G2/M arrest

In most studies where a supraadditive interaction was seen, cells were incubated with the drug prior to irradiation (38). In general the use of moderate concentrations (5-100 nmol/L) of paclitaxel in the culture medium for over 24 h lead to maximum sensitization. Most studies used actively proliferating cells in order to conduct their experiments and most investigators reached the conclusion that maximal radiosensitization occurred when cells were arrested in G2 and M, as this part of the cell cycle is the most sensitive to radiation damage. This assumption does, however, presuppose that the majority of the G2/M arrested cells will not die unless they are exposed to ionizing XRT. Plateau phase, i.e., nonproliferating, cells were found to be sensitized to radiation... 

Vikhanskaya F, Vignati S, Beccaglia P, et al. Inactivation of p53 in a human ovarian cancer cell line increases the sensitivity to paclitaxel by inducing G2/M arrest and apoptosis. Exp Cell Res 1998 241(1) 96-101. 

Wahl AF, Donaldson KL, Fairchild C, et al. Loss of normal p53 function confers sensitization to Taxol by increasing G2/M arrest and apoptosis. Nature Med 1996 2 72-79. 

Park C, Kim GY, Kim GD, Choi BT, Park YM, Choi YH. 2006. Induction of G2/M arrest and inhibition of cyclooxygenase-2 activity by curcumin in human bladder cancer T24 cells. Oncol Rep 15 1225-1231. 

Weir NM, Selvendiran K, Kutala VK, Tong L, Vishwanath S, Rajaram M, Tridanda-pani S, Anant S, Kuppusamy P. 2007. Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating Akt and p38 MAPK. Cancer Biol Ther 6 178-184. 

Treatment of human cancer cells with low nM concentrations of Epo B leads to profound growth inhibition and cell death (Table 1-1). In line with the effects on tubulin polymerization in vitro, Epo B is a more potent antiproliferative agent than Epo A, which in turn is about equipotent with paclitaxel. As observed for paclitaxel, Epo B treatment produces aberrant mitotic spindles, results in cell cycle arrest in mitosis, and eventually leads to apoptotic cell death. It is often assumed that apoptosis is a direct consequence of G2/M arrest, which in turn would be a prerequisite for growth inhibition and cell death. However, as has been elegantly demonstrated by Chen et al. in a series of recent experiments, the situation is clearly more complex, such that low concentrations of Epo B (and paclitaxel... 

Lee SE, Moore JK, Holmes A, Umezu K, Kolodner RD, Haber JE. Saccharomyces Ku70, mrel l/rad50 and RPA proteins regulate adaptation to G2/M arrest after DNA damage. Cell 1998 94(3) 399 09. 

Apigenin has also been noted to cause reversible G2/M arrest (Lepley et al., 1996). 

Lepley D, Li B, Birt DF. The chemopreventive flavonoid apigenin induced G2/M arrest in keratinocytes. Carcinogenesis 1996 17 2367-75. 

BRCA1 is essential for activating the protein kinase Chkl that regulates DNA da-mage-induced G2/M arrest (review Yarden et al., 2002). 

Other terpenoids with potential proapoptotic effects are famesol and geranylgeraniol [175], y-tocotrienol and P-lonone [176], perillyl alcohol [177], limonene [178], and paclitaxel [179], all of which induce apoptotic cell death via a signaling pathway that is independent of G2/M arrest and microtubules [180]. 

The growth inhibition of virus-transformed cells in vitro and antitumor activity in vivo of geldanamycin (85) and its derivatives [230,231], and the inhibition of DNA synthesis in murine tumor cells by 85 were reported [232,233]. Geldanamycin (85) is an antibiotic that preferentially inhibits Gl/S transition and causes G2/M arrest in human leukemia HL-60 cells. Also, it was found that 85 selectively inhibited recombinant Src tyrosine kinase without significantly inhibiting protein kinase A. The perturbation of cell cycling by 85 was accompanied by marked suppression of c-MYC expression [234]. 

Choi YH, Lee WH, Park KY, Zhang L. p53-independent induction of p2l , reduction of cyclin B1 and G2/M arrest by the isoflavone genistein in human prostate carcinoma cells. Jpn J Cancer Res 2000 91 164-173. 

Heinrich, M.C. et al., DNA cross-linker-induced G2/M arrest in group C Fanconi anemia lymphoblasts reflects normal checkpoint function, B/oorf, 91 275, 1998. 

Bae, S. J. and Choi, Y. H. (2007). Methanol extract of the seaweed Gloiopeltis furcata induces G2/M arrest and inhibits cyclooxygenase-2 activity in human hepatocarcinoma HepG2 cells. Phytother. Res. 21(1), 52-57. 

Ando T, Kawabe T, Ohara H et al. Involvement of the interaction between p21 and proliferating cell nuclear antigen for the maintenance of G2/M arrest after DNA damage. J Biol Chem 2001 276 42971-42977. 

Suppressing mechanism This mechanism includes elimination of tumor cells, including growth inhibition by induction of cell-cycle arrest or apoptosis. Apigenin has been shown to induce G2/M arrest in SW480 and Caco-2 human colon carcinoma cells [40], Resveratrol and quercetin are reported to induce the expression of caspase-3 promoting apoptosis, arresting cells in G1 phase of the cell cycle, and decrease tiunor cell invasion [41]. 

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