Different initial steps of apoptosis induced by two types of antineoplastic drugs

Takagi, Yasuaki; Hidaka, Masaaki; Sanada, Masayuki; Yoshida, Hiroki; Sekiguchi, Mutsuo

doi:10.1016/j.bcp.2008.05.008

Cited by 11 publications

(9 citation statements)

References 28 publications

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“…TMZ–induced O 6 -methylG residues are repaired by MGMT [7]. Takagi et al described the sensitivity of MGMT−/− cells to TMZ [31], and the relative D 50 value of MGMT deficient cells was found to be 33.3 here (data not shown). In newly diagnosed glioblastomas, MGMT sometimes shows low levels of activity!…”

Section: Discussionmentioning

confidence: 63%

DNA ligase IV as a new molecular target for temozolomide

Kondo

Takahashi

Mori

et al. 2009

Biochemical and Biophysical Research Communications

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This work was designed to clarify details in repair pathways acting to remove DNA double strand breaks (DSB) induced by temozolomide (TMZ). Cultured mouse embryonic fibroblasts were used which were deficient in their DNA DSB repair ability. Cell sensitivity to drug treatments was assessed using colony forming assays. The most effective molecular target which was correlated with TMZ cell sensitivity was DNA Ligase IV (Lig4). In addition, it was found that siRNA for Lig4 efficiently enhanced cell lethality induced by TMZ in human glioblastoma A172 cells. These findings suggest that down regulation of Lig4 might provide a useful tool for cell sensitization during TMZ chemotherapy.

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Section: Discussionmentioning

confidence: 63%

DNA ligase IV as a new molecular target for temozolomide

Kondo

Takahashi

Mori

et al. 2009

Biochemical and Biophysical Research Communications

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“…In MAPO2 -knockdown RF101 cells, however, the formation of active BAK dimers was significantly inhibited, thus suggesting that the cells were unable to induce apoptosis effectively even after the treatment with MNU. To obtain further evidence supporting that MAPO2 -knockdown cells are defective in the induction of apoptosis, the effect of MAPO2 -knockdown was investigated on the depolarization of the mitochondrial membrane and the activation of caspase-3, which are known to occur during the process of apoptosis [20], [24]. The two types of cells were treated with 0.4 mM MNU for 1 h and were then subjected to both assays.…”

Section: Resultsmentioning

confidence: 99%

“…The depolarization of mitochondrial membranes followed by the activation of caspase-3 is induced, through the regulation of the activities of the BCL-2 family of proteins [19], [20]. However, the precise molecular mechanism that activates the signaling cascade leading to apoptosis has been elusive.…”

Section: Introductionmentioning

confidence: 99%

The Identification of a Novel Gene, MAPO2, That Is Involved in the Induction of Apoptosis Triggered by O6-Methylguanine

et al. 2012

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O6-Methylguanine, one of alkylated DNA bases, is especially mutagenic. Cells containing this lesion are eliminated by induction of apoptosis, associated with the function of mismatch repair (MMR) proteins. A retrovirus-mediated gene-trap mutagenesis was used to isolate new genes related to the induction of apoptosis, triggered by the treatment with an alkylating agent, N-methyl-N-nitrosourea (MNU). This report describes the identification of a novel gene, MAPO2 (O6-methylguanine-induced apoptosis 2), which is originally annotated as C1orf201. The MAPO2 gene is conserved among a wide variety of multicellular organisms and encodes a protein containing characteristic PxPxxY repeats. To elucidate the function of the gene product in the apoptosis pathway, a human cell line derived from HeLa MR cells, in which the MAPO2 gene was stably knocked down by expressing specific miRNA, was constructed. The knockdown cells grew at the same rate as HeLa MR, thus indicating that MAPO2 played no role in the cellular growth. After exposure to MNU, HeLa MR cells and the knockdown cells underwent cell cycle arrest at G2/M phase, however, the production of the sub-G1 population in the knockdown cells was significantly suppressed in comparison to that in HeLa MR cells. Moreover, the activation of BAK and caspase-3, and depolarization of mitochondrial membrane, hallmarks for the induction of apoptosis, were also suppressed in the knockdown cells. These results suggest that the MAPO2 gene product might positively contribute to the induction of apoptosis triggered by O6-methylguanine.

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“…The activation of the ATR-Chk1 pathway and the G 2 /M checkpoint by low doses of S N 1-type DNA methylators and the triggered apoptotic responses hinge upon a functional MMR apparatus (Hickman and Samson, 2004;Stojic et al, 2004b). A recent study has also shown that whereas temozolomide-induced apoptosis was dependent upon the presence of MMR proteins, the cell death induced by the DNA bifunctional alkylator 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea showed no such dependence on MMR proteins (Takagi et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Bifunctional DNA Alkylator 1,3-Bis(2-chloroethyl)-1-nitrosourea Activates the ATR-Chk1 Pathway Independently of the Mismatch Repair Pathway

Cui¹,

Johnson²,

Bullock³

et al. 2009

Mol Pharmacol

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The presence of DNA damage initiates signaling through the ataxia-telangiectasia mutated kinase (ATM) and the ATM-and the Rad3-related kinase (ATR), which phosphorylate, thus activating, the checkpoint kinases (Chk) 1 and 2, which leads to cell cycle arrest. The bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) is cytotoxic primarily by inducing DNA monoadducts and ultimately, interstrand cross-links, which block DNA replication. In this study, we investigated the activation of the ATR-Chk1 pathway in response to BCNU treatment and the dependence of this response on the DNA mismatch repair (MMR) capacity. Medulloblastoma cells were exposed to low and moderate doses of BCNU, and the effects on this DNA damage signaling pathway were examined. In response to BCNU, Chk1 was found to be phosphorylated at serine 345 and exhibited increased kinase activity. Caffeine and wortmannin, which are broad-spectrum inhibitors of ATM and ATR, reduced this phosphorylation. Cell cycle analysis further revealed an accumulation of cells in the S phase in response to BCNU, an effect that was attenuated by caffeine. Small interfering RNA knockdown of ATR also reduced Chk1 phosphorylation after exposure to BCNU. However, knockdown of ATM had no effect on the observed Chk1 phosphorylation, suggesting that ATR was primarily responsible for Chk1 activation. Analysis of Chk1 activation in cells deficient in MMR proteinsMutL␣ or MutS␣ indicated that the DNA damage response induced by BCNU was independent of the MMR apparatus. This MMR-independent activation seems to be the result of DNA interstrand cross-link formation.The bifunctional DNA alkylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) has been an important component of multiple agent adjuvant chemotherapy regimens in the treatment of brain tumors. Because of its high lipophilicity, it has the capacity to cross the blood-brain barrier, essential for any brain tumor therapy. The primary cytotoxic effects of BCNU result from alkylation at the O 6 position of guanine in DNA, and the subsequent conversion of these monoadducts into DNA interstrand cross-links between the N 1

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Different initial steps of apoptosis induced by two types of antineoplastic drugs

Cited by 11 publications

References 28 publications

DNA ligase IV as a new molecular target for temozolomide

DNA ligase IV as a new molecular target for temozolomide

The Identification of a Novel Gene, MAPO2, That Is Involved in the Induction of Apoptosis Triggered by O6-Methylguanine

Bifunctional DNA Alkylator 1,3-Bis(2-chloroethyl)-1-nitrosourea Activates the ATR-Chk1 Pathway Independently of the Mismatch Repair Pathway

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