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Dipak Dasgupta - One of the best experts on this subject based on the ideXlab platform.
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Spectroscopic and Calorimetric Approach to Understand the Molecular Basis of Self-Association of Aureolic Acid Antibiotic, Chromomycin A3
Open Journal of Biophysics, 2014Co-Authors: Shreyasi Dutta, Shibojyoti Lahiri, Dipak DasguptaAbstract:Chromomycin A3 (CHR, pKa = 7.0), an aureolic acid group of antitumor antibiotic, undergoes self-association in aqueous solution in neutral and anionic forms. Self-association processes of neutral and anionic CHR have been studied in pH 5.0 and pH 9.0, respectively using different spectroscopic methods such as absorbance, fluorescence, CD, NMR and isothermal titration calorimetry (ITC). Results from these studies reveal that at low concentration (2 + CHR (CHR)3 and (CHR)3 + CHR (CHR)4. Analysis of NMR spectra of 100 μM and 1 mM CHR indicates that the self-association of CHR (neutral and anionic form) is most likely to happen via hydrophobic interaction involving the sugar moieties and surrounding water molecules. Calorimetric studies indicate that self-association of both anionic and neutral CHR is entropy driven. These observations imply that sugar substituents play a major role in their state of aggregation after biosynthesis from a gene cluster. The self-association features of the antibiotic have been compared with those of Mithramycin, an antibiotic of the same group.
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Association of aureolic acid antibiotic, Chromomycin A3 with Cu^2+ and its negative effect upon DNA binding property of the antibiotic
BioMetals, 2012Co-Authors: Shibojyoti Lahiri, Pukhrambam Grihanjali Devi, Toshifumi Takao, Saptaparni Ghosh, Ayanjeet Ghosh, Amrita Dasgupta, Dipak DasguptaAbstract:Here we have examined the association of an aureolic acid antibiotic, Chromomycin A3 (CHR), with Cu^2+. CHR forms a high affinity 2:1 (CHR:Cu^2+) complex with dissociation constant of 0.08 × 10^−10 M^2 at 25°C, pH 8.0. The affinity of CHR for Cu^2+ is higher than those for Mg^2+ and Zn^2+ reported earlier from our laboratory. CHR binds preferentially to Cu^2+ in presence of equimolar amount of Zn^2+. Complex formation between CHR and Cu^2+ is an entropy driven endothermic process. Difference between calorimetric and van’t Hoff enthalpies indicate the presence of multiple equilibria, supported from biphasic nature of the kinetics of association. Circular dichroism spectroscopy show that [(CHR)_2:Cu^2+] complex assumes a structure different from either of the Mg^2+ and Zn^2+ complex reported earlier. Both [(CHR)_2:Mg^2+] and [(CHR)_2:Zn^2+] complexes are known to bind DNA. In contrast, [(CHR)_2:Cu^2+] complex does not interact with double helical DNA, verified by means of Isothermal Titration Calorimetry of its association with calf thymus DNA and the double stranded decamer (5′-CCGGCGCCGG-3′). In order to interact with double helical DNA, the (antibiotic)_2 : metal (Mg^2+ and Zn^2+) complexes require a isohelical conformation. Nuclear Magnetic Resonance spectroscopy shows that the Cu^2+ complex adopts a distorted octahedral structure, which cannot assume the required conformation to bind to the DNA. This report demonstrates the negative effect of a bivalent metal upon the DNA binding property of CHR, which otherwise binds to DNA in presence of metals like Mg^2+and Zn^2+. The results also indicate that CHR has a potential for chelation therapy in Cu^2+ accumulation diseases. However cytotoxicity of the antibiotic might restrict the use.
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Association of aureolic acid antibiotic, Chromomycin A3 with Cu2+ and its negative effect upon DNA binding property of the antibiotic.
