Flavopiridol induces p53 via initial inhibition of Mdm2 and p21 and, independently of p53, sensitizes apoptosis-reluctant cells to tumor necrosis factor

Cancer Research

Volumn 64, Issue 10, 2004, Pages 3653-3660

  Demidenko, Zoya N ^a   Blagosklonny, Mikhail V ^a,b  

^a NEW YORK MEDICAL COLLEGE   (United States)

^b Brander Cancer Research Institute   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIN DEPENDENT KINASE; FLAVOPIRIDOL; PROTEIN MDM2; PROTEIN P21; PROTEIN P53; TUMOR NECROSIS FACTOR;

APOPTOSIS; ARTICLE; CANCER COMBINATION CHEMOTHERAPY; CELL CYCLE; CELL PROLIFERATION; CONCENTRATION RESPONSE; CONTROLLED STUDY; CYTOTOXICITY; DOWN REGULATION; DRUG EFFECT; DRUG MECHANISM; DRUG RESEARCH; DRUG SCREENING; GENE EXPRESSION; GENETIC TRANSCRIPTION; HUMAN; HUMAN CELL; LEUKEMIA CELL; MALE; NULL CELL; PREDICTION; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN INDUCTION; PROTEIN TARGETING; SENSITIZATION;

APOPTOSIS; CELL LINE, TUMOR; CYCLIN-DEPENDENT KINASE INHIBITOR P21; CYCLINS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG SYNERGISM; FLAVONOIDS; HCT116 CELLS; HL-60 CELLS; HUMANS; JURKAT CELLS; LUNG NEOPLASMS; MALE; NUCLEAR PROTEINS; PIPERIDINES; PROSTATIC NEOPLASMS; PROTO-ONCOGENE PROTEINS; PROTO-ONCOGENE PROTEINS C-MDM2; TRANSCRIPTION, GENETIC; TUMOR NECROSIS FACTOR-ALPHA; TUMOR SUPPRESSOR PROTEIN P53; U937 CELLS;

EID: 2442678063     PISSN: 00085472     EISSN: None     Source Type: Journal    
DOI: 10.1158/0008-5472.CAN-04-0204     Document Type: Article

References (57)

