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 Kawabe, T. Search for Related Content PubMed PubMed Citation Articles by Kawabe, T. Related Collections Therapeutics and Targets Therapeutics and Targets: Identification, Validation, and Markers

Minireview

G₂ checkpoint abrogators as anticancer drugs

CanBas Co. Ltd., Numazu, Japan

Requests for Reprints: Takumi Kawabe, CanBas Co. Ltd., MAKIYA Building 5F, 9 Tooriyoko-cho, Numazu, 410-0891, Japan. Phone: 81-55-954-3666; Fax: 81-55-954-3668. E-mail: takumi{at}canbas.co.jp

Many conventional anticancer treatments kill cells irrespective of whether they are normal or cancerous, so patients suffer from adverse side effects due to the loss of healthy cells. Anticancer insights derived from cell cycle research has given birth to the idea of cell cycle G₂ checkpoint abrogation as a cancer cell specific therapy, based on the discovery that many cancer cells have a defective G₁ checkpoint resulting in a dependence on the G₂ checkpoint during cell replication.

Damaged DNA in humans is detected by sensor proteins (such as hHUS1, hRAD1, hRAD9, hRAD17, and hRAD26) that transmit a signal via ATR to CHK1, or by another sensor complex (that may include H2AX, 53BP1, BRCA1, NBS1, hMRE11, and hRAD50), the signal of which is relayed by ATM to CHK2. Most of the damage signals originated by the sensor complexes for the G₂ checkpoint are conducted to CDC25C, the activity of which is modulated by 14-3-3. There are also less extensively explored pathways involving p53, p38, PCNA, HDAC, PP2A, PLK1, WEE1, CDC25B, and CDC25A.

This review will examine the available inhibitors of CHK1 (Staurosporin, UCN-01, Go6976, SB-218078, ICP-1, and CEP-3891), both CHK1 and CHK2 (TAT-S216A and debromohymenialdisine), CHK2 (CEP-6367), WEE1 (PD0166285), and PP2A (okadaic acid and fostriecin), as well as the unknown checkpoint inhibitors 13-hydroxy-15-ozoapathin and the isogranulatimides. Among these targets, CHK1 seems to be the most suitable target for therapeutic G₂ abrogation to date, although an unexplored target such as 14-3-3 or the strategy of targeting multiple proteins at once may be of interest in the future.

This article has been cited by other articles:

				S. Ashwell and S. Zabludoff DNA Damage Detection and Repair Pathways--Recent Advances with Inhibitors of Checkpoint Kinases in Cancer Therapy Clin. Cancer Res., July 1, 2008; 14(13): 4032 - 4037. [Abstract] [Full Text] [PDF]

				E. Crescenzi, G. Palumbo, J. de Boer, and H. J.M. Brady Ataxia Telangiectasia Mutated and p21CIP1 Modulate Cell Survival of Drug-Induced Senescent Tumor Cells: Implications for Chemotherapy Clin. Cancer Res., March 15, 2008; 14(6): 1877 - 1887. [Abstract] [Full Text] [PDF]

				H. L. Ball, M. R. Ehrhardt, D. A. Mordes, G. G. Glick, W. J. Chazin, and D. Cortez Function of a Conserved Checkpoint Recruitment Domain in ATRIP Proteins Mol. Cell. Biol., May 1, 2007; 27(9): 3367 - 3377. [Abstract] [Full Text] [PDF]

				I. Perez de Castro, G. de Carcer, and M. Malumbres A census of mitotic cancer genes: new insights into tumor cell biology and cancer therapy Carcinogenesis, May 1, 2007; 28(5): 899 - 912. [Abstract] [Full Text] [PDF]

				B. Gabrielli, Y. Q. Chau, N. Giles, A. Harding, F. Stevens, and H. Beamish Caffeine Promotes Apoptosis in Mitotic Spindle Checkpoint-arrested Cells J. Biol. Chem., March 9, 2007; 282(10): 6954 - 6964. [Abstract] [Full Text] [PDF]

				Y.-J. Jang, J.-H. Ji, Y.-C. Choi, C. J. Ryu, and S.-Y. Ko Regulation of Polo-like Kinase 1 by DNA Damage in Mitosis: INHIBITION OF MITOTIC PLK-1 BY PROTEIN PHOSPHATASE 2A J. Biol. Chem., January 26, 2007; 282(4): 2473 - 2482. [Abstract] [Full Text] [PDF]

				C. Vogel, C. Hager, and H. Bastians Mechanisms of Mitotic Cell Death Induced by Chemotherapy-Mediated G2 Checkpoint Abrogation Cancer Res., January 1, 2007; 67(1): 339 - 345. [Abstract] [Full Text] [PDF]

