The impact of p53 status on cellular sensitivity to antifolate drugs - PubMed (original) (raw)
Affiliations
- PMID: 11448931
Comparative Study
The impact of p53 status on cellular sensitivity to antifolate drugs
X Lu et al. Clin Cancer Res. 2001 Jul.
Abstract
The impact of p53 status on cellular sensitivity to antifolate drugs has been examined in seven human cell lines (A549, MCF7, T-47D, CCRF-CEM, COR-L23, A2780, and HCT-116) and p53 nonfunctional counterparts of two of the cell lines (HCT-116/N7 and A2780/CP70). p53 status was determined by sequencing and functional assays. The sensitivities of the cell lines to growth inhibition (sulphorhodamine B assay) produced by four antifolate drugs (Alimta, methotrexate, raltitrexed, and lometrexol) were studied. There was no clear relationship between functional p53 status and sensitivity to methotrexate or lometrexol, whereas a functional p53 status was possibly associated with resistance to Alimta- and raltitrexed-induced growth inhibition. In contrast, in the two pairs of related human tumor cell lines (HCT-116 and HCT-116/N7 and A2780 and A2780/CP70) cells with functional p53 were more sensitive to Alimta- and raltitrexed-induced growth inhibition (P = 0.002). Detailed studies were performed with the A2780 cell lines, and in the parental cells sensitivity to Alimta- and raltitrexed-induced cytotoxicity (clonogenic assay) was similar to the sensitivity determined in the sulphorhodamine B assay. However, in A2780/CP70 cells, 1 microM of drug resulted in only 40-60% growth inhibition yet > or = 85% cytotoxicity. After Alimta and raltitrexed exposure for < or = 72 h, there were no differences between the A2780 and A278/CP70 cell lines in cell cycle phase distribution, absolute cell number, or the induction of apoptosis. However, the cellular protein content of the A2780/CP70 cells was 3-6-fold higher than in A2780 cells after Alimta and raltitrexed treatment, suggesting that cells without functional p53 can maintain protein synthesis in the absence of cell division (unbalanced cell growth). In conclusion, the apparent impact of functional p53 status on sensitivity to antifolate drugs may depend upon the phenotypic/genotypic background as well as the assay used to measure cellular sensitivity.
Similar articles
- Impact of polyglutamation on sensitivity to raltitrexed and methotrexate in relation to drug-induced inhibition of de novo thymidylate and purine biosynthesis in CCRF-CEM cell lines.
Barnes MJ, Estlin EJ, Taylor GA, Aherne GW, Hardcastle A, McGuire JJ, Calvete JA, Lunec J, Pearson AD, Newell DR. Barnes MJ, et al. Clin Cancer Res. 1999 Sep;5(9):2548-58. Clin Cancer Res. 1999. PMID: 10499632 - Biological activity of the multitargeted antifolate, MTA (LY231514), in human cell lines with different resistance mechanisms to antifolate drugs.
Schultz RM, Chen VJ, Bewley JR, Roberts EF, Shih C, Dempsey JA. Schultz RM, et al. Semin Oncol. 1999 Apr;26(2 Suppl 6):68-73. Semin Oncol. 1999. PMID: 10598558 - Functional p53 is required for triptolide-induced apoptosis and AP-1 and nuclear factor-kappaB activation in gastric cancer cells.
Jiang XH, Wong BC, Lin MC, Zhu GH, Kung HF, Jiang SH, Yang D, Lam SK. Jiang XH, et al. Oncogene. 2001 Nov 29;20(55):8009-18. doi: 10.1038/sj.onc.1204981. Oncogene. 2001. PMID: 11753684 - Glutamyl hydrolase: properties and pharmacologic impact.
Galivan J, Ryan T, Rhee M, Yao R, Chave K. Galivan J, et al. Semin Oncol. 1999 Apr;26(2 Suppl 6):33-7. Semin Oncol. 1999. PMID: 10598552 Review. - Folic Acid Antimetabolites (Antifolates): A Brief Review on Synthetic Strategies and Application Opportunities.
Kovalev IS, Zyryanov GV, Santra S, Majee A, Varaksin MV, Charushin VN. Kovalev IS, et al. Molecules. 2022 Sep 22;27(19):6229. doi: 10.3390/molecules27196229. Molecules. 2022. PMID: 36234766 Free PMC article. Review.
Cited by
- Galactosylceramide Upregulates the Expression of the BCL2 Gene and Downregulates the Expression of TNFRSF1B and TNFRSF9 Genes, Acting as an Anti-Apoptotic Molecule in Breast Cancer Cells.
Suchanski J, Reza S, Urbaniak A, Woldanska W, Kocbach B, Ugorski M. Suchanski J, et al. Cancers (Basel). 2024 Jan 17;16(2):389. doi: 10.3390/cancers16020389. Cancers (Basel). 2024. PMID: 38254878 Free PMC article. - MicroRNA-874 targets phosphomevalonate kinase and inhibits cancer cell growth via the mevalonate pathway.
Aersilan A, Hashimoto N, Yamagata K, Yokoyama M, Nakayama A, Shi X, Nagano H, Sakuma I, Nohata N, Kinoshita T, Seki N, Rahmutulla B, Kaneda A, Zhahara SN, Gong Y, Nishimura M, Kawauchi S, Kawakami E, Tanaka T. Aersilan A, et al. Sci Rep. 2022 Nov 2;12(1):18443. doi: 10.1038/s41598-022-23205-w. Sci Rep. 2022. PMID: 36323841 Free PMC article. - Establishment and characterization of novel highly aggressive HER2‑positive and triple‑negative breast cancer cell lines.
Thongchot S, Jamjuntra P, Prasopsiri J, Thuwajit P, Sawasdee N, Poungvarin N, Warnnissorn M, Sa-Nguanraksa D, O-Charoenrat P, Yenchitsomanus PT, Thuwajit C. Thongchot S, et al. Oncol Rep. 2021 Dec;46(6):254. doi: 10.3892/or.2021.8205. Epub 2021 Oct 15. Oncol Rep. 2021. PMID: 34651665 Free PMC article. - Novel CDK9 inhibitor oroxylin A promotes wild-type P53 stability and prevents hepatocellular carcinoma progression by disrupting both MDM2 and SIRT1 signaling.
Yao JY, Xu S, Sun YN, Xu Y, Guo QL, Wei LB. Yao JY, et al. Acta Pharmacol Sin. 2022 Apr;43(4):1033-1045. doi: 10.1038/s41401-021-00708-2. Epub 2021 Jun 29. Acta Pharmacol Sin. 2022. PMID: 34188177 Free PMC article. - Genomic Characterization of Cisplatin Response Uncovers Priming of Cisplatin-Induced Genes in a Resistant Cell Line.
Golan Berman H, Chauhan P, Shalev S, Hassanain H, Parnas A, Adar S. Golan Berman H, et al. Int J Mol Sci. 2021 May 28;22(11):5814. doi: 10.3390/ijms22115814. Int J Mol Sci. 2021. PMID: 34071702 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Other Literature Sources
Research Materials
Miscellaneous