Biomaterial Database

Anthracyclines as Topoisomerase II Poisons: From Early Studies to New Perspectives. 2018

Jessica Marinello, and Maria Delcuratolo, and Giovanni Capranico

Department of Pharmacy and Biotechnology, University of Bologna, via Selmi 3, 40126 Bologna, Italy. jessica.marinello@unibo.it.

Mammalian DNA topoisomerases II are targets of anticancer anthracyclines that act by stabilizing enzyme-DNA complexes wherein DNA strands are cut and covalently linked to the protein. This molecular mechanism is the molecular basis of anthracycline anticancer activity as well as the toxic effects such as cardiomyopathy and induction of secondary cancers. Even though anthracyclines have been used in the clinic for more than 50 years for solid and blood cancers, the search of breakthrough analogs has substantially failed. The recent developments of personalized medicine, availability of individual genomic information, and immune therapy are expected to change significantly human cancer therapy. Here, we discuss the knowledge of anthracyclines as Topoisomerase II poisons, their molecular and cellular effects and toxicity along with current efforts to improve the therapeutic index. Then, we discuss the contribution of the immune system in the anticancer activity of anthracyclines, and the need to increase our knowledge of molecular mechanisms connecting the drug targets to the immune stimulatory pathways in cancer cells. We propose that the complete definition of the molecular interaction of anthracyclines with the immune system may open up more effective and safer ways to treat patients with these drugs.

UI	MeSH Term	Description	Entries
D007107	Immune System	The body's defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components.	Immune Systems,System, Immune,Systems, Immune
D009369	Neoplasms	New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.	Benign Neoplasm,Cancer,Malignant Neoplasm,Tumor,Tumors,Benign Neoplasms,Malignancy,Malignant Neoplasms,Neoplasia,Neoplasm,Neoplasms, Benign,Cancers,Malignancies,Neoplasias,Neoplasm, Benign,Neoplasm, Malignant,Neoplasms, Malignant
D004249	DNA Damage	Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS.	DNA Injury,DNA Lesion,DNA Lesions,Genotoxic Stress,Stress, Genotoxic,Injury, DNA,DNA Injuries
D004250	DNA Topoisomerases, Type II	DNA TOPOISOMERASES that catalyze ATP-dependent breakage of both strands of DNA, passage of the unbroken strands through the breaks, and rejoining of the broken strands. These enzymes bring about relaxation of the supercoiled DNA and resolution of a knotted circular DNA duplex.	DNA Topoisomerase (ATP-Hydrolysing),DNA Topoisomerase II,DNA Topoisomerase II alpha,DNA Topoisomerase II beta,DNA Type 2 Topoisomerase,TOP2A Protein,TOP2B Protein,Topoisomerase II,Topoisomerase II alpha,Topoisomerase II beta,Type II DNA Topoisomerase,alpha, Topoisomerase II,beta, Topoisomerase II
D004789	Enzyme Activation	Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme.	Activation, Enzyme,Activations, Enzyme,Enzyme Activations
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D000970	Antineoplastic Agents	Substances that inhibit or prevent the proliferation of NEOPLASMS.	Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D016609	Neoplasms, Second Primary	Abnormal growths of tissue that follow a previous neoplasm but are not metastases of the latter. The second neoplasm may have the same or different histological type and can occur in the same or different organs as the previous neoplasm but in all cases arises from an independent oncogenic event. The development of the second neoplasm may or may not be related to the treatment for the previous neoplasm since genetic risk or predisposing factors may actually be the cause.	Neoplasms, Metachronous,Neoplasms, Metachronous Second Primary,Neoplasms, Therapy-Related,Neoplasms, Treatment-Related,Second Malignancy,Second Neoplasm,Second Primary Neoplasms,Therapy-Associated Neoplasms,Therapy-Related Cancer,Treatment-Associated Neoplasms,Treatment-Related Cancer,Cancer, Second Primary,Metachronous Neoplasms,Metachronous Second Primary Neoplasms,Neoplasms, Therapy-Associated,Neoplasms, Treatment-Associated,Second Cancer,Second Primary Neoplasms, Metachronous,Therapy-Associated Cancer,Therapy-Related Neoplasms,Treatment-Associated Cancer,Treatment-Related Neoplasms,Cancer, Second,Cancer, Therapy-Associated,Cancer, Therapy-Related,Cancer, Treatment-Associated,Cancer, Treatment-Related,Cancers, Second,Cancers, Second Primary,Cancers, Therapy-Associated,Cancers, Therapy-Related,Cancers, Treatment-Associated,Cancers, Treatment-Related,Malignancies, Second,Malignancy, Second,Metachronous Neoplasm,Neoplasm, Metachronous,Neoplasm, Second,Neoplasm, Second Primary,Neoplasm, Therapy-Associated,Neoplasm, Therapy-Related,Neoplasm, Treatment-Associated,Neoplasm, Treatment-Related,Neoplasms, Second,Neoplasms, Therapy Associated,Neoplasms, Therapy Related,Neoplasms, Treatment Associated,Neoplasms, Treatment Related,Second Cancers,Second Malignancies,Second Neoplasms,Second Primary Cancer,Second Primary Cancers,Second Primary Neoplasm,Therapy Associated Cancer,Therapy Associated Neoplasms,Therapy Related Cancer,Therapy Related Neoplasms,Therapy-Associated Cancers,Therapy-Associated Neoplasm,Therapy-Related Cancers,Therapy-Related Neoplasm,Treatment Associated Cancer,Treatment Associated Neoplasms,Treatment Related Cancer,Treatment Related Neoplasms,Treatment-Associated Cancers,Treatment-Associated Neoplasm,Treatment-Related Cancers,Treatment-Related Neoplasm
D016923	Cell Death	The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability.	Death, Cell