Thymidylate synthase inhibition triggers apoptosis via caspases-8 and -9 in both wild-type and mutant p53 colon cancer cell lines

Backus, H. H. J.; Wouters, Dorine; Ferreira, Carlos Gil; Houten, Viola M. M. van; Brakenhoff, Ruud H.; Pinedo, H.M.; Peters, Godefridus J.

doi:10.1016/s0959-8049(03)00204-1

Cited by 50 publications

(35 citation statements)

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“…WiDr cells (25 mg total protein) and TS control protein (1 ng) were used as positive controls for the expression of p53 and TS, respectively. Western blot data has already been published (Backus et al, 2003). significantly reduced mRNA TS expression in Lovo 175X2 cells, while a slight decrease of mRNA TS was observed in Lovo 92 cells ( Figure 4A), suggesting that TS mRNA degrades at a faster rate in Lovo 175X2 cells as compared to Lovo 92 cells.…”

Section: Modulation Of Ts Expression By Inhibition Of Transcriptionsupporting

confidence: 59%

Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels

et al. 2007

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Colorectal cancer (CRC) resistance to fluoropyrimidines and other inhibitors of thymidylate synthase (TS) is a serious clinical problem often associated with increased intracellular levels of TS. Since the tumour suppressor gene p53, which is mutated in 50% of CRC, regulates the expression of several genes, it may modulate TS activity, and changes in the status of p53 might be responsible for chemoresistance. Therefore, this study was aimed to investigate TS levels and sensitivity to TS inhibitors in wild-type (wt) and mutant (mt) p53 CRC cells, Lovo and WiDr, respectively, transfected with mt and wt p53. Lovo 175X2 cells (transfected with mt p53) were more resistant to 5-fluorouracil (5-FU; 2-fold), nolatrexed (3-fold), raltitrexed (3-fold) and pemetrexed (10-fold) in comparison with the wt p53 parental cells Lovo 92. Resistance was associated with an increase in TS protein expression and catalytic activity, which might be caused by the loss of the inhibitory effect on the activity of TS promoter or by the lack of TS mRNA degradation, as suggested by the reversal of TS expression to the levels of Lovo 92 cells by adding actinomycin. In contrast, Lovo li cells, characterized by functionally inactive p53, were 3-13-fold more sensitive to nolatrexed, raltitrexed and pemetrexed, and had a lower TS mRNA, protein expression and catalytic activity than Lovo 92. However, MDM-2 expression was significantly higher in Lovo li, while no significant differences were observed in Lovo 175X2 cells with respect to Lovo 92. Finally, mt p53 WiDr transfected with wt p53 were not significantly different from mt p53 WiDr cells with respect to sensitivity to TS inhibitors or TS levels. Altogether, these results indicate that changes in the status of p53, can differently alter sensitivity to TS inhibitors by affecting TS levels, depending on activity or cell line, and might explain the lack of clear correlation between mutations in p53 and clinical outcome after chemotherapy with TS inhibitors.

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Section: Modulation Of Ts Expression By Inhibition Of Transcriptionsupporting

confidence: 59%

Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels

et al. 2007

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“…We, and others have demonstrated that the cytotoxic effects of thymidylate synthase inhibition in colorectal carcinoma cells are consistently independent of p53 (2,4,47). Furthermore, the prognostic value of p53 cannot be substantiated in patients with colorectal cancer, as there appears to be an equal number of reports attesting to its value as a poor, nonsignificant, or favorable prognostic indicator in patients with colorectal cancer undergoing thymidylate synthase inhibitor-based therapy (48).…”

Section: Expression Of P21mentioning

confidence: 91%

P21Cip1 Is a Critical Mediator of the Cytotoxic Action of Thymidylate Synthase Inhibitors in Colorectal Carcinoma Cells

et al. 2004

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We have demonstrated previously that interferon (IFN)-␥ sensitizes human colon carcinoma cell lines to the cytotoxic effects of 5-fluorouracil combined with leucovorin and to the thymidylate synthase inhibitor, ZD9331, dependent on thymineless stress-induced DNA damage, independent of p53. Here we demonstrate that the cyclin-dependent kinase (CDK) inhibitor p21Cip1 regulates thymineless stress-induced cytotoxicity in these cells. HCT116 wild-type (wt) and p53؊/؊ cells underwent apoptosis and loss in clonogenic survival when exposed to ZD9331, whereas p21Cip1 ؊/؊ cells were resistant. Cip1 ؊/؊ cells accumulated in S phase within 24 h of ZD9331 exposure; however, wt cells exited S-phase more rapidly, where apoptosis occurred before mitosis, either in late S or G 2 . Finally, the CDK inhibitor roscovitine potentiated the cytotoxic activity of ZD9331 in both wt and p21Cip1 ؊/؊ cells, strongly suggesting a role for p21Cip1 -dependent CDK inhibition in cytotoxicity induced by thymidylate synthase inhibition. In summary, p21Cip1 positively regulates the cytotoxic action of thymidylate synthase inhibitors, negatively regulates the cytotoxic action of IFN-␥, and enhances S-phase exit after thymineless stress, possibly via interaction with CDK-cyclin complexes.

