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Microalgae and Cyanobacteria as a Potential Source of Anticancer Compounds
Published in Gokare A. Ravishankar, Ranga Rao Ambati, Handbook of Algal Technologies and Phytochemicals, 2019
Several studies on the anticancer activity of ATX have been reported. For instance, Karimian et al. (2017) showed that ATX decreased the viability of T-47D and MDA-MB-231 cell lines by inducing apoptosis. In another study, Yan et al. (2017) showed that ATX was able to resensitize gemcitabine-resistant human pancreatic cancer cells (GR-HPCCs) to gemcitabine. The mechanism involved was via up-regulation of human equilibrative nucleoside transporter 1 (hENT1) and down-regulation of ribonucleoside diphosphate reductase (RRM) 1 and 2 to enhance gemcitabine-induced cell death in GR-HPCCs treated with the drug. In addition, cotreatment with ATX and gemcitabine in a tumor xenograft mouse model induced by GR-HPCCs supported the results from the in vitro study. The findings highlighted the potential use of ATX as a combination chemotherapy agent with gemcitabine in the treatment of human pancreatic cancer.
Synergistic Combinations of Hyperthermia and Inhibitors of Nucleic Acids and Protein Synthesis
Published in Leopold J. Anghileri, Jacques Robert, Hyperthermia In Cancer Treatment, 2019
Inosine and its analogues undergo phosphorolysis by the enzyme purine nucleoside Phosphorylase. The liberated bases may then be converted to the corresponding nucleotide by hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Similarly, 2′-deoxyinosine and related analogues may react with purine nucleoside Phosphorylase, the product of which (a purine base or analogue) is then converted to the corresponding ribonucleoside 5′-monophosphate. 6-Mercaptopurine (6-MP, see Figure 4) is an excellent substrate for HGPRT, resulting in the formation of 6-thioinosine-5-phosphate (T-IMP) which accumulates within the cell. This may then lead to the inhibition of several vital metabolic processes, e.g., the conversion of inosinate (IMP) to adenylosuccinate (AMPS) and then to adenosine-5′-phosphate (AMP) as well as the oxidation of IMP to xanthylate (XMP) by inosinate dehydrogenase. In addition, T-IMP may result in “pseudo-feedback inhibition” of the first committed step in the de novo pathway of purine biosynthesis. In view of these various effects, it can be appreciated that the accumulation of T-IMP (and analogues of various purine nucleotides) can cause severe metabolic disruptions and may lead to cell death.
Small-molecule CD73 inhibitors for the immunotherapy of cancer: a patent and literature review (2017–present)
Published in Expert Opinion on Therapeutic Patents, 2021
Alessio Nocentini, Clemente Capasso, Claudiu T. Supuran
e5NTs can also hydrolyze 5´-dinucleotide, 5´-trinucleotides, and complex nucleotides, such as uridine diphosphate glucose (UDP-glucose) as well as flavin adenine dinucleotide (FAD) [2]. e5NTs are ubiquitous metalloenzymes in nature, being widespread in both the animal and plant kingdoms, including microorganisms, and they use Mg2+ or Zn2+ as a cofactor in their catalysis, or more precisely a dinuclear metal center which is crucial for phosphate esters hydrolysis (see later in the text). Animal 5ʹ-nucleotidases are distinguished into two classes, the cytosolic and extracellular membrane-bound (ecto-5´-nucleotidase) forms, which are structurally unrelated to each other [3]. The cytosolic 5ʹ-nucleotidases are enzymes with a pivotal role in nucleotide metabolism [1,2]. The nucleosides produced by the activity of 5´-nucleotidases became the substrates of nucleoside phosphorylases in animals, some bacteria, and parasitic protozoa [1]. Depending on the organism, nucleoside phosphorylases and nucleoside hydrolases generate nucleobases, which are converted to nucleotides via phosphoribosylation [4]. It has been demonstrated that 5´-nucleotidase activity is regulated by the cellular content of the nucleotides and nucleosides, which depends on the phosphorylation (nucleoside kinase), and dephosphorylation (5´-nucleotides) activities, the two opposite reactions of the ribonucleoside–ribonucleotide cycle [4,5]. The ecto-5´-nucleotidase, the membrane-bound enzyme, is mainly involved in the formation of adenosine through the extracellular AMP hydrolysis (Figure 1), but also in cell–matrix and cell–cell interactions, as well as transmembrane signaling [2].
Clinical development of retroviral replicating vector Toca 511 for gene therapy of cancer
Published in Expert Opinion on Biological Therapy, 2021
Sara A. Collins, Ashish H. Shah, Derek Ostertag, Noriyuki Kasahara, Douglas J. Jolly
RRV can also be used to deliver various other prodrug activator enzymes, most of which were originally developed for use in conventional non-replicating vectors. Since RRV retain their full-length retroviral genome, additional insertion of transgene cassettes up to ~1.3 kb in size can be readily accommodated. However, larger transgenes incur genomic instability and are rapidly deleted upon serial passage of the virus. Within this size limitation, other prodrug activator genes that have shown promising results with RRV delivery in preclinical cancer models include: Herpes simplex virus thymidine kinase (HSV-TK), which converts anti-herpetic prodrugs such as ganciclovir or valacyclovir into nucleotide analog antimetabolites by phosphorylation [50,70]. However, these phosphorylated nucleotide analogs are hydrophilic and do not diffuse freely across cell membranes, and hence require intercellular gap junctions to exert an efficient bystander effect.E. coli purine nucleoside phosphorylase (PNP), which converts ribonucleoside prodrugs such as 6-methylpurine deoxyriboside or fludarabine phosphate to purine base analog antimetabolites such as 6-methylpurine and 2-fluoroadenine, respectively [33,37]; these free base compounds are highly hydrophobic and can readily diffuse across cell membranes. However, intestinal bacteria can also catalyze prodrug conversion and the prodrugs themselves exhibit some toxicity.E. coli nitroreductase (NTR), which converts prodrugs such as the dinitrobenzamide CB1954 ((5-(aziridin-1-yl)-2,4-dinitro-benzamide) into a potent alkylating agent causing DNA adducts and crosslinks [71]. This results in very rapid cell killing, but there is also prodrug conversion by intestinal bacteria.