Biometals : an international journal on the role of metal ions in biology biochemistry and medicine, 2011Co-Authors: Shibojyoti Lahiri, Pukhrambam Grihanjali Devi, Toshifumi Takao, Saptaparni Ghosh, Ayanjeet Ghosh, Amrita Dasgupta, Dipak DasguptaAbstract:Here we have examined the association of an aureolic acid antibiotic, Chromomycin A3 (CHR), with Cu2+. CHR forms a high affinity 2:1 (CHR:Cu2+) complex with dissociation constant of 0.08 × 10−10 M2 at 25°C, pH 8.0. The affinity of CHR for Cu2+ is higher than those for Mg2+ and Zn2+ reported earlier from our laboratory. CHR binds preferentially to Cu2+ in presence of equimolar amount of Zn2+. Complex formation between CHR and Cu2+ is an entropy driven endothermic process. Difference between calorimetric and van’t Hoff enthalpies indicate the presence of multiple equilibria, supported from biphasic nature of the kinetics of association. Circular dichroism spectroscopy show that [(CHR)2:Cu2+] complex assumes a structure different from either of the Mg2+ and Zn2+ complex reported earlier. Both [(CHR)2:Mg2+] and [(CHR)2:Zn2+] complexes are known to bind DNA. In contrast, [(CHR)2:Cu2+] complex does not interact with double helical DNA, verified by means of Isothermal Titration Calorimetry of its association with calf thymus DNA and the double stranded decamer (5′-CCGGCGCCGG-3′). In order to interact with double helical DNA, the (antibiotic)2 : metal (Mg2+ and Zn2+) complexes require a isohelical conformation. Nuclear Magnetic Resonance spectroscopy shows that the Cu2+ complex adopts a distorted octahedral structure, which cannot assume the required conformation to bind to the DNA. This report demonstrates the negative effect of a bivalent metal upon the DNA binding property of CHR, which otherwise binds to DNA in presence of metals like Mg2+and Zn2+. The results also indicate that CHR has a potential for chelation therapy in Cu2+ accumulation diseases. However cytotoxicity of the antibiotic might restrict the use.
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Inhibition of a Zn(II)-containing enzyme, alcohol dehydrogenase, by anticancer antibiotics, mithramycin and Chromomycin A3.
Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry, 2008Co-Authors: Pukhrambam Grihanjali Devi, Prabir K. Chakraborty, Dipak DasguptaAbstract:One of the major attributes for the biological action of the aureolic acid anticancer antibiotics Chromomycin A3 (CHR) and mithramycin (MTR) is their ability to bind bivalent cations such as Mg(II) and Zn(II) ions and form high affinity 2:1 complexes in terms of the antibiotic and the metal ion, respectively. As most of the cellular Zn(II) ion is found to be associated with proteins, we have examined the effect of MTR/CHR on the structure and function of a representative structurally well characterized Zn(II) metalloenzyme, alcohol dehydrogenase (ADH) from yeast. MTR and CHR inhibit enzyme activity of ADH with inhibitory constants of micromolar order. Results from size-exclusion column chromatography, dynamic light scattering, and isothermal titration calorimetry have suggested that the mechanism of inhibition of the metalloenzyme by the antibiotics is due to the antibiotic-induced disruption of the enzyme quaternary structure. The nature of the enzyme inhibition, the binding stoichiometry of two antibiotics per monomer, and comparable dissociation constants for the antibiotic and free (or substrate-bound) ADH imply that the association occurs as a consequence of the binding of the antibiotics to Zn(II) ion present at the structural center. Confocal microscopy shows the colocalization of the antibiotic and the metalloenzyme in HepG2 cells, thereby supporting the proposition of physical association between the antibiotic(s) and the enzyme inside the cell.
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Association of the anticancer antibiotic Chromomycin A(3) with the nucleosome: role of core histone tail domains in the binding process.
Biochemistry, 2001Co-Authors: Mohd.ayoub Mir, Dipak DasguptaAbstract:The anticancer antibiotic Chromomycin A3 is a transcription inhibitor which forms two types of complexes with Mg2+: complex I (1:1 in terms of Chromomycin A3−Mg2+) and complex II (2:1 in terms of Chromomycin A3−Mg2+). These complexes are the DNA-binding ligands. With the broad objective of elucidation of the mechanism for action of this group of transcription inhibitors in eukaryotic systems, we have studied the interaction of the antibiotic with nucleosome core particles under different conditions. We have demonstrated and characterized the role of core histone proteins, particularly the N-terminal tail domains, in the association of nucleosome with both complexes of Chromomycin. From a scrutiny of the spectroscopic features of the two bound complexes and comparison of the binding and associated thermodynamic parameters, we have shown the following. Core histone(s) stand(s) in the way of access of the ligand(s) to nucleosomal DNA. N-Terminal intact and chopped core particles interact differentially with...
Kulthida Vaeteewoottacharn - One of the best experts on this subject based on the ideXlab platform.