1. Arguello F, Alexander M, Sterry JA, et al. Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppression, and has potent antitumor activity in vivo against human leukemia and lymphoma xenografts. Blood 1998;91:2482-90.
2. Patel V, Senderowicz AM, Pinto DJ, et al. Flavopiridol, a novel cyclin-dependent kinase inhibitor, suppresses the growth of head and neck squamous cell carcinomas by inducing apoptosis. J Clin Invest 1998;102:1674-81.
3. Motwani M, Jung C, Sirotnak FM, et al. Augmentation of apoptosis and tumor regression by flavopiridol in the presence of CPT-11 in Hct116 colon cancer monolayers and xenografts. Clin Cancer Res 2001;7:4209-19.
4. Newcomb EW, Tamasdan C, Entzminger Y, et al. Flavopiridol inhibits the growth of GL261 gliomas in vivo: implications for malignant glioma therapy. Cell Cycle 2004;3:230-4.
5. Stadler WM, Vogelzang NJ, Amato R, et al. Flavopiridol, a novel cyclin-dependent kinase inhibitor, in metastatic renal cancer: a University of Chicago Phase II Consortium study. J Clin Oncol 2000;18:371-5.
6. Thomas JP, Tutsch KD, Cleary JF, et al. Phase I clinical and pharmacokinetic trial of the cyclin-dependent kinase inhibitor flavopiridol. Cancer Chemother Pharmacol 2002;50:465-72.
7. Schwartz GK, O'Reilly E, Ilson D, et al. Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors. J Clin Oncol 2002;20:2157-70.
8. Senderowicz AM. Novel small molecule cyclin-dependent kinases modulators in human clinical trials. Cancer Biol Ther 2003;2:S84-95.
9. Carlson BA, Dubay MM, Sausville EA, Brizuela L, Worland PJ. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK 4 in human breast carcinoma cells. Cancer Res 1996;56:2973-8.
10. Raju U, Nakata E, Mason KA, Ang KK, Milas L. Flavopiridol, a cyclin-dependent kinase inhibitor, enhances radiosensitivity of ovarian carcinoma cells. Cancer Res 2003;63:3263-7.
11. Rane SG, Dubus P, Mettus RV, et al. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia. Nat Genet 1999;22:44-52.
12. Tetsu O, McCormick F. Proliferation of cancer cells despite cdk2 inhibition. Cancer Cell 2003;3:233-45.
13. Ortega S, Prieto I, Odajima J, et al. Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet 2003;35:25-31.
14. Aleem E, Berthet C, Kaldis P. Cdk2 as a master of S phase entry: fact or fake? Cell Cycle 2004;3:35-7.
15. Bible KC, Kaufmann SH. Flavopiridol: a cytotoxic flavone that induces cell death in noncycling A549 human lung carcinoma cells. Cancer Res 1996;56:4856-61.
16. Rosato RR, Almenara JA, Cartee L, Betts V, Chellappan SP, Grant S. The cyclin-dependent kinase inhibitor flavopiridol disrupts sodium butyrate-induced p21WAF1/ CIP1 expression and maturation while reciprocally potentiating apoptosis in human leukemia cells. Mol Cancer Ther 2002;1:253-66.
17. Gojo I, Zhang B, Fenton R. The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and down-regulation of Mcl-1. Clin Cancer Res 2002;8:3527-38.
18. Ma Y, Cress WD, Haura EB. Flavopiridol-induced apoptosis is mediated through up-regulation of E2F1 and repression of Mcl-1. Mol Cancer Ther 2003;2:73-81.
19. Carlson B, Lahusen T, Singh S, et al. Downregulation of cyclin D1 by transcriptional repression in MCF-7 human breast carcinoma cells induced by flavopiridol. Cancer Res 1999;59:4634-41.
20. Melillo G, Sausville EA, Cloud K, Lahusen T, Varesio L, Senderowicz AM. Flavopiridol, a protein kinase inhibitor, down-regulates hypoxic induction of vascular endothelial growth factor expression in human monocytes. Cancer Res 1999;59: 5433-7.
21. Kitada S, Zapata J, Andreeff M, Reed JC. Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. Blood 2000;96:393-7.
22. Wittmann S, Bali P, Donapaty S, et al. Flavopiridol down-regulates antiapoptotic proteins and sensitizes human breast cancer cells to epothilone B-induced apoptosis. Cancer Res 2003;63:93-9.
23. Shapiro GI, Koestner DA, Matranga CB, Rollins BJ. Flavopiridol induces cell cycle arrest and p53-independent apoptosis in non-small cell lung cancer cell lines. Clin Cancer Res 1999;5:2925-38.
24. Bible KC, Bible RHJ, Kottke TJ, et al. Flavopiridol binds to duplex DNA. Cancer Res 2000;60:2419-28.
25. Peng J, Zhu Y, Milton JT, Price DH. Identification of multiple cyclin subunits of human P-TEFb. Genes Dev 1998;12:755-62.
26. Chao SH, Price DH. Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J Biol Chem 2001;276:31793-9.
27. Lam LT, Pickeral OK, Peng AC, et al. Genomic-scale measurement of mRNA turnover and the mechanisms of action of the anti-cancer drug flavopiridol. Genome Biol 2001;0041.
28. Ni Z, Schwartz BE, Werner J, Suarez JR, Lis JT. Coordination of transcription, RNA processing, and surveillance by P-TEFb kinase on heat shock genes. Mol Cell 2004;13:55-65.
29. de Azevedo WFJ, Canduri F, da Silveira NJ. Structural basis for inhibition of cyclin-dependent kinase 9 by flavopiridol. Biochem Biophys Res Commun 2002;293: 566-71.
30. Price DH. P-TEFb, a cyclin-dependent kinase controlling elongation by RNA polymerase II. Mol Cell Biol 2000;20:2629-34.
