UCN-01: a Potent Abrogator of G2 Checkpoint Function in Cancer Cells With Disrupted p53

Abstract

UCN-01 is a potent abrogator of G2 checkpoint control in cancer cells with disrupted p53 function. UCN-01 might be capable of enhancing the effectiveness of DNA-damaging agents in the treatment of tumors with cells lacking normal p53 function.

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

“…It has been reported to sensitize various cancer cells to variant DNA-damaging agents such as cisplatin (Wang et al, 1996), topoisomerase I inhibitors (Shao et al, 1997) or gemcitabine (Shi et al, 2001). However, the usage of UCN-01 on Chk1 inhibition was not totally successful since its untoward toxicities and non-specific inhibition decrease the value as a Chk1 inhibitor (Sausville et al, 2001).…”

Abrogation of the radiation-induced G2 checkpoint by the staurosporine derivative UCN-01 is associated with radiosensitisation in a subset of colorectal tumour cell lines

“…Although treatment with 25 nM UCN-01 (a non-toxic dose in S/RG/C2) abrogated the IR-induced G2 checkpoint in S/ RG/C2 (Table 1), there was no evidence of radiosensitisation in this cell line (Figure 2). It was of interest, therefore, to determine whether a higher dose of UCN-01 (300 nM) for a shorter treatment period (24 h) (a protocol described previously (Wang et al, 1996)), would be more effective at abrogation of the G2 checkpoint and would result in sensitisation to IR-induced cell death in the S/RG/ C2 cell line which was not previously sensitised. In both the HT29 and S/RG/C2 cell lines, treatment with 300 nM UCN-01 effectively abrogated the IR-induced G2 arrest.…”

“…Previous work by Wang et al (1996) has shown that UCN-01 sensitises the colorectal carcinoma cell line HT29 to IR-induced growth inhibition, however, it is not known whether this is a general response of all colorectal tumour cells. Given the frequent use of radiotherapy in treatment of colorectal cancer and the potential importance of this therapeutic strategy, the aim of this study was to determine whether UCN-01 was able to abrogate the IR-induced G2 arrest in a range of colorectal tumour cell lines, and whether this would consistently lead to radiosensitisation in these cell lines.…”

“…For example, agents such as the methylxanthines caffeine and pentoxifylline have been shown to abrogate the G2 checkpoint and increase sensitivity to IR, presumably due to the ability of these agents to cause premature, and hence lethal, mitosis after IR (Powell et al, 1995;Bracey et al, 1997). Abrogation of the G2 checkpoint and subsequent sensitisation to DNA damage-induced cell death is suggested to be specific to cells that do not express wild type p53, as these cells depend on the G2 arrest for survival after DNA damage (Powell et al, 1995;Bunch and Eastman, 1996;Wang et al, 1996;Bracey et al, 1997). Hence this may be an important treatment strategy as tumour cells may be preferentially targeted whilst causing minimal disruption to surrounding non malignant tissue.…”

“…UCN-01 has anti-tumour properties alone (Akinaga et al, 1991;Seynaeve et al, 1994) and has also been shown to abrogate the G2 checkpoint and to sensitise tumour cells to various DNA damaging agents (Bunch and Eastman, 1996;Wang et al, 1996;Yu et al, 1998). In view of these properties, UCN-01 has recently undergone phase I clinical trials (Senderowicz and Sausville, 2000).…”