Effects of the proteasome inhibitor bortezomib alone and in combination with chemotherapy in the A549 non-small-cell lung cancer cell line

Mortenson, Melinda M.; Schlieman, Michael G.; Virudachalam, Subbulakshmi; Bold, Richard J.

doi:10.1007/s00280-004-0811-4

Cited by 94 publications

(83 citation statements)

References 47 publications

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“…12,27 Others found sequential effects with regard to the time of administration using gemcitabine and carboplatin in combination with bortezomib. 14 We chose docetaxel and bortezomib as these two agents have shown to improve survival and life quality of patients with NSCLC as single agents in the second-line therapy. In contrast to p53 gene transfer, no synergism was found for the combination between bortezomib and the cytotoxic drugs.…”

Section: Discussionmentioning

confidence: 99%

“…12 The proteasome degrades the tumor suppressor p53, which is required for the transcription of a number of genes involved in cell-cycle control and DNA synthesis. 13 Wild-type p53 is stabilized by proteasome inhibition in cancer cell lines, 14,15 suggesting a mechanism of bortezomib-induced apoptosis that may be relevant in suppressing cancer progression. 16,17 We focussed on bortezomib as a promising agent to investigate if its combination with p53 gene transfer might enhance cytotoxicity in NSCLC cell lines.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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“…17,27,28 The administration of gemcitabine in combination with bortezomib resulted in sensitization, or even enhancement, of the effect of gemcitabine in preclinical models. 17,[29][30][31][32] Moreover, proteasome inhibitors may overcome tumor resistance to gemcitabine by reducing NF-kB activity, 17,28 down-regulation of Bcl-2, 15,17 and stabilization of the cyclin kinase inhibitors p21 and p27. 15 A Phase I clinical trial to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of bortezomib in combination with gemcitabine in patients with incurable advanced solid tumors was conducted.…”

Section: Methods Bortezomib Was Administered As An Intravenous Bolusmentioning

confidence: 99%

Phase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors

Ryan

Appleman

Lynch

et al. 2006

Cancer

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BACKGROUND.Bortezomib is the first proteasome inhibitor to show preliminary evidence of activity against solid tumors. Findings from preclinical studies prompted a Phase I trial to determine the maximum tolerated dose (MTD) and dose‐limiting toxicities (DLTs) of bortezomib in combination with gemcitabine in patients with recurring/refractory advanced solid tumors. The effect of gemcitabine on proteasome inhibition by bortezomib in whole blood was also investigated.METHODS.Bortezomib was administered as an intravenous bolus injection on Days 1, 4, 8, and 11, with gemcitabine (30‐minute infusion) on Days 1 and 8 of a 21‐day cycle. Groups of ≥3 patients were evaluated at each dose level. Escalating doses of gemcitabine 500 mg/m2 to 1000 mg/m2 with bortezomib 1.0 mg/m2 to 1.5 mg/m2 were planned.RESULTS.There were no DLTs in patients receiving bortezomib 1.0 mg/m2 and gemcitabine 500 mg/m2 to 1000 mg/m2 in the first 3 dose levels. Dose‐limiting nausea, vomiting, gastrointestinal obstruction, and thrombocytopenia occurred in 4 of 5 evaluable patients in dose level 4 (bortezomib 1.3 mg/m2, gemcitabine 800 mg/m2), establishing bortezomib 1.0 mg/m2 and gemcitabine 1000 mg/m2 as the MTD. Most common Grade ≥3 toxicities were neutropenia (6 patients), thrombocytopenia (5 patients), gastrointestinal disorders (6 patients), and general disorders (4 patients) such as fatigue. One patient with nonsmall cell lung carcinoma achieved a partial response and 7 achieved stable disease. Inhibition of 20S proteasome activity by bortezomib was unaffected by gemcitabine coadministration.CONCLUSION.Dosages of bortezomib and gemcitabine suitable for further evaluation of antitumor activity have been established. Cancer 2006. © 2006 American Cancer Society

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“…Novel drugs that aim at specific intracellular pathways related to the distinctive properties of cancer cells continue to be developed. It has been reported that proteasome inhibitor bortezomib (ps-341, Velcade) inhibits lung cancer cells (16,17). However, the role of Mg132 in lung cancer cells is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Proteasome inhibition by MG132 induces growth inhibition and death of human pulmonary fibroblast cells in a caspase-independent manner

You

Park

2011

Oncol Rep

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Abstract. Mg132 as a proteasome inhibitor that can induce apoptotic cell death in various cell types including lung cancer cells. We investigated the cellular effects of Mg132 on human pulmonary fibroblast (HpF) cells in relation to cell growth inhibition and death, and described the molecular mechanisms of Mg132 in HpF cell death. this agent dose-dependently inhibited the growth of HpF cells with an Ic 50 of approximately 20 µM at 24 h and induced cell death accompanied by the loss of mitochondrial membrane potential (MMp; ∆Ψ m ) and an increase in caspase-3 and -8 activities. Mg132 increased intracellular ros levels and gsH-depleted cell numbers. However, all the tested caspase inhibitors intensified HPF growth inhibition by Mg132 and caspase-9 inhibitor also enhanced cell death and MMp (∆Ψ m ) loss. Moreover, the administration of Bcl-2 sirnA augmented HpF cell death by Mg132 whereas p53, Bax, caspase-3 and -8 sirnAs did not strongly affect cell death. In addition, each caspase inhibitor and sirnA differently affects ros levels including o 2•-regardless of cell growth inhibition and cell death levels. caspase-8 and -9 inhibitors increased the number of gsH-depleted cells in Mg132-treated HpF cells. In conclusion, Mg132 induced growth inhibition and death in HpF cells in a caspase-independent manner. the growth inhibition and death of HpF cells by Mg132 and/or each caspase inhibitor or apoptosis-related sirnA were not tightly related to the changes in ros levels.

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Effects of the proteasome inhibitor bortezomib alone and in combination with chemotherapy in the A549 non-small-cell lung cancer cell line

Abstract: Bortezomib improves efficacy in combination with gemcitabine and carboplatin in NSCLC, but sequential effects are important and must be considered when developing therapeutic regimens.

Cited by 94 publications

References 47 publications

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

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

Phase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors

Proteasome inhibition by MG132 induces growth inhibition and death of human pulmonary fibroblast cells in a caspase-independent manner

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