Cyclin-dependent Kinase Inhibitor SU9516 Enhances Sensitivity to Methotrexate in Human T-cell Leukemia Jurkat Cells

Overview

Journal Cancer Sci

Specialty Oncology

Date 2010 Jan 12

PMID 20059476

Citations 6

Authors

Hitoji Uchiyama

Yoshihiro Sowa

Miki Wakada

Mayumi Yogosawa

Ryoko Nakanishi

Mano Horinaka

Chihiro Shimazaki

Masafumi Taniwaki

Toshiyuki Sakai

Affiliations

Soon will be listed here.

Abstract

Methotrexate (MTX) has been used to treat various hematological malignancies. Since MTX prevents tumor cells from proliferating by inhibiting dihydrofolate reductase (DHFR), DHFR expression is a key determinant of resistance to MTX in malignant hematological tumor cells. The antiproliferative effect of MTX was significantly enhanced by the knockdown of DHFR expression by siRNA in Jurkat cells. Therefore, a novel strategy down-regulating DHFR expression seems promising for enhancing sensitivity to MTX. We found that SU9516, a cyclin-dependent kinase inhibitor, reduced the expression of both DHFR mRNA and protein. Moreover, we found that DHFR promoter activity was attenuated by SU9516 dependent on the E2F site. Finally, pretreatment with SU9516 significantly enhanced sensitivity to MTX in a colony formation assay. We conclude that a combination of cyclin-dependent kinase inhibitors and MTX may be useful for overcoming resistance to MTX.

Citing Articles

Targeting CDK1 in cancer: mechanisms and implications.

Wang Q, Bode A, Zhang T NPJ Precis Oncol. 2023; 7(1):58.

PMID: 37311884 PMC: 10264400. DOI: 10.1038/s41698-023-00407-7.

Isatin Counteracts Diethylnitrosamine/2-Acetylaminofluorene-Induced Hepatocarcinogenesis in Male Wistar Rats by Upregulating Anti-Inflammatory, Antioxidant, and Detoxification Pathways.

Tawfik N, Mohamed W, Mahmoud H, Alqarni M, Naguib I, Fahmy A Antioxidants (Basel). 2022; 11(4).

PMID: 35453384 PMC: 9027254. DOI: 10.3390/antiox11040699.

Genomic and transcriptomic analyses reveal a tandem amplification unit of 11 genes and mutations in mismatch repair genes in methotrexate-resistant HT-29 cells.

Kim A, Shin J, Seo J Exp Mol Med. 2021; 53(9):1344-1355.

PMID: 34521988 PMC: 8492700. DOI: 10.1038/s12276-021-00668-x.

The Metabolic Profiles in Hematological Malignancies.

Liu T, Peng X, Li B Indian J Hematol Blood Transfus. 2019; 35(4):625-634.

PMID: 31741613 PMC: 6825070. DOI: 10.1007/s12288-019-01107-8.

Disparate Response to Methotrexate in Stem Versus Non-Stem Cells.

Beane O, Darling L, Fonseca V, Darling E Stem Cell Rev Rep. 2016; 12(3):340-51.

PMID: 26815725 PMC: 4880537. DOI: 10.1007/s12015-016-9645-9.

References

Iwanaga R, Komori H, Ohtani K . Differential regulation of expression of the mammalian DNA repair genes by growth stimulation. Oncogene. 2004; 23(53):8581-90. DOI: 10.1038/sj.onc.1207976. View

Schimke R . Gene amplification in cultured cells. J Biol Chem. 1988; 263(13):5989-92. View

Li X, Huang P, Cui J, Zhang J, Tang C . Novel pyrrolyllactone and pyrrolyllactam indolinones as potent cyclin-dependent kinase 2 inhibitors. Bioorg Med Chem Lett. 2003; 13(11):1939-42. DOI: 10.1016/s0960-894x(03)00312-3. View

Li W, Fan J, Hochhauser D, Banerjee D, Zielinski Z, Almasan A . Lack of functional retinoblastoma protein mediates increased resistance to antimetabolites in human sarcoma cell lines. Proc Natl Acad Sci U S A. 1995; 92(22):10436-40. PMC: 40812. DOI: 10.1073/pnas.92.22.10436. View

