Polyfunctional action of biologically active compounds in antitumor chemotherapy of cyclophosphamide

Abstract

Combinations of the known cytostatic cyclophosphamide (cyclophosphan) with hydroxamic acids (asparagylhydroxamic and salicylhydroxamic), nitric oxide donor (sodium nitrate), and an original hybrid non steroidal anti inflammatory compound, viz., diclofenachydroxamic acid nitrate salt (DHA•HNO 3 ), were studied. The use of cyclophosphan in combination with these substances increases the efficiency of chemotherapy and elongates the life of animals with leukemia P 388. The dynamics of changes in the signal from cytochrome P 450 in the liver samples after the administration of DHA•HNO 3 to the animals was studied by ESR spectro scopy. The mechanism of the action of DHA•HNO 3 enhancing the chemotherapeutic effect of cyclophosphan was proposed.Since the nature of oncological diseases is multi fac tor, studies of combinations of known cytostatics with chemisensitizing substances acting on different molecular targets in the organism become more and more signifi cant. Among such chemisensitizers are hydroxamic acids (HAs), NO donors, and inhibitors of the initial stage of prostaglandin synthesis, namely, non steroidal anti in flammatory compounds (NSAIDs). Hydroxamic acids are well known as chelating agents of variable valence ions and have been used long ago in medicine for the treatment of a whole series of diseases. 1 These are the chelating prop erties of these compounds that are responsible for the in hibition of active centers of such metal containing en zymes as histone deacylases, which is important in cell differentiation and division. 2,3 However, the main role in the inactivation of histone deacylases is attributed 4 to the ability of hydroxamic acids to generate NO rather than to their chelating properties. This work was carried out in vitro on the cell culture of Chinese hamster, where hydrogen peroxide was added to the composition of the cultivation medium, i.e., these were oxidation conditions. We have earlier showed 5 that HAs are not efficient NO donors in biological systems where reduction conditions predomi nate but their action is mainly related to the capability of chelating metal ions, which are in the composition of met alloenzymes.It is known that the antitumor effect of cytostatics is also enhanced by nitro compounds, whose reduction leads to the formation of nitrogen monoxide in the organism. 6 The mechanism of the antitumor effect of NO remains incompletely clear. It is assumed that NO inhibits a series of proteins of the DNA reparation system 7 and controls the expression of cytochrome Р 450. 8Cyclooxygenases (COX 1 and COX 2) are also im portant molecular targets in antitumor therapy. They are two isoforms of one of the key enzymes of metabolism of arachidonic acid (prostaglandin H synthase) and partici pate in cancerogenesis. 9 It is considered that COX 1 is the constitution form of prostaglandin H synthase, while COX 2 is its inducible form. Both isoforms possess two types of activity: cyclooxygenase and peroxidase. 10

Salinomycin Hydroxamic Acids: Synthesis, Structure, and Biological Activity of Polyether Ionophore Hybrids

“…In particular, such hybrids would be well suited as probes for investigating a connection between ionophore properties and selective effects against CSCs. Despite the considerable interest in hydroxamic acids in natural product hybrids, − as siderophores, inhibitors of stat3, histone deacetylase (HDAC), , and Ras signaling, as well as isosters to carboxylic acids, no such analogues have been described for polyether ionophores. A single study by Miller on the pore forming depsipeptide daptomycin highlights two hydroxamic acid derivatives of a natural product with antiporter activity .…”