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Chromomycin A3 suppresses cholangiocarcinoma growth by induction of S phase cell cycle arrest and suppression of Sp1‑related anti‑apoptotic proteins.
International journal of molecular medicine, 2020Co-Authors: Paksiree Saranaruk, Ryusho Kariya, Gunya Sittithumcharee, Parichart Boueroy, Thidarut Boonmars, Kanlayanee Sawanyawisuth, Chaisiri Wongkham, Sopit Wongkham, Seiji Okada, Kulthida VaeteewoottacharnAbstract:Cholangiocarcinoma (CCA) is a cancer of biliary epithelium. Late diagnosis and resistance to conventional chemotherapy are the major obstacles in CCA treatment. Increased expression of anti‑apoptotic proteins are observed in CCA, which might confer chemoresistance. Thus, modulations of anti‑apoptotic proteins leading to apoptotic induction is the focus of this study. Chromomycin A3 (CMA3), an anthraquinone glycoside‑mithramycin A analog, was selected. CMA3 strongly binds to GC‑rich regions in DNA, where specificity protein 1 (Sp1), a common transcription factor of apoptosis‑related proteins, is preferentially bounded. The effects of CMA3 on anti‑proliferation, cell cycle arrest and apoptosis induction in CCA cells were demonstrated by MTT assay, flow cytometry and western blot analysis. The results showed CMA3 suppressed cell proliferation in vitro in the nM range. At low doses, CMA3 inhibited cell cycle progression at S phase, while it promoted caspase‑dependent apoptosis at higher doses. CMA3 induced effects of apoptosis were through the suppression of Sp1‑related anti‑apoptotic proteins, FADD‑like IL‑1β‑converting enzyme‑inhibitory protein, myeloid cell leukemia‑1, X‑linked inhibitor of apoptosis protein, cellular inhibitor of apoptosis and survivin. The anti‑CCA effects of CMA3 were confirmed in the xenograft mouse model. CMA3 retarded xenograft tumor growth. Taken together, CMA3 induced apoptosis in CCA cells by diminishing the Sp1‑related anti‑apoptotic proteins is demonstrated. CMA3 might be useful as a chemosensitizing agent.
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Chromomycin A3 suppresses cholangiocarcinoma growth by induction of s phase cell cycle arrest and suppression of sp1 related anti apoptotic proteins
International Journal of Molecular Medicine, 2020Co-Authors: Paksiree Saranaruk, Ryusho Kariya, Gunya Sittithumcharee, Parichart Boueroy, Thidarut Boonmars, Kanlayanee Sawanyawisuth, Chaisiri Wongkham, Sopit Wongkham, Seiji Okada, Kulthida VaeteewoottacharnAbstract:Cholangiocarcinoma (CCA) is a cancer of biliary epithelium. Late diagnosis and resistance to conventional chemotherapy are the major obstacles in CCA treatment. Increased expression of anti‑apoptotic proteins are observed in CCA, which might confer chemoresistance. Thus, modulations of anti‑apoptotic proteins leading to apoptotic induction is the focus of this study. Chromomycin A3 (CMA3), an anthraquinone glycoside‑mithramycin A analog, was selected. CMA3 strongly binds to GC‑rich regions in DNA, where specificity protein 1 (Sp1), a common transcription factor of apoptosis‑related proteins, is preferentially bounded. The effects of CMA3 on anti‑proliferation, cell cycle arrest and apoptosis induction in CCA cells were demonstrated by MTT assay, flow cytometry and western blot analysis. The results showed CMA3 suppressed cell proliferation in vitro in the nM range. At low doses, CMA3 inhibited cell cycle progression at S phase, while it promoted caspase‑dependent apoptosis at higher doses. CMA3 induced effects of apoptosis were through the suppression of Sp1‑related anti‑apoptotic proteins, FADD‑like IL‑1β‑converting enzyme‑inhibitory protein, myeloid cell leukemia‑1, X‑linked inhibitor of apoptosis protein, cellular inhibitor of apoptosis and survivin. The anti‑CCA effects of CMA3 were confirmed in the xenograft mouse model. CMA3 retarded xenograft tumor growth. Taken together, CMA3 induced apoptosis in CCA cells by diminishing the Sp1‑related anti‑apoptotic proteins is demonstrated. CMA3 might be useful as a chemosensitizing agent.
