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

Geller, James I.; Szekely-Szucs, Kinga; Peták, István; Doyle, Belinda T.; Houghton, Janet A.

doi:10.1158/0008-5472.can-04-0863

Cited by 28 publications

(40 citation statements)

References 45 publications

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“…Still, we cannot exclude the possibility that the inverse relation between p21 expression and response to gefitinib and chemotherapy was principally related to the effect of 5-FU and irinotecan rather than any interaction with gefitinib. However, in contrast to our findings, a recent review of 1,809 colorectal cancer cases in the published literature suggest that, overall, greater p21 expression predicted a greater responsiveness to fluoropyrimidine-based chemotherapy that did not include an EGFR inhibitor (28). We are unaware of any other study that has examined predictors of responsiveness to gefitinib-based therapy in patients with colorectal cancer.…”

Section: Discussioncontrasting

confidence: 99%

Molecular Alterations in Tumors and Response to Combination Chemotherapy with Gefitinib for Advanced Colorectal Cancer

Ogino

Meyerhardt

Cantor

et al. 2005

Clinical Cancer Research

141

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Purpose: Recently, activating mutations of the epidermal growth factor receptor (EGFR) gene were discovered in non^small cell lung cancers sensitive to gefitinib (ZD1839, an EGFR tyrosine kinase inhibitor) but not in gefitinib-resistant cancers. Abnormalities of EGFR and related pathways may have an effect on responsiveness of advanced colorectal cancer to combination chemotherapy with gefitinib. Experimental Design: We examined patients with previously untreated metastatic colorectal cancer, who were enrolled into two phase I/II trials of combination chemotherapy (irinotecan, leucovorin, and 5-fluorouracil) and daily oral gefitinib. We obtained paraffin tissue blocks of primary tumors from 31 patients, sequenced the EGFR, KRAS, and BRAF genes, and did immunohistochemistry for EGFR, phosphorylated AKT1, p53, p21, and p27. Results:Twelve (39%) of the 31 patients experienced a partial objective response to the therapy. A novel EGFR mutation in exon 18 (c.2170G>A, p.Gly724Ser) was identified in only one patient who did not experience an objective tumor response. EGFR immunohistochemistry was not predictive of responsiveness. In contrast, loss of p21 was associated with a higher response rate to therapy (P = 0.05). Moreover, the response rate among patients whose tumors maintained p21 expression and possessed a mutation in p53 was only 9% (1 of 11, P = 0.005). Overexpression of phosphorylated AKT1 also seemed to predict a trend towards resistance to the therapy. Conclusions: p21expression in colorectal cancer, especially in combination with p53 mutation, is a predictor of resistance to the combination chemotherapy with gefitinib. Activating EGFR mutations are rare in colorectal cancer and do not seem to confer sensitivity to gefitinib and chemotherapy.

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Section: Discussioncontrasting

confidence: 99%

Molecular Alterations in Tumors and Response to Combination Chemotherapy with Gefitinib for Advanced Colorectal Cancer

Ogino

Meyerhardt

Cantor

et al. 2005

Clinical Cancer Research

141

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“…Somewhat similar findings have been reported by others who have shown that sensitivity to TRAIL and resveratrol is reduced in p21-deficient cells (31), and in accordance with these results, cancer cells display increased sensitivity to TRAIL when arrested in the G 1 phase of the cell cycle (32,33). Thus, whereas induction of p21 is conventionally thought to promote cell survival (34), our studies and those of others suggest that p21 also has proapoptotic functions (35)(36)(37).…”

Section: Discussionsupporting

confidence: 92%

Histone Deacetylase Inhibitors Enhance Lexatumumab-Induced Apoptosis via a p21Cip1-Dependent Decrease in Survivin Levels

