Targeting Apoptotic Pathways in Cancer Cells

Denicourt, Catherine; Dowdy, Steven F.

doi:10.1126/science.1102974

Cited by 107 publications

(73 citation statements)

References 11 publications

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“…Despite the growing interest and successful clinical use of targeted therapies for various malignancies, the precise mechanistic pathway responsible for triggering apoptosis in human tumor cells has lagged behind drug development (51,52). In this report we show that several structurally distinct proteasome inhibitors trigger significant apoptosis in a panel of malignant melanoma cell lines and a myeloma cell line.…”

Section: Discussionmentioning

confidence: 81%

Proteasome Inhibitors Trigger NOXA-Mediated Apoptosis in Melanoma and Myeloma Cells

et al. 2005

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Patients with metastatic melanoma or multiple myeloma have a dismal prognosis because these aggressive malignancies resist conventional treatment. A promising new oncologic approach uses molecularly targeted therapeutics that overcomes apoptotic resistance and, at the same time, achieves tumor selectivity. The unexpected selectivity of proteasome inhibition for inducing apoptosis in cancer cells, but not in normal cells, prompted us to define the mechanism of action for this class of drugs, including Food and Drug Administration-approved bortezomib. In this report, five melanoma cell lines and a myeloma cell line are treated with three different proteasome inhibitors (MG-132, lactacystin, and bortezomib), and the mechanism underlying the apoptotic pathway is defined. Following exposure to proteasome inhibitors, effective killing of human melanoma and myeloma cells, but not of normal proliferating melanocytes, was shown to involve p53-independent induction of the BH3-only protein NOXA. Induction of NOXA at the protein level was preceded by enhanced transcription of NOXA mRNA. Engagement of mitochondrial-based apoptotic pathway involved release of cytochrome c, second mitochondria-derived activator of caspases, and apoptosis-inducing factor, accompanied by a proteolytic cascade with processing of caspases 9, 3, and 8 and poly(ADP)-ribose polymerase. Blocking NOXA induction using an antisense (but not control) oligonucleotide reduced the apoptotic response by 30% to 50%, indicating a NOXAdependent component in the overall killing of melanoma cells. These results provide a novel mechanism for overcoming the apoptotic resistance of tumor cells, and validate agents triggering NOXA induction as potential selective cancer therapeutics for life-threatening malignancies such as melanoma and multiple myeloma. (Cancer Res 2005; 65(14): 6282-93)

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Section: Discussionmentioning

confidence: 81%

Proteasome Inhibitors Trigger NOXA-Mediated Apoptosis in Melanoma and Myeloma Cells

et al. 2005

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“…At present, the elimination of the resistance to apoptosis is an anticancer therapy (23). Activation of apoptotic pathways is currently considered a vital step in the development of tumors (24,25). Therefore, the identification of the mechanism underlying the apoptotic pathway is important.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Foxc2 enhances apoptosis induced by 5-fluorouracil through activation of MAPK and AKT pathways in colorectal cancer

et al. 2016

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Abstract. The chemotherapy drug 5-fluorouracil (5-FU) is fundamental for the treatment of colorectal cancer (CRC); however, drug resistance to 5-FU may occasionally occur. Abnormal expression of Forkhead box C2 gene (Foxc2) has been identified in several human cancers, but the role of Foxc2 in the progression of CRC remains unclear. The present study established a stable Foxc2-short hairpin (sh)RNA cell line, which was confirmed by western blot analysis and quantitative polymerase chain reaction. The Foxc2-shRNA cells were treated with 5-FU and the cell viability was determined by an MTT assay. Western blot analysis was performed to investigate the signaling pathway involved in 5-FU treatment. The present study identified that 5-FU increased the percentage of apoptotic CRC cells among the Foxc2/RNA interference-transfected cells compared with cells transfected with an empty vector. Therefore, the downregulation of Foxc2, induced by 5-FU, may enhance apoptosis by the downregulation of apoptotic factors, including B cell lymphoma-2 and pro-caspase-3, in Foxc2-shRNA CRC cells. Furthermore, the mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinases/protein kinase B (PI3K/AKT) pathways were essential for the sensitization effect of Foxc2 to 5-FU treatment. Overall, these findings reveal the mechanisms behind Foxc2 depletion and 5-FU treatment of CRC and suggest that Foxc2 enhances resistance to apoptosis, induced by 5-FU, through the activation of MAPK and P13K/AKT pathways, and may serve as a valuable clinical prognostic marker for CRC.

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“…One of the goals in using an anticancer drug/extract is the induction of apoptosis in cancer cells 33 . Induction of apoptosis is one of several approaches applied during cancer therapy 34 .…”

Section: Discussionmentioning

confidence: 99%

Antimutagenic and anticancer effects of Avicennia marina leaf extract on Salmonella typhimurium TA100 bacterium and human promyelocytic leukaemia HL-60 cells

Karami¹,

Majd²,

Mehrabian³

et al. 2012

ScienceAsia

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The present study evaluated the antimutagenic and anticancer activities of A. marina leaf extract. The antimutagenic activity of ethanol and water extracts of A. marina leaf (concentration 10 mg/plate for 48 h) was evaluated using the Salmonella typhimurium TA100 strain in the Ames test with (+S9) and without (−S9) metabolic activation, and its anticancer effect with concentrations of 200, 400, 450, 500, 600, and 800 µg/ml of ethanol extract for 24, 48, and 72 h on human leukaemic cell line HL-60 was assessed by MTT assay. The ethanol and water extracts of A. marina were revealed to have antimutagenic activity in the Salmonella mutation assay. The number of mutant colonies decreased in the presence of ethanol and water extract with (+S9) and without (−S9) metabolic activation. The ethanol extract showed a higher antimutagenic effect than the water extract, with an inhibition rate of 71% on the mutated bacterium. The MTT cell viability test showed an induction of cytotoxicity in HL-60 cells treated with the extract with IC50 values of 600, 400, and 280 µg/ml after 24, 48, and 72 h, respectively, in a concentration and time-dependent manner. Flow cytometric analysis confirmed the induction of apoptosis in the cells. Collectively, these results suggest that the Avicennia marina leaf extract contains bioactive compounds with antimutagenic and antileukaemic effects.

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Targeting Apoptotic Pathways in Cancer Cells

Cited by 107 publications

References 11 publications

Proteasome Inhibitors Trigger NOXA-Mediated Apoptosis in Melanoma and Myeloma Cells

Proteasome Inhibitors Trigger NOXA-Mediated Apoptosis in Melanoma and Myeloma Cells

Downregulation of Foxc2 enhances apoptosis induced by 5-fluorouracil through activation of MAPK and AKT pathways in colorectal cancer

Antimutagenic and anticancer effects of Avicennia marina leaf extract on Salmonella typhimurium TA100 bacterium and human promyelocytic leukaemia HL-60 cells

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