Modes of actions of two types of anti-neoplastic drugs, dacarbazine and ACNU, to induce apoptosis

Abstract

O(6)-Methylguanine and O(6)-chloroethylguanine, which are the primary cytotoxic DNA lesions produced by 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (dacarbazine) and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), respectively, can be repaired by O(6)-methylguanine-DNA methyltransferase (MGMT), coded by the MGMT gene. However, the two types of drugs exhibit different effects on cells defective in both MGMT and MLH1 functions, the latter being related to the cellular activity to recognize mismatched bases of DNA for inducing apoptosis. Human cells deficient in both MGMT and MLH1 are resistant to the killing effect of dacarbazine and exhibit an increased mutant frequency after treatment with dacarbazine. On the other hand, these doubly deficient cells are sensitive to the killing action of ACNU and there is no significant increase in ACNU-induced mutant frequency. A mismatch recognition complex, composed of MSH2, MSH6, MLH1, PMS2 and PCNA, is formed after exposing MGMT-deficient cells to dacarbazine, but not in cells treated with ACNU. In contrast, the phosphorylation of Chk1 efficiently occurs in cells treated with dacarbazine as well as with ACNU, the former being in MLH1-dependent manner, whereas the latter in MLH1-independent manner. Therefore, the signals delivered from different sources would merge at the step of Chk1 activation or at an earlier step, and the subsequent process leading to apoptosis appears to be common.

Combination of oncolytic adenovirus and dacarbazine enhances antitumor ability against uveal melanoma cells via cell cycle block

“…3 and 4). It has been previously reported that DTIC (2 mM) kills cells in a manner related to apoptosis, 22 and our results exhibited that DTIC (5 ug/ml) primarily led to cell arrest in the G 1 phase in UM cell lines. Nevertheless, the differences in action of DTIC may be due to different concentrations used (2 mM vs. 5 mg/ml).…”

A novel protein, MAPO1, that functions in apoptosis triggered by O6-methylguanine mispair in DNA

“…The MutSa, consisting of MSH2 and MSH6, and PCNA complex first recognizes O 6 -meG:T mispair in DNA and then MutLa, composed of MLH1 and PMS2, binds to the initial complex. The formation of the mismatch recognition complex is indispensable for the activation of DNA damage signaling as well as the induction of apoptosis (Hidaka et al, 2005;Yoshioka et al, 2006;Sanada et al, 2007).…”

“…A new apoptosis-inducing protein, MAPO1 K Komori et al Sanada et al, 2007). These results imply that KH101 cells might have a defect in a gene involved in the induction of cell death caused by MNU-induced O 6 -methylguanine.…”

“…The activation of ATR kinase and phosphorylation of its downstream targets have been shown to take place in an MMR protein-dependent manner in cells treated with MNU (Caporali et al, 2004;Stojic et al, 2004;Sanada et al, 2007). The MMR protein-dependent release of cytochrome c from mitochondria and activation of caspases, which are hallmarks for apoptosis, also occur in the case of O 6 -methylguanine-induced apoptosis (Ochs and Kaina, 2000;Takagi et al, 2003;Hickman and Samson, 2004).…”

“…The MMR protein-dependent release of cytochrome c from mitochondria and activation of caspases, which are hallmarks for apoptosis, also occur in the case of O 6 -methylguanine-induced apoptosis (Ochs and Kaina, 2000;Takagi et al, 2003;Hickman and Samson, 2004). As apoptosis caused by bulky DNA lesions that block DNA replication occurs even in cells deficient in MMR proteins (Peng et al, 2007;Sanada et al, 2007), the apoptosis pathway induced by O 6 -methylguanine, which does not block DNA replication, appears to be distinct from the former. It is highly likely that other proteins are also involved in the pathway.…”