Structural comparison of anticancer drug-DNA complexes: adriamycin and daunomycin

Frederick, Christin; Williams, Loren Dean; Ughetto, G.; Marel, Gijs A. van der; Boom, Jacques H. van; Rich, Alexander; Wang, A.H.-J.

doi:10.1021/bi00462a016

Cited by 556 publications

(461 citation statements)

References 31 publications

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“…the helical rise at the central TpA step is much greater (0.42 nm) and the roll angle is increased to 12'. The distortions at the central base pairs in the d(CGTACG) -daunomycin complex and the even greater distortions at the TpA step in the d(TGTACA) -4'-epiadriamycin complex are coincident with changes in the drug conformation relative to that of complexes of anthracycline antibiotics with the d(CGATCG) complexed with daunomycin (Wang et al, 1987) and d(CGTACG) coniplexed with adriamycin and daunomycin (Frederick et al, 1990).…”

Section: Results and Dlscusslonmentioning

confidence: 95%

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Anthracycline binding to DNA

Leonard

Brown

Hunter

1992

European Journal of Biochemistry

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Crystallographic methods have been applied to determine the high-resolution structure of the complex formed between the self-complementary oligonucleotide d(TGTACA) and the anthracycline antibiotic 4-epiadriamycin. The complex crystallises in the tetragonal system, space group P4,212 with c1 = 2.802 nm and c = 5.293 nm, and an asymmetric unit consisting of a single D N A strand, one drug molecule and 34 solvent molecules. The refinement converged with an R factor of 0.17 for the 2381 reflections with F a 3oF in the resolution range 0.70-0.14 nm. Two asymmetric units associate such that a distorted B-DNA-type hexanucleotide duplex is formed incorporating two drug molecules that are intercalated at the TpG steps. The amino sugar of 4'-epiadriamycin binds in the minor groove of the duplex and displays different interactions from those observed in previously determined structures. Interactions between the hydrophilic groups of the amino sugar and the oligonucleotidc are all mediated by solvent molecules. Ultraviolet melting measurements and comparison with other anthracycline-DNA complexes suggest that these indirect interactions have a powerful stabilising effect on the complex.Nucleic acids and the proteins that interact with them are primary targets for chemotherapy (Fisher and Aristoff, 1988). The development of new antibiotics and anticancer agents is guided by knowledge of how such compounds interact with specific biochemical targets and thereby exert their influence.Anthracycline antibiotics are of particular interest as potent antitumour agents which bind to both DNA and the DNAbinding protein topoisomerase 11. It has been demonstrated that interactions with DNA are primarily responsible for the biological activity of anthracyclines (Valentini et al., 1985). Despite the fact that these antibiotics have been used clinically for the treatment of ccrtain cancers, they possess serious side effects, most notably cardiotoxicity. It is important to characterise the structures formed betwecn anthracycline antibiotics and DNA in order to understand the precise nature of the molecular intcractions. The structural information may then facilitate the rational design of improved, more selective anticancer, antibiotic or anti-viral agents.The two most-studied anthracyclines are adriamycin and daunomycin. Various methods have been used to study the interactions of these molecules with D N A (Chaires. 1990). Thesc include thooretical studies (Chen ct al., 1985, Pullman, 1987, 1991 and techniques such as DNA footprinting , Skavobogaty et al., 1988a, both of which provide evidence for preferential binding to certain DNA sequences. Of note is thc observation that thesc compounds recognise and bind to three consecutive base pairs. Rcceiitly, a series of X-ray structures have appeared which

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Section: Results and Dlscusslonmentioning

confidence: 95%

“…r.m.s., root mean square. have characteriscd the molecular intcractions between these molecules and a number of oligonucleotides (Wang et al, 1987, Moore et al, 1989, Frederick et al, 1990. These studies have shown that the aglycone moiety intercalates at a pyriniidine-purine step, d(CpG) and the amino sugar binds in the minor groove of the B-DNA duplex.…”

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confidence: 99%

Anthracycline binding to DNA

Leonard

Brown

Hunter

1992

European Journal of Biochemistry

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“…To measure the time resolved gene responses to Roc-A, RNA was isolated from Roc-A-treated (50 nM) normal T and Jurkat T cells at t 5 [0, 1,2,3,4,6,8,10,14,20,28,36] and t 5 [0. 5,1,2,3,4,5,6,7,8,10,12,14,16,20,24,28,32,36] hr, respectively. The quality of total RNA was controlled with an Agilent 2100 Bioanalyzer (Agilent Technologies GmbH, Berlin, Germany).…”

Section: Rna Preparation and Dna Microarray Analysismentioning

confidence: 99%

“…23 To investigate whether Roc-A acts as an intercalator, we compared the action of Roc-A to that of the DNA intercalation anticancer drug doxorubicin (trade name Adriamycin). 24 When DNA is damaged, DSBs trigger recruitment of ATM to the damage site which in turn phosphorylates histone H2AX (yielding gH2AX) leading to foci formation. 25,26 Therefore, we used gH2AX as a readout to investigate the status of gH2AX levels in living cells following Roc-A treatment.…”

