scholarly journals Tumor Necrosis Factor α-dependent Drug Resistance to Purine and Pyrimidine Analogues in Human Colon Tumor Cells Mediated through IKK

2004 ◽  
Vol 280 (9) ◽  
pp. 7634-7644 ◽  
Author(s):  
Ling-Chi Wang ◽  
Cindy Yen Okitsu ◽  
Ebrahim Zandi
Keyword(s):  
Drug Resistance ◽  
Tumor Necrosis Factor ◽  
Tumor Cells ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Human Colon ◽  
Colon Tumor ◽  
Pyrimidine Analogues ◽  
Factor Α ◽  
Necrosis Factor

Antioxidant defense mechanisms of human mesothelioma and lung adenocarcinoma cells

2000 ◽  
Vol 278 (4) ◽  
pp. L696-L702 ◽  
Author(s):  
Kristiina Järvinen ◽  
Petra Pietarinen-Runtti ◽  
Kaija Linnainmaa ◽  
Kari O. Raivio ◽  
Cecile M. Krejsa ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
A549 Cells ◽  
Cytotoxic Drugs ◽  
Sod Activity ◽  
Glutamylcysteine Synthetase ◽  
Factor Α ◽  
Necrosis Factor

The development of drug resistance of tumors is multifactorial and still poorly understood. Some cytotoxic drugs generate free radicals, and, therefore, antioxidant enzymes may contribute to drug resistance. We investigated the levels of manganese superoxide dismutase (Mn SOD), its inducibility, and its protective role against tumor necrosis factor-α and cytotoxic drugs (cisplatin, epirubicin, methotrexate, and vindesin) in human pleural mesothelioma (M14K) and pulmonary adenocarcinoma (A549) cells. We also studied other major antioxidant mechanisms in relation to oxidant and drug resistance of these cells. A549 cells were more resistant than M14K cells toward both oxidants (hydrogen peroxide and menadione) and all the cytotoxic drugs tested. M14K cells contained higher basal Mn SOD activity than A549 cells (28.3 ± 3.4 vs. 1.8 ± 0.3 U/mg protein), and Mn SOD activity was significantly induced by tumor necrosis factor-α only in A549 cells (+524%), but the induction did not offer any protection during subsequent oxidant or drug exposure. Mn SOD was not induced significantly in either of these cell lines by any of the cytotoxic drugs (0.007–2 μM, 48 h) tested when assessed by Northern blotting, Western blotting, or specific activity. A549 cells contained higher catalase activity than M14K cells (7.6 ± 1.3 vs. 3.6 ± 0.5 nmol O2⋅ min−1⋅ mg protein−1). They also contained twofold higher levels of glutathione and higher immunoreactivity of the heavy subunit of γ-glutamylcysteine synthetase than M14K cells. Experiments with inhibitors of γ-glutamylcysteine synthetase and catalase supported our conclusion that mechanisms associated with glutathione contribute to the drug resistance of these cells.

scholarly journals Endogenous Bak inhibitors Mcl-1 and Bcl-xL: differential impact on TRAIL resistance in Bax-deficient carcinoma

2010 ◽  
Vol 188 (6) ◽  
pp. 851-862 ◽  
Author(s):  
Bernhard Gillissen ◽  
Jana Wendt ◽  
Antje Richter ◽  
Anja Richter ◽  
Annika Müer ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Cells ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Death Receptor ◽  
Apoptosis Pathway ◽  
Mitochondrial Apoptosis Pathway ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Necrosis Factor

Tumor necrosis factor (α)–related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that preferentially kills tumor cells with limited cytotoxicity to nonmalignant cells. However, signaling from death receptors requires amplification via the mitochondrial apoptosis pathway (type II) in the majority of tumor cells. Thus, TRAIL-induced cell death entirely depends on the proapoptotic Bcl-2 family member Bax, which is often lost as a result of epigenetic inactivation or mutations. Consequently, Bax deficiency confers resistance against TRAIL-induced apoptosis. Despite expression of Bak, Bax-deficient cells are resistant to TRAIL-induced apoptosis. In this study, we show that the Bax dependency of TRAIL-induced apoptosis is determined by Mcl-1 but not Bcl-xL. Both are antiapoptotic Bcl-2 family proteins that keep Bak in check. Nevertheless, knockdown of Mcl-1 but not Bcl-xL overcame resistance to TRAIL, CD95/FasL and tumor necrosis factor (α) death receptor ligation in Bax-deficient cells, and enabled TRAIL to activate Bak, indicating that Mcl-1 rather than Bcl-xL is a major target for sensitization of Bax-deficient tumors for death receptor–induced apoptosis via the Bak pathway.

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