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The Fight Against Cancer
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
An example of a naturally occurring intercalating agent is doxorubicin; isolated from Streptomyces peucetius; it belongs to a group of antibiotics called anthracyclines. It has a tetracyclic ring system, where three of the rings are planar and intercalate the DNA double helix in the major groove. The charged amino group on the sugar ring forms an important ionic bond with the negatively charged phosphate groups of the DNA backbone, crucial for the drugs activity.
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Doxorubicin (see next scheme), isolated from the soil bacterium Streptomyces peucetius and structurally closely related to Daunorubicin and Epirubicin is one of the most important chemotherapeutic antitumor drugs, a cytotoxic anthracycline. Its antineoplastic activity relies on the intercalation between base pairs in the DNA helix (adducts between guanine and DOX) with the consequence of impaired DNA replication and protein synthesis. Furthermore, DOX is a topoisomerase II inhibitor; topoisomerase is involved in a variety of nuclear processes such as DNA replication, transcription, etc. Finally, DNA damage and cell death is caused by an oxidation of the quinone structure of the iron chelator DOX through a variety of NAD(P)H-oxidoreductases resulting in the generation of semiquinone radicals reacting with oxygen to superoxide and hydrogen peroxide; complexes formed between DOX and Fe catalyze the conversion of hydrogen peroxide to highly reactive hydroxyl radicals. This drug-induced release of free radicals causes oxidative stress that contributes to the toxicity of the anthracycline antibiotics (Yang et al., 2014; Agudelo et al., 2014). Increased levels of reactive oxygen species and lipid peroxidation are among others also responsible for DOX’s cardiotoxicity (Chatterjee et al., 2010, and literature cited therein).
Cardio-oncology: How a new discipline arrived
Published in Susan F. Dent, Practical Cardio-Oncology, 2019
Susan F. Dent, Nestor Gahungu, Moira Rushton-Marovac, Josee Ivars, Carlo Cipolla, Daniel J. Lenihan
Daunorubicin was the first anthracycline-based cancer therapy to be identified from the soil bacterium Streptomyces peucetius in the 1950s (12). Since this discovery, several other anthracycline drugs have been discovered and found to be effective as chemotherapeutic agents (13,14).
LncRNA-IQCH-AS1 sensitizes thyroid cancer cells to doxorubicin via modulating the miR-196a-5p/PPP2R1B signalling pathway
Published in Journal of Chemotherapy, 2023
Thyroid cancer, which is located within the thyroid gland, is a prevalent human endocrine tumour, associating with poor diagnosis and survival rates in worldwide especially for the advanced and aggressive thyroid cancer [1]. Currently, surgery and radioiodine therapy (I-131 therapy) are the primarily therapeutic approaches for thyroid cancer [2]. In addition, chemotherapy with the combination of radiation therapy has been applied for anaplastic thyroid cancer [3]. Doxorubicin, which is an antibiotic derived from the Streptomyces peucetius bacterium, has been widely applied as an anti-cancer agent [4]. Doxorubicin functions through inhibiting the enzyme topoisomerase II to intercalate within DNA base pairs, leading to DNA strands breaking to inhibit both DNA and RNA synthesis [4,5]. Although doxorubicin has achieved improved survival rate for thyroid cancer patients, a large fraction of patients was aggravated by adverse effects and developed doxorubicin resistance, arising a severe challenge for its widely applications [6]. Thus, understanding the underlying molecular mechanisms and specific biotargets of the acquired doxorubicin resistance is an urgent task.
Development of stimuli-responsive intelligent polymer micelles for the delivery of doxorubicin
Published in Journal of Drug Targeting, 2020
Fan Yang, Jiangkang Xu, Manfei Fu, Jianbo Ji, Liqun Chi, Guangxi Zhai
Cancer still remains one of the most severe threats to the human health in the 21st first century. Nowadays, a range of treatment protocols has been developed in clinic, including surgery, chemotherapy, and radiotherapy. Chemotherapy, with many irreplaceable advantages, had become one of the most effective therapeutic strategies for cancer treatment in nowadays [1,2]. Doxorubicin (DOX), which found in the bacteria Streptomyces peucetius, is one of the most important antitumor compounds in chemotherapeutic fields. Then it was widely used in several cancers therapeutic, including breast cancer, acute lymphocytic leukaemia, bladder cancer, prostate cancer, non-small cell lung cancer and thyroid cancer in the clinic [3–6]. However, the cardiotoxicity of DOX is the main reason for its limitation in clinical application. In other words, the effective treatment of DOX often requires a high dose, which may further aggravate adverse toxic side effects to some extent because of the poor drug selectivity [7].
Development and evaluation of doxorubicin self nanoemulsifying drug delivery system with Nigella Sativa oil against human hepatocellular carcinoma
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Afreen Usmani, Anuradha Mishra, Md Arshad, Asif Jafri
Four decades ago, doxorubicin renowned as early anthracyclines was isolated from Streptomyces peucetius and it is one of the effective drugs for cancer chemotherapy. According to reports, doxorubicin follows seven different mechanisms of producing cellular dysfunction or death [4]. It is commonly believed that the anticancer activities of doxorubicin on cancer cells are associated with nucleotide base intercalation. The DOX molecule stabilizes the topoisomerase II enzyme and breaks the DNA chain for copying, stopping the DNA double helix from resealing and, therefore, prevents the progression of replication [5]. Crystallographic information recommends that the planar tetracyclic fraction of the molecule intercalates among two base pairs of the DNA, whereas the amino sugar sites within the minor groove and interacts with flanking base pairs instantly adjacent to the intercalation site. Furthermore, the tumor-suppressor protein p53 is responsible for many forms of genotoxic agent-induced apoptosis [6]. Doxorubicin-induced programmed cell death could lead to therapeutic effects and toxicities [4]. In spite of the good efficacy of doxorubicin, cardiotoxicity is the serious side effect following treatment. In addition, anthracyclines are likely to cause alopecia and myelosuppression and oral ulcerations [7].