This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, D.-M. Articles by Jeong, S. Search for Related Content PubMed PubMed Citation Articles by Kim, D.-M. Articles by Jeong, S.

Rapid Induction of Apoptosis by Combination of Flavopiridol and Tumor Necrosis Factor (TNF)- or TNF-related Apoptosis-inducing Ligand in Human Cancer Cell Lines

LG Life Sciences, Ltd./R&D Park, Drug Discovery Institute, Daejeon, 305-380, Korea

Flavopiridol is one of the first cyclin-dependent kinase inhibitors undergoing clinical tests. We found that the combination treatment of flavopiridol (100–500 nM) with tumor necrosis factor (TNF)- (10 ng/ml) induced a rapid and eminent apoptosis, 20 ± 5% in 6-h treatment, in a human non-small cell lung carcinoma cell line, A549, as determined by the increase of sub-G₁ fraction in flow cytometry. A similar observation was also made in human colon cancer cell lines, HCT-116 and HCT-15, but not in Rat2, a rat fibroblast cell line. In A549 cells, the cytotoxic synergy by the combination treatment involved the activation of caspase-1, caspase-3, and caspase-8 and generated huge chromosomal degradation. The treatment schedules were so important that only the treatments of flavopiridol concomitantly with or followed by TNF- showed the pronounced apoptosis in A549 cells. Prior treatment of TNF- inhibited the apoptosis by the following combination treatment, leading to little cell death. Yet, such inhibition was reversed when 100 µM of 5,6-dichloro-1-ß-D-ribofuranosyl-benzimidazole, a transcription inhibitor, was present during the TNF- pretreatment, suggesting that the inhibitory pretreatment of TNF- might involve antiapoptotic gene expression at the transcriptional level. TNF- treatment resulted in nuclear factor (NF)-B activation, revealed by NF-B activity reporter assay. In contrast, flavopiridol was found to inhibit the NF-B-dependent gene transcription, which might give an explanation for the synergistic effect of flavopiridol with TNF-. TNF-related apoptosis-inducing ligand (TRAIL; 100 ng/ml) also caused a rapid and strong cytotoxic synergy with flavopiridol. In contrast to TNF-, however, all of the treatment sequences supported the synergy by TRAIL and flavopiridol. The combination of flavopiridol with TNF- or TRAIL may be of use for the development in cancer therapy.

This article has been cited by other articles:

				Y. Takada, G. Sethi, B. Sung, and B. B. Aggarwal Flavopiridol Suppresses Tumor Necrosis Factor-Induced Activation of Activator Protein-1, c-Jun N-Terminal Kinase, p38 Mitogen-Activated Protein Kinase (MAPK), p44/p42 MAPK, and Akt, Inhibits Expression of Antiapoptotic Gene Products, and Enhances Apoptosis through Cytochrome c Release and Caspase Activation in Human Myeloid Cells Mol. Pharmacol., May 1, 2008; 73(5): 1549 - 1557. [Abstract] [Full Text] [PDF]

				G. T. Stathopoulos, T. P. Sherrill, W. Han, R. T. Sadikot, F. E. Yull, T. S. Blackwell, and B. Fingleton Host Nuclear Factor-{kappa}B Activation Potentiates Lung Cancer Metastasis Mol. Cancer Res., March 1, 2008; 6(3): 364 - 371. [Abstract] [Full Text] [PDF]

				C. Palacios, R. Yerbes, and A. Lopez-Rivas Flavopiridol Induces Cellular FLICE-Inhibitory Protein Degradation by the Proteasome and Promotes TRAIL-Induced Early Signaling and Apoptosis in Breast Tumor Cells. Cancer Res., September 1, 2006; 66(17): 8858 - 8869. [Abstract] [Full Text] [PDF]

				G. I. Shapiro Cyclin-Dependent Kinase Pathways As Targets for Cancer Treatment J. Clin. Oncol., April 10, 2006; 24(11): 1770 - 1783. [Abstract] [Full Text] [PDF]

				H. Hasegawa, Y. Yamada, K. Komiyama, M. Hayashi, M. Ishibashi, T. Yoshida, T. Sakai, T. Koyano, T.-S. Kam, K. Murata, et al. Dihydroflavonol BB-1, an extract of natural plant Blumea balsamifera, abrogates TRAIL resistance in leukemia cells Blood, January 15, 2006; 107(2): 679 - 688. [Abstract] [Full Text] [PDF]

				L. M. Lashinger, K. Zhu, S. A. Williams, M. Shrader, C. P.N. Dinney, and D. J. McConkey Bortezomib Abolishes Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Resistance via a p21-Dependent Mechanism in Human Bladder and Prostate Cancer Cells Cancer Res., June 1, 2005; 65(11): 4902 - 4908. [Abstract] [Full Text] [PDF]

				A. Papageorgiou, L. Lashinger, R. Millikan, H. B. Grossman, W. Benedict, C. P. N. Dinney, and D. J. McConkey Role of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand in Interferon-Induced Apoptosis in Human Bladder Cancer Cells Cancer Res., December 15, 2004; 64(24): 8973 - 8979. [Abstract] [Full Text] [PDF]

				Y. Dai, M. Rahmani, X.-Y. Pei, P. Dent, and S. Grant Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms Blood, July 15, 2004; 104(2): 509 - 518. [Abstract] [Full Text] [PDF]

				M. Taniai, A. Grambihler, H. Higuchi, N. Werneburg, S. F. Bronk, D. J. Farrugia, S. H. Kaufmann, and G. J. Gores Mcl-1 Mediates Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Resistance in Human Cholangiocarcinoma Cells Cancer Res., May 15, 2004; 64(10): 3517 - 3524. [Abstract] [Full Text] [PDF]

				Z. N. Demidenko and M. V. Blagosklonny Flavopiridol Induces p53 via Initial Inhibition of Mdm2 and p21 and, Independently of p53, Sensitizes Apoptosis-Reluctant Cells to Tumor Necrosis Factor Cancer Res., May 15, 2004; 64(10): 3653 - 3660. [Abstract] [Full Text] [PDF]

				Y. Takada and B. B. Aggarwal Flavopiridol Inhibits NF-{kappa}B Activation Induced by Various Carcinogens and Inflammatory Agents through Inhibition of I{kappa}B{alpha} Kinase and p65 Phosphorylation: ABROGATION OF CYCLIN D1, CYCLOOXYGENASE-2, AND MATRIX METALLOPROTEASE-9 J. Biol. Chem., February 6, 2004; 279(6): 4750 - 4759. [Abstract] [Full Text] [PDF]