Ming-hon Hou - One of the best experts on this subject based on the ideXlab platform.
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The binding of the Co(II) complex of dimeric Chromomycin A3 to GC sites with flanking G:G mismatches
Journal of inorganic biochemistry, 2012Co-Authors: Yu-wen Chen, Ming-hon HouAbstract:Some neurological diseases are correlated with expansion of (CXG)n trinucleotide repeats, which contain many contiguous GpC flanked by mismatched X/X base pair. This study focused on the binding of the Co(II) complex of dimeric Chromomycin A3(Chro), CoII(Chro)2, to DNA with CXG trinucleotide repeats. The present study showed that GC sites with flanking G:G mismatches provide an excellent binding site for CoII(Chro)2 as shown by surface plasmon resonance and fluorescence analysis, compared to GC sites with flanking A:A, T:T, or C:C mismatches. In addition, we measured the ability of CoII(Chro)2 to act on the hairpin DNA of (CGG)16. We observed that CoII(Chro)2 could stabilize and trap the cruciform conformation of (CGG)16. Furthermore, two CoII(Chro)2 molecules may bind at the two GpC sites separated by at least one GC site in the hairpin structure of (CGG)16. In a synthetic self-priming DNA model, 5′-(CGG)16(CCG)6-3′, CoII(Chro)2 can interfere with the expansion process of CGG triplet repeats, as shown by a gel electrophoretic expansion assay. Here, we first report the acting of CoII(Chro)2, the groove-binding drug, to trinucleotide repeats. Our results provide the possible biological consequence of CoII(Chro)2 bound to CGG triplet repeat sequences.
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The crucial role of divalent metal ions in the DNA-acting efficacy and inhibition of the transcription of dimeric Chromomycin A3.
PloS one, 2012Co-Authors: Chun-wei Hsu, Show-mei Chuang, Ming-hon HouAbstract:Chromomycin A3 (Chro) is capable of forming a stable dimeric complex via chelation with Ni(II), Fe(II) and Co(II). According to the circular dichroism study, the dimer conformations are significantly different among the Fe(II)-, Co(II)-, and Ni(II)-containing dimeric Chro complexes; however, the dimer conformations were preserved at high temperatures. Furthermore, we conducted a systematic study to determine the effects of these divalent metal ions on the DNA-acting efficacy of dimeric Chro, including its DNA-binding affinity, DNA stabilization capacity, DNA cleavage activity, and the inhibition of transcription both in vitro and within cells. Kinetic analyses using surface plasmon resonance (SPR) showed that Ni(II)(Chro)(2) exhibited the highest K(a) with a value of 1.26 × 10(7) M(-1), which is approximately 1.6- and 3.7-fold higher than the K(a) values obtained for Co(II)(Chro)(2) and Fe(II)(Chro)(2), respectively. The T(m) and ΔG values for the DNA duplex increased after the addition of drug complexes in the following order: Ni(II)(Chro)(2)>Co(II)(Chro)(2)>Fe(II)(Chro)(2). In the DNA integrity assays, the DNA cleavage rate of Co(II)(Chro)(2) (1.2 × 10(-3) s(-1)) is higher than those of Fe(II)(Chro)(2) and Ni(II)(Chro)(2), which were calculated to be 1 × 10(-4) and 3.1 × 10(-4) s(-1), respectively. Consistent with the SPR and UV melting results, Ni(II)(Chro)(2) possesses the highest inhibitory effect on in vitro transcription and c-myc transcription within cells compared to Co(II)(Chro)(2) and Fe(II)(Chro)(2). By comparing the cytotoxicity among Co(II)(Chro)(2), Fe(II)(Chro)(2), and Ni(II)(Chro)(2) to several cancer cell lines, our studies concluded that Ni(II)(Chro)(2) displayed more potential antitumor activities than Co(II)(Chro)(2) and Fe(II)(Chro)(2) did due to its higher DNA-acting efficacy. Changes to the divalent metal ions in the dimeric Chro complexes have been correlated with improved anticancer profiles. The availability of new metal derivatives of Chro may introduce new possibilities for exploiting the unique properties of this class of compounds for therapeutic applications.
