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

SIMPLE SUMMARY: Doxorubicin (DOX) is widely used in the treatment of breast cancer. However, resistance limits its effectiveness. In particular, breast cancer stem cells (BCSCs) are associated with DOX resistance. We have previously demonstrated the potential of a polymeric nanocarrier based on a suitably functionalized hyperbranched polyethylenimine that preferentially targets BCSCs. ATM kinase is a key mediator of DNA damage response, so its inhibition has become an attractive therapeutic concept in cancer therapy for the sensitization of cancer cells to chemotherapeutic drugs. Herein, we tested the potential of this drug delivery system that encapsulates an ATM inhibitor to target and sensitize mammospheres—considered as a model system of BCSCs—to an anticancer drug, while having a comparably lower cytotoxic effect against bulk tumor cells. 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.