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Sub-cellular Biochemistry 2007Chemotherapy has been a major approach to treat cancer. Both constituents of chromatin, chromosomal DNA and the associated chromosomal histone proteins are the molecular... (Review)
Review
Chemotherapy has been a major approach to treat cancer. Both constituents of chromatin, chromosomal DNA and the associated chromosomal histone proteins are the molecular targets of the anticancer drugs. Small DNA binding ligands, which inhibit enzymatic processes with DNA substrate, are well known in cancer chemotherapy. These drugs inhibit the polymerase and topoisomerase activity. With the advent in the knowledge of chromatin chemistry and biology, attempts have shifted from studies of the structural basis of the association of these drugs or small ligands (with the potential of drugs) with DNA to their association with chromatin and nucleosome. These drugs often inhibit the expression of specific genes leading to a series of biochemical events. An overview will be given about the latest understanding of the molecular basis of their action. We shall restrict to those drugs, synthetic or natural, whose prime cellular targets are so far known to be chromosomal DNA.
Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Chromatin; Chromatin Assembly and Disassembly; Cross-Linking Reagents; Crystallography; DNA; DNA Adducts; DNA Methylation; DNA Modification Methylases; DNA, Cruciform; Enzyme Inhibitors; Epigenesis, Genetic; G-Quadruplexes; Gene Expression Regulation, Neoplastic; Humans; Intercalating Agents; Molecular Structure; Nucleic Acid Conformation; Nucleic Acid Synthesis Inhibitors; Thermodynamics; Topoisomerase Inhibitors
PubMed: 17484128
DOI: 10.1007/1-4020-5466-1_8 -
Nucleic Acids Research Apr 2020Alkylation is one of the most ubiquitous forms of DNA lesions. However, the motif preferences and substrates for the activity of the major types of alkylating agents...
Alkylation is one of the most ubiquitous forms of DNA lesions. However, the motif preferences and substrates for the activity of the major types of alkylating agents defined by their nucleophilic substitution reactions (SN1 and SN2) are still unclear. Utilizing yeast strains engineered for large-scale production of single-stranded DNA (ssDNA), we probed the substrate specificity, mutation spectra and signatures associated with DNA alkylating agents. We determined that SN1-type agents preferably mutagenize double-stranded DNA (dsDNA), and the mutation signature characteristic of the activity of SN1-type agents was conserved across yeast, mice and human cancers. Conversely, SN2-type agents preferably mutagenize ssDNA in yeast. Moreover, the spectra and signatures derived from yeast were detectable in lung cancers, head and neck cancers and tumors from patients exposed to SN2-type alkylating chemicals. The estimates of mutation loads associated with the SN2-type alkylation signature were higher in lung tumors from smokers than never-smokers, pointing toward the mutagenic activity of the SN2-type alkylating carcinogens in cigarettes. In summary, our analysis of mutations in yeast strains treated with alkylating agents, as well as in whole-exome and whole-genome-sequenced tumors identified signatures highly specific to alkylation mutagenesis and indicate the pervasive nature of alkylation-induced mutagenesis in cancers.
Topics: Adenine; Alkylating Agents; Animals; DNA Glycosylases; DNA, Fungal; DNA, Single-Stranded; Humans; Mice; Mutagenesis; Mutation; Neoplasms; Yeasts
PubMed: 32133535
DOI: 10.1093/nar/gkaa150 -
Cells Oct 2022The tumor suppressor PTEN mainly inhibits the PI3K/Akt pathway in the cytoplasm and maintains DNA stability in the nucleus. The status of PTEN remains therapeutic...
The tumor suppressor PTEN mainly inhibits the PI3K/Akt pathway in the cytoplasm and maintains DNA stability in the nucleus. The status of PTEN remains therapeutic effectiveness for chemoresistance of the DNA alkylating agent temozolomide (TMZ) in glioblastoma (GB). However, the underlying mechanisms of PTEN's interconnected role in the cytoplasm and nucleus in TMZ resistance are still unclear. In this study, we report that TMZ-induced PTEN nuclear import depends on PTEN ubiquitylation modification by Smurf1. The Smurf1 suppression decreases the TMZ-induced PTEN nuclear translocation and enhances the DNA damage. In addition, Smurf1 degrades cytoplasmic PTEN K289E (the nuclear-import-deficient PTEN mutant) to activate the PI3K/Akt pathway under TMZ treatment. Altogether, Smurf1 interconnectedly promotes PTEN nuclear function (DNA repair) and cytoplasmic function (activation of PI3K/Akt pathway) to resist TMZ. These results provide a proof-of-concept demonstration for a potential strategy to overcome the TMZ resistance in PTEN wild-type GB patients by targeting Smurf1.
