Dihydrotanshinone Triggers Porimin-Dependent Oncosis by ROS-Mediated Mitochondrial Dysfunction in Non-Small-Cell Lung Cancer
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Published:2023-07-26
Issue:15
Volume:24
Page:11953
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Zhang Dongjie1,
Yuan Renyikun2,
Pan Jiaping2,
Fan Qiumei2,
Sun Kaili2,
Xu Zhipeng2,
Gao Xiang2,
Wang Qinqin2,
He Jia2,
Ye Yaqing1,
Mu Zhengrong3,
Leng Jing1,
Gao Hongwei2
Affiliation:
1. College of Basic Medical, Guangxi University of Chinese Medicine, Nanning 530200, China
2. College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530200, China
3. College of Basic Medical, Guangxi Medical University, Nanning 530200, China
Abstract
Lung cancer is one of the leading causes of cancer death. Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancer diagnoses. Dihydrotanshinone (DHT) is a compound extract from Salvia miltiorrhiza, which has favorable anti-inflammatory and anti-cancer activities. However, the role of DHT in NSCLC has not been fully studied. The anti-cancer drugs used for treating lung cancer often lead to apoptosis; however, the drug resistance of apoptosis restricts the effect of these drugs. Oncosis is a passive form of cell death that is different from apoptosis. It is characterized by cell swelling, and Porimin is a specific marker for oncosis. In this study, the role of DHT in mediating oncosis in A549 cells was investigated. In vitro, the MTS assay was used to detect cell activity after DHT treatment. Microscopy and electron microscopy were used to observe cell morphology changes. Western blotting was used to detect protein expression. Flow cytometry was used to detect intracellular reactive oxygen species (ROS) level, calcium ion (Ca2+) level, and cell mortality. The intracellular Lactic dehydrogenase (LDH) level was detected by an LDH detection kit after DHT treatment. The ATP level was detected using an ATP detection kit. In vivo, Lewis lung cancer (LLC) xenograft mice were used to evaluate the anti-tumor effect of DHT. Hematoxylin and eosin (HE) staining was used to detect the pathology of lung cancer tumors. The detection of Porimin in the tumor tissues of the mice after DHT administration was assessed by immunohistochemistry (IHC). The results of this study showed that DHT treatment changed the cell morphology; destroyed the mitochondrial structure; increased the expression of Porimin; increased the levels of LDH, ROS, and Ca2+; decreased the mitochondrial membrane potential and ATP level; and played an anti-tumor role in vitro by mediating oncosis in A549 cells. The in vivo studies showed that DHT could effectively inhibit tumor growth. The results of protein detection and IHC detection in the tumor tissues showed that the expression of Porimin was increased and that oncosis occurred in the tumor tissues of mice. DHT triggered Porimin-dependent oncosis by ROS-mediated mitochondrial dysfunction in NSCLC. The in vivo studies showed that DHT could inhibit tumor growth in LLC xenograft mice by triggering oncosis. This study indicates the potential for DHT to treat NSCLC.
Funder
China-ASEAN International Innovative Center for Health Industry of Traditional Chinese Medicine
the Guangxi Science and Technology Base and Talent Special Project
the National Natural Science Foundation of China
Guangxi Natural Science Foundation
Undergraduate innovation and entrepreneurship training program
the Project of Guangxi Overseas “100 persons plan” High-level Expert, and the Project of cultivating High-level Talent Teams in the Qi Huang Project of Guangxi University of Chinese Medicine
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis