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The cytotoxic potential of cationic triangulenes against tumour cells.

ABSTRACT: TOTA (trioxatriangulenium ion) is a close-shelled carbocation known to intercalate strongly with the DNA double helix (J. Reynisson, G. B. Schuster, S. B. Howerton, L. D. Williams, R. N. Barnett, C. L. Cleveland, U. Landman, N. Harrit, J. B. Chaires, J. Am. Chem. Soc. 2003, 125, 2072). The cytotoxicity of TOTA and its four close structural analogues, ADOTA, Pr-ADOTA, Pr-DAOTA and n-Butyl-TATA were tested against the breast cancer cell line MDA-MB-231 and colon cancer cell line HCT116. The most potent derivatives Pr-ADOTA and Pr-DAOTA had IC50 values of ?80 nM for MDA-MB-231 but slightly higher for HCT116 in the low hundreds nM range. A 3D model assay of HCT116 spheroids was also used, mimicking a tumour environment, again both Pr-ADOTA and Pr-DAOTA were very active with IC50 values of 38 nM and 21 nM, respectively. Molecular modelling suggest that the planar derivatives intercalate between the base pairs of the DNA double helix. However, only modest DNA double stranded DNA cleavage was observed using the ?H2AX assay as compared to camptothecin, a topoisomerase I poison suggesting a different mechanism. Finally, a robust density functional theory (DFT) model was built to predict the pK R+ stability values, i.e., to design derivatives, which predominantly have a non-intercalating buckled form in healthy tissues followed by a nucleophilic attach of water on the central carbon, but a planar form at relatively low pH values rendering them only cytotoxic in the interior of tumours.

SUBMITTER: Leung E

PROVIDER: S-EPMC7478161 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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The cytotoxic potential of cationic triangulenes against tumour cells.

Leung Euphemia E Pilkington Lisa I LI Naiya Mohinder M MM Barker David D Zafar Ayesha A Eurtivong Chatchakorn C Reynisson Jóhannes J

MedChemComm 20190821 11

TOTA (trioxatriangulenium ion) is a close-shelled carbocation known to intercalate strongly with the DNA double helix (J. Reynisson, G. B. Schuster, S. B. Howerton, L. D. Williams, R. N. Barnett, C. L. Cleveland, U. Landman, N. Harrit, J. B. Chaires, J. Am. Chem. Soc. 2003, 125, 2072). The cytotoxicity of TOTA and its four close structural analogues, ADOTA, Pr-ADOTA, Pr-DAOTA and n-Butyl-TATA were tested against the breast cancer cel ...[more]

PMID: 32952994

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Project description:Cytotoxic CD8+ T (Tc) cells are the main executors of transformed and cancer cells during cancer immunotherapy. The latest clinical results evidence a high efficacy of novel immunotherapy agents that modulate Tc cell activity against bad prognosis cancers. However, it has not been determined yet whether the efficacy of these treatments can be affected by selection of tumoural cells with mutations in the cell death machinery, known to promote drug resistance and cancer recurrence. Here, using a model of prophylactic tumour vaccination based on the LCMV-gp33 antigen and the mouse EL4 T lymphoma, we analysed the molecular mechanism employed by Tc cells to eliminate cancer cells in vivo and the impact of mutations in the apoptotic machinery on tumour development. First of all, we found that Tc cells, and perf and gzmB are required to efficiently eliminate EL4.gp33 cells after LCMV immunisation during short-term assays (1-4 h), and to prevent tumour development in the long term. Furthermore, we show that antigen-pulsed chemoresistant EL4 cells overexpressing Bcl-XL or a dominant negative form of caspase-3 are specifically eliminated from the peritoneum of infected animals, as fast as parental EL4 cells. Notably, antigen-specific Tc cells control the tumour growth of the mutated cells, as efficiently as in the case of parental cells. Altogether, expression of the anti-apoptotic mutations does not confer any advantage for tumour cells neither in the short-term survival nor in long-term tumour formation. Although the mechanism involved in the elimination of the apoptosis-resistant tumour cells is not completely elucidated, neither necroptosis nor pyroptosis seem to be involved. Our results provide the first experimental proof that chemoresistant cancer cells with mutations in the main cell death pathways are efficiently eliminated by Ag-specific Tc cells in vivo during immunotherapy and, thus, provide the molecular basis to treat chemoresistant cancer cells with CD8 Tc-based immunotherapy.

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The cytotoxic potential of cationic triangulenes against tumour cells.

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The cytotoxic potential of cationic triangulenes against tumour cells.

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