Topics: Humans; Temozolomide; Glioblastoma; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Cell Line, Tumor; Drug Resistance, Neoplasm; Alkylating Agents; PTEN Phosphohydrolase; Ubiquitin-Protein Ligases
PubMed: 36291166
DOI: 10.3390/cells11203302 -
Redox Biology May 2022Overproduction of reactive oxygen species (ROS) drives inflammation and mutagenesis. However, the role of the DNA damage response in immune responses remains largely...
Overproduction of reactive oxygen species (ROS) drives inflammation and mutagenesis. However, the role of the DNA damage response in immune responses remains largely unknown. Here we found that stabilization of the mismatch repair (MMR) protein MSH6 in response to alkylation damage requires interactions with the molybdopterin synthase associating complex (MPTAC) and Ada2a-containing histone acetyltransferase complex (ATAC). Furthermore, MSH6 promotes sterol biosynthesis via the mevalonate pathway in a MPTAC- and ATAC-dependent manner. MPTAC reduces the source of alkylating agents (ROS). Therefore, the association between MMR proteins, MPTAC, and ATAC promotes anti-inflammation response and reduces alkylating agents. The inflammatory responses measured by xanthine oxidase activity are elevated in Lymphoblastoid Cell Lines (LCLs) from some Fragile X-associated disorders (FXD) patients, suggesting that alkylating agents are increased in these FXD patients. However, MPTAC is disrupted in LCLs from some FXD patients. In LCLs from other FXD patients, interaction between MSH6 and ATAC was lost, destabilizing MSH6. Thus, impairment of MPTAC and ATAC may cause alkylation damage resistance in some FXD patients.
Topics: Alkylating Agents; Alkylation; DNA Damage; DNA Repair; DNA-Binding Proteins; Humans; Reactive Oxygen Species; Sterols
PubMed: 35189552
DOI: 10.1016/j.redox.2022.102270 -
Bulletin Du Cancer Feb 1999
Review
Topics: Animals; Antineoplastic Agents, Alkylating; Clinical Trials, Phase I as Topic; DNA, Neoplasm; Dioxoles; Humans; Isoquinolines; Tetrahydroisoquinolines; Trabectedin; Tumor Cells, Cultured
PubMed: 10094523
DOI: No ID Found -
Bioorganic & Medicinal Chemistry Sep 2014Introducing novel building blocks to solid-phase peptide synthesis, we readily synthesized long-chain hairpin pyrrole-imidazole (PI) polyamide-chlorambucil conjugates 3...
Sequence-specific DNA alkylation and transcriptional inhibition by long-chain hairpin pyrrole-imidazole polyamide-chlorambucil conjugates targeting CAG/CTG trinucleotide repeats.
Introducing novel building blocks to solid-phase peptide synthesis, we readily synthesized long-chain hairpin pyrrole-imidazole (PI) polyamide-chlorambucil conjugates 3 and 4 via the introduction of an amino group into a GABA (γ-turn) contained in 3, to target CAG/CTG repeat sequences, which are associated with various hereditary disorders. A high-resolution denaturing polyacrylamide sequencing gel revealed sequence-specific alkylation both strands at the N3 of adenines or guanines in CAG/CTG repeats by conjugates 3 and 4, with 11bp recognition. In vitro transcription assays using conjugate 4 revealed that specific alkylation inhibited the progression of RNA polymerase at the alkylating sites. Chiral substitution of the γ-turn with an amino group resulted in higher binding affinity observed in SPR assays. These assays suggest that conjugates 4 with 11bp recognition has the potential to cause specific DNA damage and transcriptional inhibition at the alkylating sites.
Topics: Alkylation; Chlorambucil; DNA; Imidazoles; Nylons; Pyrroles; Structure-Activity Relationship; Transcription, Genetic; Trinucleotide Repeats
PubMed: 25127467
DOI: 10.1016/j.bmc.2014.07.019 -
Neuroendocrinology 2015Alkylating agents, such as streptozocin and dacarbazine, have been reported as active in neuroendocrine neoplasms (NENs). Temozolomide (TMZ) is an oral, potentially less... (Review)
Review
Alkylating agents, such as streptozocin and dacarbazine, have been reported as active in neuroendocrine neoplasms (NENs). Temozolomide (TMZ) is an oral, potentially less toxic derivative of dacarbazine, which has shown activity both as a single agent and in combination with other drugs. Nevertheless, its role in NENs has not been well defined. Several retrospective and prospective phase I-II studies have been published describing its use in a variety of NENs. In a retrospective series, the combination of capecitabine and TMZ was reported to be associated with a particularly high tumour response in pancreatic NENs as a first-line treatment. Although in NENs, determination of the O6-methylguanine-DNA methyltransferase (MGMT) status has been suggested as a predictive biomarker of response, its role still remains investigational, awaiting validation along with the establishment of the optimal detection method. Metronomic schedules have been reported to potentially overcome MGMT-related drug resistance. Toxicity is manageable if well monitored. We reviewed the literature regarding pharmacological and clinical aspects of TMZ, focusing on specific settings of NENs, different schedules, toxicity and safety profiles, and potential predictive biomarkers of response.
Topics: Antineoplastic Agents, Alkylating; Dacarbazine; Humans; Neuroendocrine Tumors; Temozolomide
PubMed: 25924937
DOI: 10.1159/000430816 -
MBio Apr 2022Unique DNA repair enzymes that provide self-resistance against therapeutically important, genotoxic natural products have been discovered in bacterial biosynthetic gene...
Unique DNA repair enzymes that provide self-resistance against therapeutically important, genotoxic natural products have been discovered in bacterial biosynthetic gene clusters (BGCs). Among these, the DNA glycosylase AlkZ is essential for azinomycin B production and belongs to the HTH_42 superfamily of uncharacterized proteins. Despite their widespread existence in antibiotic producers and pathogens, the roles of these proteins in production of other natural products are unknown. Here, we determine the evolutionary relationship and genomic distribution of all HTH_42 proteins from and use a resistance-based genome mining approach to identify homologs associated with known and uncharacterized BGCs. We find that AlkZ-like (AZL) proteins constitute one distinct HTH_42 subfamily and are highly enriched in BGCs and variable in sequence, suggesting each has evolved to protect against a specific secondary metabolite. As a validation of the approach, we show that the AZL protein, HedH4, associated with biosynthesis of the alkylating agent hedamycin, excises hedamycin-DNA adducts with exquisite specificity and provides resistance to the natural product in cells. We also identify a second, phylogenetically and functionally distinct subfamily whose proteins are never associated with BGCs, are highly conserved with respect to sequence and genomic neighborhood, and repair DNA lesions not associated with a particular natural product. This work delineates two related families of DNA repair enzymes-one specific for complex alkyl-DNA lesions and involved in self-resistance to antimicrobials and the other likely involved in protection against an array of genotoxins-and provides a framework for targeted discovery of new genotoxic compounds with therapeutic potential. Bacteria are rich sources of secondary metabolites that include DNA-damaging genotoxins with antitumor/antibiotic properties. Although produce a diverse number of therapeutic genotoxins, efforts toward targeted discovery of biosynthetic gene clusters (BGCs) producing DNA-damaging agents is lacking. Moreover, work on toxin-resistance genes has lagged behind our understanding of those involved in natural product synthesis. Here, we identified over 70 uncharacterized BGCs producing potentially novel genotoxins through resistance-based genome mining using the azinomycin B-resistance DNA glycosylase AlkZ. We validate our analysis by characterizing the enzymatic activity and cellular resistance of one AlkZ ortholog in the BGC of hedamycin, a potent DNA alkylating agent. Moreover, we uncover a second, phylogenetically distinct family of proteins related to Escherichia coli YcaQ, a DNA glycosylase capable of unhooking interstrand DNA cross-links, which differs from the AlkZ-like family in sequence, genomic location, proximity to BGCs, and substrate specificity. This work defines two families of DNA glycosylase for specialized repair of complex genotoxic natural products and generalized repair of a broad range of alkyl-DNA adducts and provides a framework for targeted discovery of new compounds with therapeutic potential.
