Some characteristics of DNA strand scission by macromolecular antitumor antibiotic C-1027 containing a novel enediyne chromophore

Sugiura, Yukio; Matsumoto, Teruyuki

doi:10.1021/bi00072a008

Cited by 64 publications

(46 citation statements)

References 26 publications

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“…In contrast, radiomimetic drugs usually cause only a subset of the IR-induced DNA damage. C-1027 primarily attacks the deoxyribose C-4Ј atom, and to a lesser extent C-1Ј, and produces both single and double strand breaks by cleaving DNA strands two base pairs apart at specific sequences (5Ј-TAT and 5Ј-AGA) (21,36). Radiomimetic drug-induced DNA damage is also more sequence-or regionspecific, as opposed to random damage induced by IR (37).…”

Section: Discussionmentioning

confidence: 99%

Cellular Responses to the DNA Strand-scission Enediyne C-1027 Can Be Independent of ATM, ATR, and DNA-PK Kinases

Dzięgielewski

Beerman

2002

Journal of Biological Chemistry

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The current paradigm based upon ionizing radiation (IR) studies states that cells deficient in either ataxiatelangiectasia-mutated kinase (ATM) or related phosphatidylinositol 3 (PI 3) -kinases (ATR and DNA-PK) are hypersensitive to DNA strand breaks because they are unable to rapidly activate downstream effectors such as p53. Here we have contrasted cell responses to IR and C-1027, a radiomimetic antibiotic that induces DNA strand breaks. At equal levels of DNA double strand breaks, cell lines with inactive ATM or other phosphatidylinositol 3-kinases displayed classical hypersensitivity to IR but not to C-1027. Moreover, phosphorylation of p53 Ser-15 induced by C-1027 was independent of ATM, ATR, or DNA-PK function. We have concluded that the model based on IR studies cannot always be directly applied to DNA damage induced by other strand-scission agents.

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Section: Discussionmentioning

confidence: 99%

Cellular Responses to the DNA Strand-scission Enediyne C-1027 Can Be Independent of ATM, ATR, and DNA-PK Kinases

Dzięgielewski

Beerman

2002

Journal of Biological Chemistry

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“…In the controls (lanes 1 and 7), the majority of radiolabel remained within the well. However, increased migration of 14 C-radiolabeled DNA into the gel was apparent with 0.5-5 nM C-1027 (lanes 8-10) and 0.5-2 µM neocarzinostatin (lanes [11][12][13]. DNA from cells X-irradiated with 2-120 Gy (lanes 1-6) was used to compare enediynes with an agent that produces a predictable amount of DNA damage Figure 2b is a graphic representation of data from multiple pulse-field gels showing that the fraction of 14 C-radiolabeled DNA remaining in the well decreased as the X-ray dose increased.…”

Section: Cytotoxicity Of C-1027 and Neocarzinostatin In 293 Cellsmentioning

confidence: 99%

The Cellular Response to DNA Damage Induced by the Enediynes C-1027 and Neocarzinostatin Includes Hyperphosphorylation and Increased Nuclear Retention of Replication Protein A (RPA) and Trans Inhibition of DNA Replication

Kuo

et al. 2001

Biochemistry

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This study examined the cellular response to DNA damage induced by antitumor enediynes C-1027 and neocarzinostatin. Treatment of cells with either agent induced hyperphosphorylation of RPA32, the middle subunit of replication protein A, and increased nuclear retention of RPA. Nearly all of the RPA32 that was not readily extractable from the nucleus was hyperphosphorylated, compared to < or =50% of the soluble RPA. Enediyne concentrations that induced RPA32 hyperphosphorylation also decreased cell-free SV40 DNA replication competence in extracts of treated cells. This decrease did not result from damage to the DNA template, indicating trans-acting inhibition of DNA replication. Enediyne-induced RPA hyperphosphorylation was unaffected by the replication elongation inhibitor aphidicolin, suggesting that the cellular response to enediyne DNA damage was not dependent on elongation of replicating DNA. Neither recovery of replication competence nor reversal of RPA effects occurred when treated cells were further incubated in the absence of drug. C-1027 and neocarzinostatin doses that caused similar levels of DNA damage resulted in equivalent increases in RPA32 hyperphosphorylation and RPA nuclear retention and decreases in replication activity, suggesting a common response to enediyne-induced DNA damage. By contrast, DNA damage induced by C-1027 was at least 5-fold more cytotoxic than that induced by neocarzinostatin.

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“…In addition, LDM is a new potent anti-angiogenesis agent with markedly antimetastatic activity [9]. The potent efficacy of LDM was ascribed to its DNA strand-scission activity [13]. LDM is presently undergoing phase II clinical trials in China.…”

Section: Introductionmentioning

confidence: 99%

Enediyne lidamycin induces apoptosis in human multiple myeloma cells through activation of p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase

Lin¹,

Shang²,

Zhen³

2009

Int J Hematol

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In the present study, the effects of lidamycin (LDM), a member of the enediyne antibiotic family, on two human multiple myeloma (MM) cell lines, U266 and SKO-007, were evaluated. In MTS assay, LDM showed much more potent cytotoxicity than conventional anti-MM agents to both cell lines. The IC(50) values of LDM for the U266 and SKO-007 cells were 0.0575 +/- 0.0015 and 0.1585 +/- 0.0166 nM, respectively, much lower than those of adriamycin, dexamethasone, and vincristine. Mechanistically, LDM triggered MM cells apoptosis by increasing the levels of cleaved poly ADP-ribose polymerase (PARP) and caspase-3/7. In addition, activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) was a critical mediator in LDM-induced cell death. Inhibition of the expression of p38 MAPK and JNK by pharmacological inhibitors reversed the LDM-induced apoptosis through decreasing the level of cleaved PARP and caspase-3/7. Interestingly, phosphorylation of extracellular signal-related kinase was increased by LDM; conversely, MEK inhibitor synergistically enhanced LDM-induced cytotoxicity and apoptosis in MM cells. The results demonstrated that LDM suppresses MM cell growth through the activation of p38 MAPK and JNK, with the potential to be developed as a chemotherapeutic agent for MM.

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Some characteristics of DNA strand scission by macromolecular antitumor antibiotic C-1027 containing a novel enediyne chromophore

Cited by 64 publications

References 26 publications

Cellular Responses to the DNA Strand-scission Enediyne C-1027 Can Be Independent of ATM, ATR, and DNA-PK Kinases

Cellular Responses to the DNA Strand-scission Enediyne C-1027 Can Be Independent of ATM, ATR, and DNA-PK Kinases

The Cellular Response to DNA Damage Induced by the Enediynes C-1027 and Neocarzinostatin Includes Hyperphosphorylation and Increased Nuclear Retention of Replication Protein A (RPA) and Trans Inhibition of DNA Replication

Enediyne lidamycin induces apoptosis in human multiple myeloma cells through activation of p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase

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