A Triphenylphosphonium-Functionalized Delivery System for an ATM Kinase Inhibitor That Ameliorates Doxorubicin
Venturina Stagni1,2, Archontia Kaminari3, Claudia Contadini2,4
1Institute of Molecular Biology and Pathology, National Research Council (CNR), 00183 Rome, Italy.
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.
Insights
Triphenylphosphonium-functionalized nanocarriers effectively deliver the ATM kinase inhibitor KU-55933 (KU) to breast cancer mammospheres, enhancing chemotherapy efficacy against resistant cells.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Ataxia-telangiectasia mutated (ATM) kinase is crucial for cellular stress responses and promotes cancer stem cell growth.
- ATM inhibitors, like KU-55933 (KU), are investigated for cancer chemotherapy.
- Targeting ATM offers a potential strategy against chemotherapy-resistant cancers.
Purpose of the Study:
- To evaluate a triphenylphosphonium-functionalized nanocarrier for delivering KU to breast cancer cells.
- To compare the efficacy of encapsulated KU against cells in 2D monolayers versus 3D mammospheres.
- To assess the combined effect of encapsulated KU and doxorubicin on breast cancer cells.
Main Methods:
- Utilized a triphenylphosphonium-functionalized nanocarrier system for KU encapsulation.
- Assayed KU effects on breast cancer cells grown as 2D monolayers and 3D mammospheres.
- Investigated the sensitization of mammospheres to doxorubicin by encapsulated KU.
Main Results:
- Encapsulated KU demonstrated efficacy against chemotherapy-resistant breast cancer mammospheres.
- KU showed lower cytotoxicity against adherent monolayer cells compared to mammospheres.
- Encapsulated KU significantly sensitized mammospheres to doxorubicin, with a weaker effect on adherent cells.
Conclusions:
- Triphenylphosphonium-functionalized nanocarriers are effective drug delivery systems for KU.
- This delivery system enhances KU's efficacy against resistant breast cancer mammospheres.
- Such systems represent a valuable addition to chemotherapeutic strategies targeting proliferating cancers.