Blake M, Azizkhan J . Transcription factor E2F is required for efficient expression of the hamster dihydrofolate reductase gene in vitro and in vivo. Mol Cell Biol. 1989; 9(11):4994-5002. PMC: 363651. DOI: 10.1128/mcb.9.11.4994-5002.1989. View

Lane M, Yu B, Rice A, Lipson K, Liang C, Sun L . A novel cdk2-selective inhibitor, SU9516, induces apoptosis in colon carcinoma cells. Cancer Res. 2001; 61(16):6170-7. View

Haber D, Beverley S, Kiely M, Schimke R . Properties of an altered dihydrofolate reductase encoded by amplified genes in cultured mouse fibroblasts. J Biol Chem. 1981; 256(18):9501-10. View

Chave K, Ryan T, Chmura S, Galivan J . Identification of single nucleotide polymorphisms in the human gamma-glutamyl hydrolase gene and characterization of promoter polymorphisms. Gene. 2003; 319:167-75. DOI: 10.1016/s0378-1119(03)00807-2. View

Schwartz G, Ilson D, Saltz L, OReilly E, Tong W, Maslak P . Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma. J Clin Oncol. 2001; 19(7):1985-92. DOI: 10.1200/JCO.2001.19.7.1985. View

10.

Rhee M, Wang Y, Nair M, Galivan J . Acquisition of resistance to antifolates caused by enhanced gamma-glutamyl hydrolase activity. Cancer Res. 1993; 53(10 Suppl):2227-30. View

11.

Mohammadi M, McMahon G, Sun L, Tang C, Hirth P, Yeh B . Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science. 1997; 276(5314):955-60. DOI: 10.1126/science.276.5314.955. View

12.

Nakano K, Mizuno T, Sowa Y, Orita T, Yoshino T, Okuyama Y . Butyrate activates the WAF1/Cip1 gene promoter through Sp1 sites in a p53-negative human colon cancer cell line. J Biol Chem. 1997; 272(35):22199-206. DOI: 10.1074/jbc.272.35.22199. View

13.

Brasier A, Tate J, Habener J . Optimized use of the firefly luciferase assay as a reporter gene in mammalian cell lines. Biotechniques. 1989; 7(10):1116-22. View

14.

Senderowicz A, Headlee D, Stinson S, Lush R, Kalil N, Villalba L . Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms. J Clin Oncol. 1998; 16(9):2986-99. DOI: 10.1200/JCO.1998.16.9.2986. View

15.

Liu G, Gandara D, Lara Jr P, Raghavan D, Doroshow J, Twardowski P . A Phase II trial of flavopiridol (NSC #649890) in patients with previously untreated metastatic androgen-independent prostate cancer. Clin Cancer Res. 2004; 10(3):924-8. DOI: 10.1158/1078-0432.ccr-03-0050. View

16.

Goker E, Waltham M, Kheradpour A, Trippett T, Mazumdar M, Elisseyeff Y . Amplification of the dihydrofolate reductase gene is a mechanism of acquired resistance to methotrexate in patients with acute lymphoblastic leukemia and is correlated with p53 gene mutations. Blood. 1995; 86(2):677-84. View

17.

Matsui T, Sowa Y, Yoshida T, Murata H, Horinaka M, Wakada M . Sulforaphane enhances TRAIL-induced apoptosis through the induction of DR5 expression in human osteosarcoma cells. Carcinogenesis. 2006; 27(9):1768-77. DOI: 10.1093/carcin/bgl015. View

18.

Aklilu M, Kindler H, Donehower R, Mani S, Vokes E . Phase II study of flavopiridol in patients with advanced colorectal cancer. Ann Oncol. 2003; 14(8):1270-3. DOI: 10.1093/annonc/mdg343. View

19.

Banerjee D, Mayer-Kuckuk P, Capiaux G, Budak-Alpdogan T, Gorlick R, Bertino J . Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase. Biochim Biophys Acta. 2002; 1587(2-3):164-73. DOI: 10.1016/s0925-4439(02)00079-0. View

20.

Nakata S, Yoshida T, Shiraishi T, Horinaka M, Kouhara J, Wakada M . 15-Deoxy-Delta12,14-prostaglandin J(2) induces death receptor 5 expression through mRNA stabilization independently of PPARgamma and potentiates TRAIL-induced apoptosis. Mol Cancer Ther. 2006; 5(7):1827-35. DOI: 10.1158/1535-7163.MCT-06-0023. View