Pretreatment with AT-101 enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of breast cancer cells by inducing death receptors 4 and 5 protein levels

Kısım, Aslı; Atmaca, Harika; Çakar, Burcu; Karabulut, Bülent; Sezgin, Canfeza; Uzunoğlu, Selim; Uslu, Rüçhan; Karaca, Burçak

doi:10.1007/s00432-012-1187-1

Cited by 20 publications

(7 citation statements)

References 15 publications

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“…Similar to previously published studies [ 38 ], we observed that gossypol and ApoG2 did not affect the proliferation of normal breast epithelial cells. This observation can, in part, be explained by the negligible levels of copper present in these cells as compared to breast cancer cells [ 39 ].…”

Section: Discussionsupporting

confidence: 92%

Mobilization of Intracellular Copper by Gossypol and Apogossypolone Leads to Reactive Oxygen Species-Mediated Cell Death: Putative Anticancer Mechanism

Zubair

Azim

Khan

et al. 2016

IJMS

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There is compelling evidence that serum, tissue and intracellular levels of copper are elevated in all types of cancer. Copper has been suggested as an important co-factor for angiogenesis. It is also a major metal ion present inside the nucleus, bound to DNA bases, particularly guanine. We have earlier proposed that the interaction of phenolic-antioxidants with intracellular copper leads to the generation of reactive oxygen species (ROS) that ultimately serve as DNA cleaving agents. To further validate our hypothesis we show here that the antioxidant gossypol and its semi-synthetic derivative apogossypolone induce copper-mediated apoptosis in breast MDA-MB-231, prostate PC3 and pancreatic BxPC-3 cancer cells, through the generation of ROS. MCF10A breast epithelial cells refractory to the cytotoxic property of these compounds become sensitized to treatment against gossypol, as well as apogossypolone, when pre-incubated with copper. Our present results confirm our earlier findings and strengthen our hypothesis that plant-derived antioxidants mobilize intracellular copper instigating ROS-mediated cellular DNA breakage. As cancer cells exist under significant oxidative stress, this increase in ROS-stress to cytotoxic levels could be a successful anticancer approach.

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Section: Discussionsupporting

confidence: 92%

Mobilization of Intracellular Copper by Gossypol and Apogossypolone Leads to Reactive Oxygen Species-Mediated Cell Death: Putative Anticancer Mechanism

Zubair

Azim

Khan

et al. 2016

IJMS

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“…Numerous compounds have been reported to synergistically act with TRAIL to potentiate apoptosis in these cells, including chemotherapeutic drugs and natural compounds. [40][41][42][43][44][45] Our results added the usage of brequinar into this continuously growing list of agents that can be utilized in TRAIL combinatorial therapy. Interestingly, the combined treatment of brequinar and TRAIL did not harm the mammary epithelial cells HMEC suggesting normal cells possess own mechanisms to overcome the sensitization effect.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the mitochondrial pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase by doxorubicin and brequinar sensitizes cancer cells to TRAIL-induced apoptosis

Haapa-Paananen

Kaminskyy

et al. 2013

Oncogene

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent in selectively killing tumor cells. However, TRAIL monotherapy has not been successful as many cancer cells are resistant to TRAIL. Chemotherapeutic agents, such as doxorubicin have been shown to act synergistically with TRAIL, but the exact mechanisms of actions are poorly understood. In this study, we performed high-throughput small interfering RNA screening and genome-wide gene expression profiling on doxorubicin-treated U1690 cells to explore novel mechanisms underlying doxorubicin-TRAIL synergy. The screening and expression profiling results were integrated and dihydroorotate dehydrogenase (DHODH) was identified as a potential candidate. DHODH is the rate-limiting enzyme in the pyrimidine synthesis pathway, and its expression was downregulated by doxorubicin. We demonstrated that silencing of DHODH or inhibition of DHODH activity by brequinar dramatically increased the sensitivity of U1690 cells to TRAIL-induced apoptosis both in 2D and 3D cultures, and was accompanied by downregulation of c-FLIPL as well as by mitochondrial depolarization. In addition, uridine, an end product of the pyrimidine synthesis pathway was able to rescue the sensitization effects initiated by both brequinar and doxorubicin. Furthermore, several other cancer cell lines, LNCaP, MCF-7 and HT-29 were also shown to be sensitized to TRAIL by brequinar. Taken together, our findings have identified a novel protein target and its inhibitor, brequinar, as a potential agent in TRAIL-based combinatorial cancer therapy and highlighted for the first time the importance of mitochondrial DHODH enzyme and pyrimidine pathway in mediating TRAIL sensitization in cancer cells.

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“…Lumbar intervertebral disc degeneration is manifested with chronic pains in waist and legs, numbness and fatigue [ 7 , 8 ]. Previous studies suggested the participation of cytokines as critical inflammatory factors in the occurrence and progression of degenerative osteoarticular disease and osteoarthritis [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

Correlation between Polymorphism of TRAIL Gene and Condition of Intervertebral Disc Degeneration

Shu

Liang

2015

Med Sci Monit

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BackgroundTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been suggested to be related with the pathogenesis and progression of osteoarticular degenerations. This study therefore aimed to investigate the relationship between the polymorphism of the TRAIL gene and the pathogenesis and severity of intervertebral disc degeneration (IDD) via detection of serum TRAIL expression levels.Material/MethodsA total of 100 IDD patients in our hospital were recruited in the experimental group, while another cohort of 100 healthy individuals was employed as the control group. Blood samples collected from all people were quantified for TRAIL level using enzyme-linked immunosorbent assay (ELISA), in addition to allele and genotype frequency analysis via fluorescent PCR for TRAIL gene.ResultsAt loci 1525 and 1529 in 3′-untranslated region (UTR) of 5th exon of TRAIL gene, 3 different genotypes were identified: experimental group had higher frequency of 1525CG/1595CC, 1525G and 1595C alleles, compared to the control group (p<0.05). Patients under Schneiderman grade IV had significantly higher allele frequency compared to those at grade II or III. Serum TRAIL level was also higher in the experimental group compared to the control group, and in grade IV patients compared to grade II or III patients (p<0.05).ConclusionsThe G/C mutation at loci 1525/1595 of TRAIL gene may induce the progression of IDD, as the down-regulation of TRAIL can aggravate the severity of the disease.

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Pretreatment with AT-101 enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of breast cancer cells by inducing death receptors 4 and 5 protein levels

Cited by 20 publications

References 15 publications

Mobilization of Intracellular Copper by Gossypol and Apogossypolone Leads to Reactive Oxygen Species-Mediated Cell Death: Putative Anticancer Mechanism

Mobilization of Intracellular Copper by Gossypol and Apogossypolone Leads to Reactive Oxygen Species-Mediated Cell Death: Putative Anticancer Mechanism

Inhibition of the mitochondrial pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase by doxorubicin and brequinar sensitizes cancer cells to TRAIL-induced apoptosis

Correlation between Polymorphism of TRAIL Gene and Condition of Intervertebral Disc Degeneration

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