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Studies of Sequence-Specific DNA Binding, DNA Cleavage, and Topoisomerase I Inhibition by the Dimeric Chromomycin A3 Complexed with FeII†
Biochemistry, 2008Co-Authors: Ming-hon Hou, Hsin-ying Lin, Jeu-ming P. YuannAbstract:Chromomycin A3 (Chro) has been evidenced to exhibit much higher binding affinity toward FeII by forming a highly stable 2:1 drug/metal complex, compared to its structural analogue, mithramycin (Mith). Different properties of the [(Chro)2−FeII] complex acting on DNA, such as sequence specificity, DNA cleavage, and topoisomerase I (TopI) inhibition were studied. Kinetic analyses of surface plasmon resonance showed that the affinity of the [(Chro)2−FeII] complex upon binding to hairpin DNA duplexes containing various tetranucleotide sequences follows the order: GGCC > CGCG > CCGG ∼ GCGC > AGCT > ACGT > TGCA > TCGA. According to circular dichroism (CD) studies, most hairpin DNA duplexes appeared to retain their B-type conformations in the presence of the [(Chro)2−FeII] complex, except the duplex containing the GGCC sequence, which exhibited the features of both A- and B-type DNA. In DNA-cleavage assays, the [(Chro)2−FeII] complex was shown to cause single-stranded cleavage of plasmid DNA because of a Fenton-t...
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Crystal structure of the [Mg2+‐(Chromomycin A3)2]–d(TTGGCCAA)2 complex reveals GGCC binding specificity of the drug dimer chelated by a metal ion
Nucleic acids research, 2004Co-Authors: Ming-hon Hou, Howard Robinson, Yi-gui Gao, Andrew H.-j. WangAbstract:The anticancer antibiotic Chromomycin A3 (Chro) is a DNA minor groove binding drug belonging to the aureolic family. Chro likely exerts its activity by interfering with replication and transcription. Chro forms a dimer, mediated by a divalent metal ion, which binds to G/C-rich DNA. Herein we report the first crystal structure of Chro bound to d(TTG GCCAA)2 DNA duplex solved by multiwavelength anomalous diffraction (MAD) based on the chelated Co3+ ion. The structure of the Mg2+ complex was subsequently refined at 2.15 Å resolution, which revealed two complexes of metal-coordinated dimers of Chro bound to the octamer DNA duplex in the asymmetric unit. The metal ion is octahedrally coordinated to the O1 and O9 oxygen atoms of the chromophore (CPH), and two water molecules act as the fifth and sixth ligands. The two coordinated water molecules are hydrogen bonded to O2 atoms of C5 and C13 bases. The Chro dimer binds at and significantly widens the minor groove of the GGCC sequence. The long axis of each chromophore lies along and stacks over the sugar–phosphate backbone with the two attached saccharide moieties (rings A/B and C/D/E) wrapping across the minor groove. DNA is kinked by 30° and 36° in the two complexes, respectively. Six G-specific hydrogen bonds between Chro and DNA provide the GGCC sequence specificity. Interestingly, DNA in concert with Chro appears to act as an effective template to catalyze the deamination of Co(NH3)63+, as shown by circular dichroism and crystal structure data. Our results present useful structural information for designing new anticancer drug derivatives in the future.
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crystal structure of the mg2 Chromomycin A3 2 d ttggccaa 2 complex reveals ggcc binding specificity of the drug dimer chelated by a metal ion
Nucleic Acids Research, 2004Co-Authors: Ming-hon Hou, Howard Robinson, Yi-gui Gao, Andrew H.-j. WangAbstract:The anticancer antibiotic Chromomycin A3 (Chro) is a DNA minor groove binding drug belonging to the aureolic family. Chro likely exerts its activity by interfering with replication and transcription. Chro forms a dimer, mediated by a divalent metal ion, which binds to G/C-rich DNA. Herein we report the first crystal structure of Chro bound to d(TTG GCCAA)2 DNA duplex solved by multiwavelength anomalous diffraction (MAD) based on the chelated Co3+ ion. The structure of the Mg2+ complex was subsequently refined at 2.15 Å resolution, which revealed two complexes of metal-coordinated dimers of Chro bound to the octamer DNA duplex in the asymmetric unit. The metal ion is octahedrally coordinated to the O1 and O9 oxygen atoms of the chromophore (CPH), and two water molecules act as the fifth and sixth ligands. The two coordinated water molecules are hydrogen bonded to O2 atoms of C5 and C13 bases. The Chro dimer binds at and significantly widens the minor groove of the GGCC sequence. The long axis of each chromophore lies along and stacks over the sugar–phosphate backbone with the two attached saccharide moieties (rings A/B and C/D/E) wrapping across the minor groove. DNA is kinked by 30° and 36° in the two complexes, respectively. Six G-specific hydrogen bonds between Chro and DNA provide the GGCC sequence specificity. Interestingly, DNA in concert with Chro appears to act as an effective template to catalyze the deamination of Co(NH3)63+, as shown by circular dichroism and crystal structure data. Our results present useful structural information for designing new anticancer drug derivatives in the future.