31. Poele RHT, Okorokov AL, Joel SP. RNA synthesis block by 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) triggers p53-dependent apoptosis in human colon carcinoma cells. Oncogene 1999;18:5765-72.
32. Nahta R, Trent S, Yang C, Schmidt EV. Epidermal growth factor receptor expression is a candidate target of the synergistic combination of trastuzumab and flavopiridol in breast cancer. Cancer Res 2003;63:3626-31.
33. Alonso M, Tamasdan C, Miller DC, Newcomb EW. Flavopiridol induces apoptosis in glioma cell lines independent of retinoblastoma and p53 tumor suppressor pathway alterations by a caspase-independent pathway. Mol Cancer Ther 2003;2:139-50.
34. Blagosklonny MV, Demidenko ZN, Fojo T. Inhibition of transcription results in accumulation of Wt p53 followed by delayed outburst of p53-inducible proteins: p53 as a sensor of transcriptional integrity. Cell Cycle 2002;1:67-74.
35. Konig A, Schwartz GK, Mohammad RM, Al-Katib A, Gabrilove JL. The novel cyclin-dependent kinase inhibitor flavopiridol downregulates Bcl-2 and induces growth arrest and apoptosis in chronic B-cell leukemia lines. Blood 1997;90:4307-12.
36. Blagosklonny MV, Giannakakou P, Romanova LY, Ryan KM, Vousden KH, Fojo T. Inhibition of HIF-1- and wild-type p53-stimulated transcription by codon Arg 175 p53 mutants with selective loss of functions. Carcinogenesis 2001;22:861-7.
37. Inga A, Storici F, Darden T, Resnick M. Differential transactivation by the p53 transcription factor is highly dependent on p53 level and promoter target sequence. Mol Cell Biol 2002;22:8612-25.
38. Bar-Or RL, Maya R, Segel LA, Alon U, Levine AJ, Oren M. Generation of oscillations by the p53-mdm2 feedback loop: a theoretical and experimental study. Proc Natl Acad Sci USA 2000;97:11250-5.
39. Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin ASJ. NF-κB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 1998;281:1680-3.
40. Natoli G, Costanzo A, Guido F, et al. Nuclear factor κ B-independent cytoprotective pathways originating at tumor necrosis factor receptor-associated factor 2. J Biol Chem 1998;273:31262-72.
41. Hayon IL, Haupt Y. p53: an internal investigation. Cell Cycle 2002;1:111-6.
42. An WG, Hwang SG, Trepel JB, Blagosklonny MV. Protease inhibitor-induced apoptosis: accumulation wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of proteasome inhibition. Leukemia 2000;14:1276-83.
43. Pepper C, Thomas A, Hoy T, et al. Leukemic and non-leukemic lymphocytes from patients with Li Fraumeni syndrome demonstrate loss of p53 function, Bcl-2 family dysregulation and intrinsic resistance to conventional chemotherapeutic drugs but not flavopiridol. Cell Cycle 2003;2:53-8.
44. Parker BW, Kaur G, Nieves-Neira W, et al. Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. Blood 1998;91:458-65.
45. Schwartz GK. CDK inhibitors: cell cycle arrest versus apoptosis. Cell Cycle 2002; 1:122-3.
46. Houghton JA. Apoptosis and drug response. Curr Opin Oncol 1999;11:475-81.
47. Zhivotovsky B, Orrenius S. Defects in the apoptotic machinery of cancer cells: role in drug resistance. Semin Cancer Biol 2003;13:125-34.
48. Kim Y, Suh N, Sporn M, Reed JC. An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis. J Biol Chem 2002;277: 22320-9.
49. Kim D, Koo SY, Jeon K, et al. Rapid induction of apoptosis by combination of flavopiridol and tumor necrosis factor (TNF)-α or TNF-related apoptosis-inducing ligand in human cancer cell lines. Cancer Res 2003;63:621-6.
50. Cartee L, Wang Z, Decker RH, et al. The cyclin-dependent kinase inhibitor (CDKI) flavopiridol disrupts phorbol 12-myristate 13-acetate-induced differentiation and CDKI expression while enhancing apoptosis in human myeloid leukemia cells. Cancer Res 2001;61:2583-91.
51. Sax JK, Dash BC, Hong R, Dicker DT, El-Deiry WS. The cyclin-dependent kinase inhibitor butyrolactone is a potent inhibitor of p21WAF1/CIP1 expression. Cell Cycle 2002;1:90-6.
52. Rokhlin OW, Cohen MB. Bisindolylmaleimide IX induces reversible and time-dependent tumor necrosis factor receptor family-mediated caspase activation and cell death. Cancer Biol Ther 2003;2:266-70.
53. Tillman DM, Izeradjene K, Szucs KS, Douglas L, Houghton JA. Rottlerin sensitizes colon carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via uncoupling of the mitochondria independent of protein kinase C. Cancer Res 2003;63:5118-25.
54. Aklilu M, Kindler HL, Donehower RC, Mani S, Vokes EE. Phase II study of flavopiridol in patients with advanced colorectal cancer. Ann Oncol 2003;14:1270-3.
55. Liu G, Gandara DR, Lara PNJ, et al. A phase II trial of flavopiridol (NSC #649890) in patients with previously untreated metastatic androgen-independent prostate cancer. Clin Cancer Res 2004;10:924-8.
56. Motwani M, Delohery TM, Schwartz GK. Sequential dependent enhancement of caspase activation and apoptosis by flavopiridol on paclitaxel-treated human gastric and breast cancer cells. Clin Cancer Res 1999;5:1876-83.
57. Osathanondh R, Goldstein DP, Pastorfide GB. Actinomycin D as the primary agent for gestational trophoblastic disease. Cancer 1975;36:863-6.