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Title: SLXM-2, a derivative of cyclophosphamide: mechanism of growth inhibition on hepatocarcinoma 22 cells.
Author: Pang LP, Huang W, Sun Q, Guo W, Li RT, Cui JR.
Journal: Anticancer Drugs; 2008 Feb; 19(2):167-74. PubMed ID: 18176113.
Abstract:
Restructuring of cyclophosphamide (CPA) is a promising method for the development of antineoplastic therapy. This study investigated the inhibitory effects of a derivative of CPA, SLXM-2, on hepatocarcinoma 22 (H22) transplanted into ICR mice as well as its effects on the survival time of mice transplanted with the ascitic fluid-type H22. We found that SLXM-2 inhibited tumor growth and prolonged survival time. Moreover, the compound had little effect in vivo on leukocytes and body weight and a higher lethal dose 50 than CPA. The cell cycle analysis by flow cytometry revealed that SLXM-2 arrested tumor cells in both the S and G2 phases, and the arrest in the G2 phase increased in a dose-dependent manner. Western blotting and reverse transcription-PCR experiments indicated that the observed G2 arrest was associated with an increase of cyclin B1, whereas cell division cycle protein 2 (Cdc2) remained constant. The results, however, showed an accumulation of tyrosine 15 phosphorylated Cdc2 and a reduction of threonine 161 phosphorylated Cdc2. In addition, SLXM-2 led to a decrease in cyclin-dependent kinase 7 and Cdc25c kinase, which participated in inhibiting the G2/M transition. Our data identified two upstream targets leading to the inactivity of the cyclin B1/Cdc2 complex, which explained the arrest in the G2/M phase following SLXM-2 treatment. These results demonstrated the antitumor activity of SLXM-2 and its potential use as an antineoplastic drug.

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