Paksiree Saranaruk - One of the best experts on this subject based on the ideXlab platform.
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Chromomycin A3 suppresses cholangiocarcinoma growth by induction of S phase cell cycle arrest and suppression of Sp1‑related anti‑apoptotic proteins.
International journal of molecular medicine, 2020Co-Authors: Paksiree Saranaruk, Ryusho Kariya, Gunya Sittithumcharee, Parichart Boueroy, Thidarut Boonmars, Kanlayanee Sawanyawisuth, Chaisiri Wongkham, Sopit Wongkham, Seiji Okada, Kulthida VaeteewoottacharnAbstract:Cholangiocarcinoma (CCA) is a cancer of biliary epithelium. Late diagnosis and resistance to conventional chemotherapy are the major obstacles in CCA treatment. Increased expression of anti‑apoptotic proteins are observed in CCA, which might confer chemoresistance. Thus, modulations of anti‑apoptotic proteins leading to apoptotic induction is the focus of this study. Chromomycin A3 (CMA3), an anthraquinone glycoside‑mithramycin A analog, was selected. CMA3 strongly binds to GC‑rich regions in DNA, where specificity protein 1 (Sp1), a common transcription factor of apoptosis‑related proteins, is preferentially bounded. The effects of CMA3 on anti‑proliferation, cell cycle arrest and apoptosis induction in CCA cells were demonstrated by MTT assay, flow cytometry and western blot analysis. The results showed CMA3 suppressed cell proliferation in vitro in the nM range. At low doses, CMA3 inhibited cell cycle progression at S phase, while it promoted caspase‑dependent apoptosis at higher doses. CMA3 induced effects of apoptosis were through the suppression of Sp1‑related anti‑apoptotic proteins, FADD‑like IL‑1β‑converting enzyme‑inhibitory protein, myeloid cell leukemia‑1, X‑linked inhibitor of apoptosis protein, cellular inhibitor of apoptosis and survivin. The anti‑CCA effects of CMA3 were confirmed in the xenograft mouse model. CMA3 retarded xenograft tumor growth. Taken together, CMA3 induced apoptosis in CCA cells by diminishing the Sp1‑related anti‑apoptotic proteins is demonstrated. CMA3 might be useful as a chemosensitizing agent.
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Chromomycin A3 suppresses cholangiocarcinoma growth by induction of s phase cell cycle arrest and suppression of sp1 related anti apoptotic proteins
International Journal of Molecular Medicine, 2020Co-Authors: Paksiree Saranaruk, Ryusho Kariya, Gunya Sittithumcharee, Parichart Boueroy, Thidarut Boonmars, Kanlayanee Sawanyawisuth, Chaisiri Wongkham, Sopit Wongkham, Seiji Okada, Kulthida VaeteewoottacharnAbstract:Cholangiocarcinoma (CCA) is a cancer of biliary epithelium. Late diagnosis and resistance to conventional chemotherapy are the major obstacles in CCA treatment. Increased expression of anti‑apoptotic proteins are observed in CCA, which might confer chemoresistance. Thus, modulations of anti‑apoptotic proteins leading to apoptotic induction is the focus of this study. Chromomycin A3 (CMA3), an anthraquinone glycoside‑mithramycin A analog, was selected. CMA3 strongly binds to GC‑rich regions in DNA, where specificity protein 1 (Sp1), a common transcription factor of apoptosis‑related proteins, is preferentially bounded. The effects of CMA3 on anti‑proliferation, cell cycle arrest and apoptosis induction in CCA cells were demonstrated by MTT assay, flow cytometry and western blot analysis. The results showed CMA3 suppressed cell proliferation in vitro in the nM range. At low doses, CMA3 inhibited cell cycle progression at S phase, while it promoted caspase‑dependent apoptosis at higher doses. CMA3 induced effects of apoptosis were through the suppression of Sp1‑related anti‑apoptotic proteins, FADD‑like IL‑1β‑converting enzyme‑inhibitory protein, myeloid cell leukemia‑1, X‑linked inhibitor of apoptosis protein, cellular inhibitor of apoptosis and survivin. The anti‑CCA effects of CMA3 were confirmed in the xenograft mouse model. CMA3 retarded xenograft tumor growth. Taken together, CMA3 induced apoptosis in CCA cells by diminishing the Sp1‑related anti‑apoptotic proteins is demonstrated. CMA3 might be useful as a chemosensitizing agent.
