A Triphenylphosphonium-Functionalized Delivery System for an ATM Kinase Inhibitor That Ameliorates Doxorubicin Resistance in Breast Carcinoma Mammospheres

Venturina Stagni; Archontia Kaminari; Claudia Contadini; Daniela Barilà; Rosario Luigi Sessa; Zili Sideratou; Spiros A Vlahopoulos; Dimitris Tsiourvas

doi:10.3390/cancers15051474

A Triphenylphosphonium-Functionalized Delivery System for an ATM Kinase Inhibitor That Ameliorates Doxorubicin Resistance in Breast Carcinoma Mammospheres

Cancers (Basel). 2023 Feb 25;15(5):1474. doi: 10.3390/cancers15051474.

Authors

Venturina Stagni^{1

2}, Archontia Kaminari³, Claudia Contadini^{2

4}, Daniela Barilà^{2

4}, Rosario Luigi Sessa^{1

2}, Zili Sideratou³, Spiros A Vlahopoulos⁵, Dimitris Tsiourvas³

Affiliations

¹ Institute of Molecular Biology and Pathology, National Research Council (CNR), 00183 Rome, Italy.
² Laboratory of Cell Signaling, IRCCS, Fondazione Santa Lucia, 00179 Rome, Italy.
³ Institute of Nanoscience and Nanotechnology, NCSR ''Demokritos", 15310 Aghia Paraskevi, Greece.
⁴ Department of Biology, University of Tor Vergata, 00133 Rome, Italy.
⁵ Horemeio Research Laboratory, First Department of Paediatrics, N.K.U.A, 11527 Athens, Greece.

Abstract

The enzyme ataxia-telangiectasia mutated (ATM) kinase is a pluripotent signaling mediator which activates cellular responses to genotoxic and metabolic stress. It has been shown that ATM enables the growth of mammalian adenocarcinoma stem cells, and therefore the potential benefits in cancer chemotherapy of a number of ATM inhibitors, such as KU-55933 (KU), are currently being investigated. We assayed the effects of utilizing a triphenylphosphonium-functionalized nanocarrier delivery system for KU on breast cancer cells grown either as a monolayer or in three-dimensional mammospheres. We observed that the encapsulated KU was effective against chemotherapy-resistant mammospheres of breast cancer cells, while having comparably lower cytotoxicity against adherent cells grown as monolayers. We also noted that the encapsulated KU sensitized the mammospheres to the anthracycline drug doxorubicin significantly, while having only a weak effect on adherent breast cancer cells. Our results suggest that triphenylphosphonium-functionalized drug delivery systems that contain encapsulated KU, or compounds with a similar impact, are a useful addition to chemotherapeutic treatment schemes that target proliferating cancers.

Keywords: ataxia-telangiectasia mutated kinase; cancer stem cells; triphenylphosphonium cation.

Grants and funding

A.K. was funded by the Operational Program “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014–2020) and co-financed by GSRT Greece and the European Union (European Regional Development Fund), project MIS 5002567, implemented under the “Action for the Strategic Development on the Research and Technological Sector” initiative. This work was partially supported by NCSR internal project No EE11968, entitled “Synthesis and characterization of nanostructured materials for environmental applications”. V.S. was supported by a research grant from Regione Lazio PROGETTI DI GRUPPI DI RICERCA 2020, project ID: A0375-2020-36597. This work has been supported by research grants from Associazione Italiana per la Ricerca sul Cancro AIRC-IG2021-n.26230, and the Italian Ministry of Health, RF-2016-02362022. The work of D.B. and C.C. was also supported by AIRC-IG2021-n.26230.