Comparison of Antitumor Effects of Combined and Separate Treatment with NO Synthase Inhibitor T1023 and PDK1 Inhibitor Dichloroacetate

Филимонова, М. В.; Podosinnikova, T S; Samsonova, A. S.; Макарчук, В. М.; Шевченко, Л. И.; Filimonov, Alexander

doi:10.1007/s10517-019-04655-1

Cited by 3 publications

(3 citation statements)

References 3 publications

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“…Moreover, BX795 synergizes with cisplatin to markedly reduce the epithelial-mesenchymal transition (EMT) in oral squamous cell carcinoma [ 240 ]. Dichloroacetat synergizes with the nitric oxide synthase (NOS) inhibitor T1023, reducing tumor growth [ 241 ]. It has been illustrated that PHT-427, a dual inhibitor of AKT and PDK1, exhibits promising inhibitory effects in various tumors by binding the PH domains of AKT and PDK1 [ 242 ].…”

Section: Inhibitors Targeting S6ks For Cancer Therapiesmentioning

confidence: 99%

Beyond controlling cell size: functional analyses of S6K in tumorigenesis

Xie

et al. 2022

Cell Death Dis

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As a substrate and major effector of the mammalian target of rapamycin complex 1 (mTORC1), the biological functions of ribosomal protein S6 kinase (S6K) have been canonically assigned for cell size control by facilitating mRNA transcription, splicing, and protein synthesis. However, accumulating evidence implies that diverse stimuli and upstream regulators modulate S6K kinase activity, leading to the activation of a plethora of downstream substrates for distinct pathobiological functions. Beyond controlling cell size, S6K simultaneously plays crucial roles in directing cell apoptosis, metabolism, and feedback regulation of its upstream signals. Thus, we comprehensively summarize the emerging upstream regulators, downstream substrates, mouse models, clinical relevance, and candidate inhibitors for S6K and shed light on S6K as a potential therapeutic target for cancers.

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Section: Inhibitors Targeting S6ks For Cancer Therapiesmentioning

confidence: 99%

Beyond controlling cell size: functional analyses of S6K in tumorigenesis

Xie

et al. 2022

Cell Death Dis

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“…We have assessed the combined use of T1023 and DCA (in the form of sodium salt—Na-DCA) in the model of solid Ehrlich carcinoma (SEC) in mice [ 21 , 22 ]. It was found that the combined use of T1023 (daily, i.p., 60 mg/kg) and Na-DCA (every other day, i.g., 162 mg/kg) causes a synergistic antitumor effect at different stages of SEC development, in comparison with their separate application.…”

Section: Introductionmentioning

confidence: 99%

Combination of NOS- and PDK-Inhibitory Activity: Possible Way to Enhance Antitumor Effects

Филимонова

Shitova

Soldatova

et al. 2022

IJMS

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We have previously demonstrated a high antitumor potential of NOS inhibitor T1023 (1-isobutanoyl-2-isopropylisothiourea hydrobromide): antitumor antiangiogenic activity in several animal tumor models and its ability to synergistically enhance the antitumor effects of bevacizumab, cyclophosphamide and γ-radiation. At the same time, rather rapid adaptation of experimental neoplasias to T1023 treatment was often observed. We attempted to enhance the antitumor activity of this NOS inhibitor by supplementing its molecular structure with a PDK-inhibiting fragment, dichloroacetate (DCA), which is capable of hypoxia-oriented toxic effects. We synthesized compound T1084 (1-isobutanoyl-2-isopropylisothiourea dichloroacetate). Its toxic properties, NOS-inhibiting and PDK-inhibiting activity in vivo, and antitumor activity on the mouse Ehrlich carcinoma model (SEC) were investigated in compare with T1023 and Na-DCA. We found that the change of the salt-forming acid from HBr to DCA does not increase the toxicity of 1-isobutanoyl-2-isopropylisothiourea salts, but significantly expands the biochemical and anti-tumor activity. New compound T1084 realizes in vivo NOS-inhibiting and PDK-inhibiting activity, quantitatively, at the level of the previous compounds, T1023 and Na-DCA. In two independent experiments on SEC model, a pronounced synergistic antitumor effect of T1084 was observed in compare with T1023 and Na-DCA at equimolar doses. There were no signs of SEC adaptation to T1084 treatment, while experimental neoplasia rapidly desensitized to the separate treatment of both T1023 and Na-DCA. The totality of the data obtained indicates that the combination of antiangiogenic and hypoxia-oriented toxic effects (in this case, within the molecular structure of the active substance) can increase the antitumor effect and suppress the development of hypoxic resistance of neoplasias. In general, the proposed approach can be used for the design of new anticancer agents.

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“…So, some time ago, while screening linear and cyclic isothioureas, we identified and synthesized a large group of isothiourea derivatives (Figure 1A) that are competitive inhibitors of NOS (Proskuryakov et al, 2002(Proskuryakov et al, , 2005Proskuryakov et al, 2010;Filimonova et al, 2012a). Further, we found that some compounds of this group (such as T1023, T1082, T1084) are promising for further pharmacological development-as hypoxic radioprotectors that provide effective prevention of hematopoietic and gastrointestinal acute radiation syndromes, and radiotherapy complications (Filimonova et al, 2020b(Filimonova et al, , 2021(Filimonova et al, , 2022bSaburova et al, 2020), as well as antitumor, antiangiogenic agents (Filimonova et al, 2019a;2019b;2022a).…”

Section: Introductionmentioning

confidence: 99%

Preclinical studies of NOS inhibitor T1059 vasopressor activity on the models of acute hemorrhagic shock in rats and dogs

et al. 2022

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The development of new effective and safe vasopressors is one of the ways to increase the effectiveness of the treatment of hypotensive disorders, the severe forms of which remain a common cause of death in all countries of the world. Previously, we synthesized the original compound T1059, a selective inhibitor of eNOS/iNOS which has a pronounced vasoconstrictive effect. Here we show its vasopressor activity in models of the early stage of acute hemorrhagic shock in rats and dogs, as part of preclinical studies. The results indicate NOS inhibitor T1059 as a potent long-acting vasopressor. Its single parenteral administration in sufficiently safe doses (1/50–1/9 LD10), caused in rats and dogs a rapid increase in vascular tone, accompanied by a prolonged hypertensive effect (within 90–120 min in rats, and within 115 min in dogs). The repeated administration of T1059 at low doses (1/3 of the first dose) made it possible to considerably (by at least 60 min) prolong a significant vasopressor effect. In all schemes, T1059 administration considerably inhibited the development of threatening cardiorespiratory disorders and significantly (p = 0.0026–0.0098) increased the short-term survival of experimental animals, formally extending the duration of the “golden hour” by 2 times. These data indicate that NOS inhibitors and, in particular, compound T1059, are able to create new opportunities in the treatment of hypotensive disorders, including the provision of assistance at the prehospital stage of treatment of such pathologies.

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Comparison of Antitumor Effects of Combined and Separate Treatment with NO Synthase Inhibitor T1023 and PDK1 Inhibitor Dichloroacetate

Cited by 3 publications

References 3 publications

Beyond controlling cell size: functional analyses of S6K in tumorigenesis

Beyond controlling cell size: functional analyses of S6K in tumorigenesis

Combination of NOS- and PDK-Inhibitory Activity: Possible Way to Enhance Antitumor Effects

Preclinical studies of NOS inhibitor T1059 vasopressor activity on the models of acute hemorrhagic shock in rats and dogs

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