				S.-K. Sha, T. Sato, H. Kobayashi, M. Ishigaki, S. Yamamoto, H. Sato, A. Takada, S. Nakajyo, Y. Mochizuki, J. M. Friedman, et al. Cell cycle phenotype-based optimization of G2-abrogating peptides yields CBP501 with a unique mechanism of action at the G2 checkpoint Mol. Cancer Ther., January 1, 2007; 6(1): 147 - 153. [Abstract] [Full Text] [PDF]

				A. I. Robles, M. H. Wright, B. Gandhi, S. S. Feis, C. L. Hanigan, A. Wiestner, and L. Varticovski Schedule-Dependent Synergy between the Heat Shock Protein 90 Inhibitor 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin and Doxorubicin Restores Apoptosis to p53-Mutant Lymphoma Cell Lines. Clin. Cancer Res., November 1, 2006; 12(21): 6547 - 6556. [Abstract] [Full Text] [PDF]

				R. P Singh and R. Agarwal Mechanisms of action of novel agents for prostate cancer chemoprevention. Endocr. Relat. Cancer, September 1, 2006; 13(3): 751 - 778. [Abstract] [Full Text] [PDF]

				M. M. Caffarel, D. Sarrio, J. Palacios, M. Guzman, and C. Sanchez {Delta}9-Tetrahydrocannabinol Inhibits Cell Cycle Progression in Human Breast Cancer Cells through Cdc2 Regulation. Cancer Res., July 1, 2006; 66(13): 6615 - 6621. [Abstract] [Full Text] [PDF]

				E. Koller, S. Propp, H. Zhang, C. Zhao, X. Xiao, M. Chang, S. A. Hirsch, P. J. Shepard, S. Koo, C. Murphy, et al. Use of a Chemically Modified Antisense Oligonucleotide Library to Identify and Validate Eg5 (Kinesin-Like 1) as a Target for Antineoplastic Drug Development Cancer Res., February 15, 2006; 66(4): 2059 - 2066. [Abstract] [Full Text] [PDF]

				K. J. Campbell, J. M. Witty, S. Rocha, and N. D. Perkins Cisplatin Mimics ARF Tumor Suppressor Regulation of RelA (p65) Nuclear Factor-{kappa}B Transactivation Cancer Res., January 15, 2006; 66(2): 929 - 935. [Abstract] [Full Text] [PDF]

				Y. Seo, T. Yan, J. E. Schupp, K. Yamane, T. Radivoyevitch, and T. J. Kinsella The Interaction between Two Radiosensitizers: 5-Iododeoxyuridine and Caffeine Cancer Res., January 1, 2006; 66(1): 490 - 498. [Abstract] [Full Text] [PDF]

				M. I. Walton, S. C. Wilson, I. R. Hardcastle, A. R. Mirza, and P. Workman An evaluation of the ability of pifithrin-{alpha} and -{beta} to inhibit p53 function in two wild-type p53 human tumor cell lines Mol. Cancer Ther., September 1, 2005; 4(9): 1369 - 1377. [Abstract] [Full Text] [PDF]

				P. N. Lara Jr, P. C. Mack, T. Synold, P. Frankel, J. Longmate, P. H. Gumerlock, J. H. Doroshow, and D. R. Gandara The Cyclin-Dependent Kinase Inhibitor UCN-01 Plus Cisplatin in Advanced Solid Tumors: A California Cancer Consortium Phase I Pharmacokinetic and Molecular Correlative Trial Clin. Cancer Res., June 15, 2005; 11(12): 4444 - 4450. [Abstract] [Full Text] [PDF]

				U. K. Mukhopadhyay, A. M. Senderowicz, and G. Ferbeyre RNA Silencing of Checkpoint Regulators Sensitizes p53-Defective Prostate Cancer Cells to Chemotherapy while Sparing Normal Cells Cancer Res., April 1, 2005; 65(7): 2872 - 2881. [Abstract] [Full Text] [PDF]

				L. M. Karnitz and S. J. H. Arlander Chk1, a Novel Target to Sensitize Tumor Cells to Replication Inhibitors Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 254 - 257. [Full Text] [PDF]

				E. C. Dees, S. D. Baker, S. O'Reilly, M. A. Rudek, S. B. Davidson, C. Aylesworth, K. Elza-Brown, M. A. Carducci, and R. C. Donehower A Phase I and Pharmacokinetic Study of Short Infusions of UCN-01 in Patients with Refractory Solid Tumors Clin. Cancer Res., January 15, 2005; 11(2): 664 - 671. [Abstract] [Full Text] [PDF]