Topics: Alkylating Agents; Anti-Bacterial Agents; Biological Products; DNA; DNA Adducts; DNA Glycosylases; Mutagens; Streptomyces
PubMed: 35311535
DOI: 10.1128/mbio.03297-21 -
Genes Jun 2023The inhibition of histone deacetylases (HDACs) holds promise as a potential anti-cancer therapy as histone and non-histone protein acetylation is frequently disrupted in...
The inhibition of histone deacetylases (HDACs) holds promise as a potential anti-cancer therapy as histone and non-histone protein acetylation is frequently disrupted in cancer, leading to cancer initiation and progression. Additionally, the use of a histone deacetylase inhibitor (HDACi) such as the class I HDAC inhibitor-valproic acid (VPA) has been shown to enhance the effectiveness of DNA-damaging factors, such as cisplatin or radiation. In this study, we found that the use of VPA in combination with talazoparib (BMN-673-PARP1 inhibitor-PARPi) and/or Dacarbazine (DTIC-alkylating agent) resulted in an increased rate of DNA double strand breaks (DSBs) and reduced survival (while not affecting primary melanocytes) and the proliferation of melanoma cells. Furthermore, the pharmacological inhibition of class I HDACs sensitizes melanoma cells to apoptosis following exposure to DTIC and BMN-673. In addition, the inhibition of HDACs causes the sensitization of melanoma cells to DTIV and BMN-673 in melanoma xenografts in vivo. At the mRNA and protein level, the histone deacetylase inhibitor downregulated RAD51 and FANCD2. This study aims to demonstrate that combining an HDACi, alkylating agent and PARPi could potentially enhance the treatment of melanoma, which is commonly recognized as being among the most aggressive malignant tumors. The findings presented here point to a scenario in which HDACs, via enhancing the HR-dependent repair of DSBs created during the processing of DNA lesions, are essential nodes in the resistance of malignant melanoma cells to methylating agent-based therapies.
Topics: Humans; Histone Deacetylase Inhibitors; Valproic Acid; Poly(ADP-ribose) Polymerase Inhibitors; Dacarbazine; Histone Deacetylases; Antineoplastic Agents; Melanoma; DNA; Alkylating Agents
PubMed: 37372475
DOI: 10.3390/genes14061295 -
Proceedings of the National Academy of... Apr 1995Key studies defining the DNA alkylation properties and selectivity of a new class of exceptionally potent, naturally occurring antitumor antibiotics including CC-1065,... (Comparative Study)
Comparative Study Review
Key studies defining the DNA alkylation properties and selectivity of a new class of exceptionally potent, naturally occurring antitumor antibiotics including CC-1065, duocarmycin A, and duocarmycin SA are reviewed. Recent studies conducted with synthetic agents containing deep-seated structural changes and the unnatural enantiomers of the natural products and related analogs have defined the structural basis for the sequence-selective alkylation of duplex DNA and fundamental relationships between chemical structure, functional reactivity, and biological properties. The agents undergo a reversible, stereoelectronically controlled adenine-N3 addition to the least substituted carbon of the activated cyclopropane within selected AT-rich sites. The preferential AT-rich non-covalent binding selectivity of the agents within the narrower, deeper AT-rich minor groove and the steric accessibility to the alkylation site that accompanies deep AT-rich minor groove penetration control the sequence-selective DNA alkylation reaction and stabilize the resulting adduct. For the agents that possess sufficient reactivity to alkylate DNA, a direct relationship between chemical or functional stability and biological potency has been defined.
Topics: Alkylating Agents; Antibiotics, Antineoplastic; Base Sequence; Binding Sites; Consensus Sequence; DNA; Duocarmycins; Indoles; Leucomycins; Models, Molecular; Molecular Sequence Data; Molecular Structure; Nucleic Acid Conformation; Pyrroles; Structure-Activity Relationship
PubMed: 7731958
DOI: 10.1073/pnas.92.9.3642