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“…It has also been described that this stimulus can produce apoptosis in p53 mutant cells (15). In colorectal cancer cells, there was an increased level of FASL and apoptosis induction during thymineless death after 5-FU treatment, via activation of nuclear factor-nB and activator protein-1 transcription factors (16), as well as in thymidylate synthase -deficient cells, after treatment with DNA-damaging agents (17).…”

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confidence: 96%

FAS/FAS Ligand Ratio: A Marker of Oxaliplatin-Based Intrinsic and Acquired Resistance in Advanced Colorectal Cancer

Nadal¹,

Maurel²,

Gallego³

et al. 2005

Clinical Cancer Research

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Purpose: Oxaliplatin-5-fluorouracil combinations have increased responses in first-line therapy up to 40% in advanced colorectal cancer. Unfortunately, those patients who will respond are unknown and initially sensitive patients become rapidly resistant to current therapies. FAS (CD95) and FAS ligand (FASL; CD95L) have been implicated in chemosensitivity through leading to apoptosis in response to DNA-damaging drugs.Whereas the proapoptotic role of FAS and FASL is well characterized, the function of their soluble forms as predictors of chemosensitivity remains unknown. Patients and Methods: Blood samples were obtained from 68 patients with advanced colorectal cancer who received oxaliplatin-5-fluorouracil combinations in first-line therapy. Computed tomographic scans were done every 3 months and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. ELISA soluble FAS and soluble FASL analysis were done before treatment and every 3 months until disease progression. Ratios between soluble FAS and soluble FASL were established and its values and variations through time were related to treatment responses. Results: We found a significant increase in soluble FAS levels and a significant decrease in FASL at 3 months compared with baseline (13.2 versus 10.02 ng/mL; P = 0.0001; 0.07 versus 0.14 ng/mL; P = 0.007, respectively). A significant increase in the soluble FASL levels up to 9 months (fourth to fifth extractions; 0.26 ng/mL) of therapy compared with first to third extractions (0.11ng/mL; P = 0.003) was also found. A random effect regression statistical model determined that >1.2-fold increase in soluble FAS/soluble FASL ratio was a marker of chemosensitivity (P = 0.001). Conclusions: These data strongly indicate that an increment of soluble FAS/soluble FASL ratio after treatment could be an excellent marker of chemosensitivity in colorectal cancer. On the other hand, a decreased ratio after treatment can be a predictor of chemoresistance despite an initial response.Colorectal cancer is the most common cancer in western Europe, with f70 new cases a year per 100,000 inhabitants. In spite of advances in screening, 15% to 20% of patients show initially advanced disease, and 30% to 50% are destined to metastasize. Recently, oxaliplatin/5-fluorouracil (5-FU)/leucovorin or irinotecan-5-FU/leucovorin have increased responses in first-line therapy up to 40%, with median survival between 16 and 20 months, but 2-year overall survival still remains <20% (1, 2). Unfortunately, those patients who will benefit from first-line chemotherapy are unknown. Furthermore, the initially sensitive patients become rapidly resistant to current therapies.The FAS (CD95) receptor is a cell surface protein that mediates apoptotic cell death on triggering by FAS ligand (FASL). This interaction causes FAS receptor homo-oligomerization and this leads to activation of the caspase cascade (apoptotic extrinsic pathway). A FASL-independent activation of the FAS receptor has also been described (3).Whereas proapopt...

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Thymidylate synthase inhibition triggers apoptosis via caspases-8 and -9 in both wild-type and mutant p53 colon cancer cell lines

Cited by 50 publications

References 28 publications

Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels

Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels

P21Cip1 Is a Critical Mediator of the Cytotoxic Action of Thymidylate Synthase Inhibitors in Colorectal Carcinoma Cells

FAS/FAS Ligand Ratio: A Marker of Oxaliplatin-Based Intrinsic and Acquired Resistance in Advanced Colorectal Cancer

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