction

“…Despite variances in toxicity rates, similar levels of cell death-associated nucleosomes were measured following treatment with the two drugs, thereby indicating the varying efficacy in blocking cell proliferation and apoptosis induction. In addition, the current findings confirm that cytoplasmic nucleosomal fragments are useful tools for evaluating apoptosis in intact cells, as DNA degradation occurs several hours before plasma membrane breakdown during the apoptotic process (21). The primary goal of the present study was to investigate GAS5 accumulation in exosomes during apoptotic induction triggered by two different mechanisms, e.g., microtubule stabilization and DNA strand breaks.…”

Nuclear Factor κB Inhibitors Alleviate and the Proteasome Inhibitor PS-341 Exacerbates Radiation Toxicity in Zebrafish Embryos

“…In addition to reducing the activation state of NF-κB by inhibiting proteasomal degradation of IκB, PS-341 affects many other pathways and targets, leading to high expression levels of several proapoptotic proteins in certain experimental conditions. 23 In vitro, PS-341 has been found to enhance antitumor cell effects of select chemotherapeutic agents 6,24 , tumor cell targeting antibodies 25 , and ionizing radiation 26 . Yet, little is known about the combined effects of PS-341 and ionizing radiation on normal cells and tissues of vertebrate organisms.…”