Nawrocki¹,

Carew

Leslie³

et al. 2007

Cancer Research

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in malignant cells by binding to the death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). Several agents that therapeutically exploit this phenomenon are being developed. We investigated the anticancer activity of two novel, highly specific agonistic monoclonal antibodies to TRAIL-R1 (mapatumumab, HGS-ETR1) and TRAIL-R2 (lexatumumab, HGS-ETR2) in colon cancer cell lines. Our analyses revealed that colon cancer cells display significantly higher surface expressions of TRAIL-R2 than TRAIL-R1, and are more sensitive to lexatumumabinduced apoptosis. The proapoptotic effects of lexatumumab in TRAIL-resistant HCT8 and HT29 cells were dramatically augmented by the histone deacetylase inhibitors trichostatin A or suberoylanilide hydroxamic acid. The presence of p21, but not p53, was critical for the synergy between lexatumumab and histone deacetylase inhibitors. The absence of p21 did not interfere with the formation of the death-inducing signaling complex by lexatumumab, suggesting the involvement of other apoptotic and/or cell cycle regulators. Indeed, treatment with suberoylanilide hydroxamic acid greatly reduced the expression of the inhibitor of apoptosis protein survivin and cdc2 activity in HCT116 p21 +/+ cells but not in the HCT116 p21 À/À cells. Inhibition of cdc2 activity with flavopiridol decreased survivin expression and sensitized the p21-deficient cells to lexatumumab-induced apoptosis. Similarly, small interfering RNA-mediated knockdown of survivin also enhanced lexatumumab-mediated cell death. Therefore, survivin expression plays a key role in lexatumumab resistance, and reducing survivin expression by inhibiting cdc2 activity is a promising strategy to enhance the anticancer activity of lexatumumab. [Cancer Res 2007;67(14):6987-94]

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“…Related to this finding, recent research has indicated that Tomudex, another potent inhibitor of TS activity, induced p21 upregulation in human colorectal cancer cells, also through a p53-independent route, as did thymidine deprivation in TS deficient cells. 9 It is therefore possible that p21 upregulation may play a role in Pemetrexed-induced cell cycle arrest in myeloma cells sensitive to this compound. Temporally, after induction of cell cycle arrest, MM1S cells treated with Pemetrexed entered in apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have indicated that p21 is upregulated in a p53-independent manner in the presence of TS inhibitors in human colorectal cancer cell lines, as did thymine deprivation in TS-deficient cells. 9 In the breast cancer line MCF7, and in the colon cancer cell lines HCT116 and RKO, Fas was involved in the induction of apoptosis in response to TS inhibitors. 10 More recently, it has been shown that Pemetrexed provoked dephosphorylation of AKT in human lung cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

Pemetrexed acts as an antimyeloma agent by provoking cell cycle blockade and apoptosis

et al. 2007

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Multiple myeloma (MM) is a malignancy of terminally differentiated B lymphocytes, characterized by accumulation of a monotypic plasma cell population in the bone marrow, monoclonal immunoglobulin in serum and/or urine and osteolytic lesions. Despite recent advances in the treatment, MM remains an incurable disease. This calls for an effort to develop novel therapeutics in order to eradicate the disease. Here we have evaluated the potential antimyeloma action of Pemetrexed, an antifolate drug that has shown promising results in other neoplastic diseases. Pemetrexed had a potent antimyeloma effect on cell lines sensitive and resistant to conventional therapeutic agents, and was also efficient on fresh cells from patients and in a murine MM model. Furthermore, Pemetrexed abrogated the protective action on MM cell death of several growth factors produced by the bone marrow microenvironment. Mechanistic studies indicated that Pemetrexed provoked this action by a combined effect that included cell cycle blockade, probably by p21 upregulation, and induction of apoptosis through caspase-dependent and -independent mechanisms. These data, together with the fact that Pemetrexed is already licensed for the therapy of other neoplastic diseases, opens the possibility for the inclusion of Pemetrexed in the therapeutic armamentarium to battle MM.

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

Cited by 28 publications

References 45 publications

Molecular Alterations in Tumors and Response to Combination Chemotherapy with Gefitinib for Advanced Colorectal Cancer

Molecular Alterations in Tumors and Response to Combination Chemotherapy with Gefitinib for Advanced Colorectal Cancer

Histone Deacetylase Inhibitors Enhance Lexatumumab-Induced Apoptosis via a p21Cip1-Dependent Decrease in Survivin Levels

Pemetrexed acts as an antimyeloma agent by provoking cell cycle blockade and apoptosis

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