Andrew H.-j. Wang - One of the best experts on this subject based on the ideXlab platform.
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Crystal structure of the [Mg2+‐(Chromomycin A3)2]–d(TTGGCCAA)2 complex reveals GGCC binding specificity of the drug dimer chelated by a metal ion
Nucleic acids research, 2004Co-Authors: Ming-hon Hou, Howard Robinson, Yi-gui Gao, Andrew H.-j. WangAbstract:The anticancer antibiotic Chromomycin A3 (Chro) is a DNA minor groove binding drug belonging to the aureolic family. Chro likely exerts its activity by interfering with replication and transcription. Chro forms a dimer, mediated by a divalent metal ion, which binds to G/C-rich DNA. Herein we report the first crystal structure of Chro bound to d(TTG GCCAA)2 DNA duplex solved by multiwavelength anomalous diffraction (MAD) based on the chelated Co3+ ion. The structure of the Mg2+ complex was subsequently refined at 2.15 Å resolution, which revealed two complexes of metal-coordinated dimers of Chro bound to the octamer DNA duplex in the asymmetric unit. The metal ion is octahedrally coordinated to the O1 and O9 oxygen atoms of the chromophore (CPH), and two water molecules act as the fifth and sixth ligands. The two coordinated water molecules are hydrogen bonded to O2 atoms of C5 and C13 bases. The Chro dimer binds at and significantly widens the minor groove of the GGCC sequence. The long axis of each chromophore lies along and stacks over the sugar–phosphate backbone with the two attached saccharide moieties (rings A/B and C/D/E) wrapping across the minor groove. DNA is kinked by 30° and 36° in the two complexes, respectively. Six G-specific hydrogen bonds between Chro and DNA provide the GGCC sequence specificity. Interestingly, DNA in concert with Chro appears to act as an effective template to catalyze the deamination of Co(NH3)63+, as shown by circular dichroism and crystal structure data. Our results present useful structural information for designing new anticancer drug derivatives in the future.
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crystal structure of the mg2 Chromomycin A3 2 d ttggccaa 2 complex reveals ggcc binding specificity of the drug dimer chelated by a metal ion
Nucleic Acids Research, 2004Co-Authors: Ming-hon Hou, Howard Robinson, Yi-gui Gao, Andrew H.-j. WangAbstract:The anticancer antibiotic Chromomycin A3 (Chro) is a DNA minor groove binding drug belonging to the aureolic family. Chro likely exerts its activity by interfering with replication and transcription. Chro forms a dimer, mediated by a divalent metal ion, which binds to G/C-rich DNA. Herein we report the first crystal structure of Chro bound to d(TTG GCCAA)2 DNA duplex solved by multiwavelength anomalous diffraction (MAD) based on the chelated Co3+ ion. The structure of the Mg2+ complex was subsequently refined at 2.15 Å resolution, which revealed two complexes of metal-coordinated dimers of Chro bound to the octamer DNA duplex in the asymmetric unit. The metal ion is octahedrally coordinated to the O1 and O9 oxygen atoms of the chromophore (CPH), and two water molecules act as the fifth and sixth ligands. The two coordinated water molecules are hydrogen bonded to O2 atoms of C5 and C13 bases. The Chro dimer binds at and significantly widens the minor groove of the GGCC sequence. The long axis of each chromophore lies along and stacks over the sugar–phosphate backbone with the two attached saccharide moieties (rings A/B and C/D/E) wrapping across the minor groove. DNA is kinked by 30° and 36° in the two complexes, respectively. Six G-specific hydrogen bonds between Chro and DNA provide the GGCC sequence specificity. Interestingly, DNA in concert with Chro appears to act as an effective template to catalyze the deamination of Co(NH3)63+, as shown by circular dichroism and crystal structure data. Our results present useful structural information for designing new anticancer drug derivatives in the future.