Combined anticancer therapy with imidazoacridinone analogue C‐1305 and paclitaxel in human lung and colon cancer xenografts—Modulation of tumour angiogenesis

Article

作者: Moszyńska, Adrianna ; Świtalska, Marta ; Bagiński, Maciej ; Bartoszewski, Rafał ; Gawrońska, Małgorzata ; Dąbrowska, Aleksandra M. ; Milczarek, Magdalena ; Krzymiński, Karol ; Wietrzyk, Joanna ; Filip‐Psurska, Beata ; Psurski, Mateusz

Abstract:

The acridanone derivative 5‐dimethylaminopropylamino‐8‐hydroxytriazoloacridinone (C‐1305) has been described as a potent inhibitor of cancer cell growth. Its mechanism of action in in vitro conditions was attributed, among others, to its ability to bind and stabilize the microtubule network and subsequently exhibit its tumour‐suppressive effects in synergy with paclitaxel (PTX). Therefore, the objective of the present study was to analyse the effects of the combined treatment of C‐1305 and PTX in vivo. In addition, considering the results of previous genomic analyses, particular attention was given to the effects of this treatment on tumour angiogenesis. Treatment with C‐1305 revealed antitumor effect in A549 lung cancer cells, and combined treatment with PTX showed tendency to anticancer activity in HCT116 colon cancer xenografts. It also improved tumour blood perfusion in both tumour models. The plasma level of CCL2 was increased and that of PDGF was decreased after combined treatment with C‐1305 and PTX. The experimental results showed that the levels of FGF1, TGF‐β and Ang‐4 decreased, whereas the levels of ERK1/2 and Akt phosphorylation increased in HCT116 tumour tissue following combined treatment with both drugs. The results of in vitro capillary‐like structure formation assay demonstrated the inhibiting effect of C‐1305 on this process. Although previous in vitro and in vivo studies suggested a positive effect of C‐1305 on cancer cells, combined treatment of HCT116 human colon and A549 lung cancer cells with both PTX and C‐1305 in vivo showed that the antitumor activity was restricted and associated with the modulation of tumour angiogenesis.

2021-12-01·Cellular & molecular biology letters

Triazoloacridone C-1305 impairs XBP1 splicing by acting as a potential IRE1α endoribonuclease inhibitor

Article

作者: Pogorzelska, Aneta ; Collawn, James F ; Bartoszewski, Rafal ; Bartoszewska, Sylwia ; Bagiński, Maciej ; Crossman, David K ; Króliczewski, Jarosław

Abstract:

Inositol requiring enzyme 1 alpha (IRE1α) is one of three signaling sensors in the unfolding protein response (UPR) that alleviates endoplasmic reticulum (ER) stress in cells and functions to promote cell survival. During conditions of irrevocable stress, proapoptotic gene expression is induced to promote cell death. One of the three signaling stressors, IRE1α is an serine/threonine-protein kinase/endoribonuclease (RNase) that promotes nonconventional splicing of XBP1 mRNA that is translated to spliced XBP1 (XBP1s), an active prosurvival transcription factor. Interestingly, elevated IRE1α and XBP1s are both associated with poor cancer survival and drug resistance. In this study, we used next-generation sequencing analyses to demonstrate that triazoloacridone C-1305, a microtubule stabilizing agent that also has topoisomerase II inhibitory activity, dramatically decreases XBP1s mRNA levels and protein production during ER stress conditions, suggesting that C-1305 does this by decreasing IRE1α’s endonuclease activity.

2020-08-01·Journal of pharmaceutical analysis2区 · 医学

Electrochemical and in silico approaches for liver metabolic oxidation of antitumor-active triazoloacridinone C-1305

2区 · 医学

ArticleOA

作者: Potęga, Agnieszka ; Żelaszczyk, Dorota ; Mazerska, Zofia

5-Dimethylaminopropylamino-8-hydroxytriazoloacridinone (C-1305) is a promising antitumor compound developed in our laboratory. A better understanding of its metabolic transformations is still needed to explain the multidirectional mechanism of pharmacological action of triazoloacridinone derivatives at all. Thus, the aim of the current work was to predict oxidative pathways of C-1305 that would reflect its phase I metabolism. The multi-tool analysis of C-1305 metabolism included electrochemical conversion and in silico sites of metabolism predictions in relation to liver microsomal model. In the framework of the first approach, an electrochemical cell was coupled on-line to an electrospray ionization mass spectrometer. The effluent of the electrochemical cell was also injected onto a liquid chromatography column for the separation of different products formed prior to mass spectrometry analysis. In silico studies were performed using MetaSite software. Standard microsomal incubation was employed as a reference procedure. We found that C-1305 underwent electrochemical oxidation primarily on the dialkylaminoalkylamino moiety. An unknown N-dealkylated and hydroxylated C-1305 products have been identified. The electrochemical system was also able to simulate oxygenation reactions. Similar pattern of C-1305 metabolism has been predicted using in silico approach. Both proposed strategies showed high agreement in relation to the generated metabolic products of C-1305. Thus, we conclude that they can be considered as simple alternatives to enzymatic assays, affording time and cost efficiency.

100 项与 C-1305 相关的药物交易

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