Aripiprazole sensitizes head and neck cancer cells to ionizing radiation by enhancing the production of reactive oxygen species

Abstract

Drug repositioning is an alternative process for drug development in cancer. Specifically, it is a strategy for the discovery of new antitumor drugs by screening previously approved clinical drugs. On the basis of this strategy, aripiprazole, an antipsychotic drug, was found to have anticancer activity. In this study, we investigated the radiosensitizing effects of aripiprazole on head and neck cancer cells at sublethal doses of ionizing radiation (IR) in vitro and in vivo. Treatment with aripiprazole suppressed the growth of head and neck cancer cells in a concentration‐dependent manner, as evidenced by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay. Intriguingly, aripiprazole significantly enhanced the sensitivity of these cells to the IC 50 dose of IR. The combination of aripiprazole with IR synergistically increased annexin and propidium iodide double‐positive and terminal deoxynucleotidyl transferase dUTP nick end labeling‐positive cell populations, and induced cleaved poly(ADP‐ribose) polymerase and caspase‐3 expression, indicating the induction of apoptosis in these cells. Aripiprazole and IR‐induced apoptosis were accompanied by an increase in reactive oxygen species and was almost completely suppressed by the addition of the antioxidant, N‐acetylcysteine. Finally, aripiprazole greatly sensitized xenograft tumors to IR at doses that did not affect tumor growth. Taken together, these results suggest that aripiprazole could be considered a potent radiosensitizer for head and neck cancer.

First-Line Combination Treatment with Low-Dose Bipolar Drugs for ABCB1-Overexpressing Drug-Resistant Cancer Populations

“…In addition, <2.5 µM aripiprazole has no apoptotic effects on in vitro cancer cell lines [21,23,28]. However, combination treatment with low-dose aripiprazole increased apoptosis in radiation-treated head and neck cancer cell models [28]. Furthermore, this study showed that the sensitization mechanism of radiation + aripiprazole combined therapy mainly involved an increase in reactive oxygen species.…”

“…With the administration of aripiprazole at a low-dose of <2.5 µM, cancer cells have phenotypically normal proliferation and may grow similarly to untreated cancer cells. In addition, <2.5 µM aripiprazole has no apoptotic effects on in vitro cancer cell lines [21,23,28]. However, combination treatment with low-dose aripiprazole increased apoptosis in radiation-treated head and neck cancer cell models [28].…”

“…Recent studies demonstrated that low-dose aripiprazole is a sensitizer of combination treatments in in vitro cancer cell lines [21,23,28]. With the administration of aripiprazole at a low-dose of <2.5 µM, cancer cells have phenotypically normal proliferation and may grow similarly to untreated cancer cells.…”

Drug Repurposing: Therapeutic Role of Aripiprazole in the Cartilage Defect

“…Recently, aripiprazole was reported to have anticancer 33 and radio-sensitizing effects in various cancers, including head and neck cancer [34][35][36][37] . Kim et al argued that aripiprazole has antitumor effects via an important target molecule lined with Src, other than for psychotic purposes 37 .…”

Quetiapine Significantly Improves the Effectiveness of Radiotherapy in Combating Hepatocellular Carcinoma Progression in a Hep3B Xenograft Mouse Model

“…Olanzapine, an atypical antipsychotic, has been shown to increase the sensitivity of lung and pancreatic cancer cells to chemotherapeutic agents, including 5-fluorouracil, gemcitabine, and cisplatin (16). Aripiprazole, an atypical antipsychotic, has been identified as a radiosensitizer that boosts the therapeutic efficacy of radiation by upregulating the generation of reactive oxygen species (ROS) in head and neck cancer cells (17).…”