Section: Roc-a Does Not Induce Massive Dna Damage As Compared To Dna mentioning

confidence: 99%

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

et al. 2013

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Targeting the cancer cell cycle machinery is an important strategy for cancer treatment. Cdc25A is an essential regulator of cycle progression and checkpoint response. Over-expression of Cdc25A occurs often in human cancers. In this study, we show that Rocaglamide-A (Roc-A), a natural anticancer compound isolated from the medicinal plant Aglaia, induces a rapid phosphorylation of Cdc25A and its subsequent degradation and, thereby, blocks cell cycle progression of tumor cells at the G1-S phase. Roc-A has previously been shown to inhibit tumor proliferation by blocking protein synthesis. In this study, we demonstrate that besides the translation inhibition Roc-A can induce a rapid degradation of Cdc25A by activation of the ATM/ATRChk1/Chk2 checkpoint pathway. However, Roc-A has no influence on cell cycle progression in proliferating normal T lymphocytes. Investigation of the molecular basis of tumor selectivity of Roc-A by a time-resolved microarray analysis of leukemic vs. proliferating normal T lymphocytes revealed that Roc-A activates different sets of genes in tumor cells compared with normal cells. In particular, Roc-A selectively stimulates a set of genes responsive to DNA replication stress in leukemic but not in normal T lymphocytes. These findings further support the development of Rocaglamide for antitumor therapy.In normal cells, the cell division cycle is tightly controlled. Cancer cells are characterized by deregulation in the cell division cycle, which is associated with increased DNA replication and elevated cellular proliferation. 1-3 Therefore, targeting the cancer cell cycle machinery has been considered to be a rational strategy for cancer treatment. 4 Cell division is governed by cyclin dependent kinases (CDKs) that are tightly regulated by cyclins and CDK inhibitors (CDKIs). Tumor-associated cell cycle defects often show alterations in CDK expression or/and activity. 2 Typically, CDK4 and CDK6 that are crucial for G1 checkpoint control are often over-expressed in many malignancies. 2,3 Evidence shows that deregulation of CDK4 and CDK6 activity is associated with a wide variety of tumors. 2 Moreover, elevated expressions of the cell division cycle 25 (Cdc25) phosphatases, in particular, the isoform Cdc25A, which is essential for cell cycle transitions of G1-S and S-G2, has been shown in different cancers and their over-expression often correlates with more aggressive disease and poor prognosis. 1,5 Recently, genetic studies indicate that CDK2, CDK4 and CDK6 are not essential for the mammalian cell cycle. Instead, they are only required for the proliferation of specific cell types. 2 Thus, targeting the activities of CDK2, CDK4 and CDK6 may be a promising approach for cancer treatment.Rocaglamides (Roc; 5 Flavaglines), derived from the traditional Chinese medicinal plant Aglaia, are a group of naturally occurring herbal chemicals. A number of Roc compounds have been shown to possess potent inhibitory effects on tumor growth in vitro and in vivo in animal models with IC 50 concentrations at the n...

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“…Reactive oxygen species (ROS) may also cause DNA damage. To investigate the mechanisms of tagalsins‐induced DNA damage, we compared tagalsins with doxorubicin (trade name adriamycin) which damages DNA by d(CGTACG) intercalation 20. Jurkat T cells were treated with TC, TF or doxorubicin in the absence or presence of the anti‐oxidant N ‐acetyl‐cysteine (NAC).…”

Section: Resultsmentioning

confidence: 99%

Mangrove dolabrane‐type of diterpenes tagalsins suppresses tumor growth viaROS‐mediated apoptosis and ATM/ATR–Chk1/Chk2‐regulated cell cycle arrest

Neumann

Yang

Köhler

et al. 2015

Intl Journal of Cancer

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Natural compounds are an important source for drug development. With an increasing cancer rate worldwide there is an urgent quest for new anti‐cancer drugs. In this study, we show that a group of dolabrane‐type of diterpenes, collectively named tagalsins, isolated from the Chinese mangrove genus Ceriops has potent cytotoxicity on a panel of hematologic cancer cells. Investigation of the molecular mechanisms by which tagalsins kill malignant cells revealed that it induces a ROS‐mediated damage of DNA. This event leads to apoptosis induction and blockage of cell cycle progression at S‐G2 phase via activation of the ATM/ATR—Chk1/Chk2 check point pathway. We further show that tagalsins suppress growth of human T‐cell leukemia xenografts in vivo. Tagalsins show only minor toxicity on healthy cells and are well tolerated by mice. Our study shows a therapeutic potential of tagalsins for the treatment of hematologic malignancies and a new source of anticancer drugs.

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Structural comparison of anticancer drug-DNA complexes: adriamycin and daunomycin

Cited by 556 publications

References 31 publications

Anthracycline binding to DNA

Anthracycline binding to DNA

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

Mangrove dolabrane‐type of diterpenes tagalsins suppresses tumor growth viaROS‐mediated apoptosis and ATM/ATR–Chk1/Chk2‐regulated cell cycle arrest

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