Isofraxidin enhances hyperthermia‑induced apoptosis via redox modification in acute monocytic leukemia U937 cells

Li,Peng; Zhao,Qing-Li; Rehman,Mati Ur; Jawaid,Paras; Cui,Zheng-Guo; Ahmed,Kanwal; Kondo,Takashi; Saitoh,Jun-Ichi; Noguchi,Kyo

doi:10.3892/mmr.2023.12928

Isofraxidin enhances hyperthermia‑induced apoptosis via redox modification in acute monocytic leukemia U937 cells

Authors:
- Peng Li
- Qing-Li Zhao
- Mati Ur Rehman
- Paras Jawaid
- Zheng-Guo Cui
- Kanwal Ahmed
- Takashi Kondo
- Jun-Ichi Saitoh
- Kyo Noguchi
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Affiliations: Department of Radiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930‑0194, Japan, Department of Environmental Health, University of Fukui School of Medical Sciences, Fukui 910‑8505, Japan, Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University of Health Sciences, Jeddah 9515, Kingdom of Saudi Arabia
Published online on: January 2, 2023 https://doi.org/10.3892/mmr.2023.12928
Article Number: 41

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Abstract

The cell‑killing potential of most chemotherapeutic agents is enhanced by a temperature elevation. Isofraxidin (IF) is a coumarin compound widely found in plants, such as the Umbelliferae or Chloranthaceae families. IF induces anticancer effects in lung and colorectal cancer. To the best of our knowledge, the combined effects of hyperthermia (HT) and IF on heat‑induced apoptosis have not been reported. Acute monocytic leukemia U937 cells were exposed to HT with or without IF pre‑treatment. Apoptosis was measured by Annexin V‑FITC/PI double staining assay using flow cytometry and cell viability was observed by cell counting kit assay, DNA fragmentation. The mechanism involved in the combination was explored by measuring changes in the mitochondrial membrane potential, (MMP), intracellular ROS generation, expression of apoptosis related protein, and intracellular calcium ion level. It was demonstrated that IF enhanced HT‑induced apoptosis in U937 cells. The results demonstrated that combined treatment enhanced mitochondrial membrane potential loss and transient superoxide generation increased protein expression levels of caspase‑3, caspase‑8 and phosphorylated‑JNK and intracellular calcium levels. Moreover, the role of caspases and JNK was confirmed using a pan caspase inhibitor (zVAD‑FMK) and JNK inhibitor (SP600125) in U937 cells. Collectively, the data demonstrated that IF enhanced HT‑induced apoptosis via a reactive oxygen species mediated mitochondria/caspase‑dependent pathway in U937 cells.

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