Overcoming Multidrug Resistance by Activating Unfolded Protein Response of the Endoplasmic Reticulum in Cisplatin-Resistant A2780/CisR Ovarian Cancer Cells

Jung, Euitaek; Koh, Dongsoo; Lim, Yoongho; Shin, Soon Young; Lee, Young Han

doi:10.5483/bmbrep.2020.53.2.108

Cited by 14 publications

(8 citation statements)

References 24 publications

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“…In ovarian cancer cells, CP enhances ROS levels to induce ER stress. Then, UPR activates that overcomes drug resistance [101]. It seems that ROS levels can be considered as a biomarker for predicting response of cancer cells to chemotherapy.…”

Section: Ros Cisplatin Chemotherapy and Related Molecular Pathways Cisplatin Sensitivitymentioning

confidence: 99%

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

et al. 2021

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The failure of chemotherapy is a major challenge nowadays, and in order to ensure effective treatment of cancer patients, it is of great importance to reveal the molecular pathways and mechanisms involved in chemoresistance. Cisplatin (CP) is a platinum-containing drug with anti-tumor activity against different cancers in both pre-clinical and clinical studies. However, drug resistance has restricted its potential in the treatment of cancer patients. CP can promote levels of free radicals, particularly reactive oxygen species (ROS) to induce cell death. Due to the double-edged sword role of ROS in cancer as a pro-survival or pro-death mechanism, ROS can result in CP resistance. In the present review, association of ROS with CP sensitivity/resistance is discussed, and in particular, how molecular pathways, both upstream and downstream targets, can affect the response of cancer cells to CP chemotherapy. Furthermore, anti-tumor compounds, such as curcumin, emodin, chloroquine that regulate ROS and related molecular pathways in increasing CP sensitivity are described. Nanoparticles can provide co-delivery of CP with anti-tumor agents and by mediating photodynamic therapy, and induce ROS overgeneration to trigger CP sensitivity. Genetic tools, such as small interfering RNA (siRNA) can down-regulate molecular pathways such as HIF-1α and Nrf2 to promote ROS levels, leading to CP sensitivity. Considering the relationship between ROS and CP chemotherapy, and translating these findings to clinic can pave the way for effective treatment of cancer patients.

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Section: Ros Cisplatin Chemotherapy and Related Molecular Pathways Cisplatin Sensitivitymentioning

confidence: 99%

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

et al. 2021

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“…Cisplatin is widely used as a clinical anticancer drug and has been reported as one of the most effective chemotherapeutic drugs for OC [ 30 , 31 ]. Choi et al confirmed that Scutellaria baicalensis combined with cisplatin has a synergistic anticancer effect on human OC cells [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Fuzheng Jiedu Decoction Induces Apoptosis and Enhances Cisplatin Efficacy in Ovarian Cancer Cells In Vitro and In Vivo through Inhibiting the PI3K/AKT/mTOR/NF-κB Signaling Pathway

Yang

et al. 2022

BioMed Research International

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Objectives. This study is aimed at investigating the anticancer activity of Fuzheng Jiedu decoction (FJD) alone or in combination with cisplatin in ovarian cancer (OC) models, as well as its underlying mechanisms of action. Methods. The anticancer activities of FJD, cisplatin, and the combination of the PI3K inhibitor (LY294002, LY) or activator (IGF-1) were evaluated in OC cell lines in vitro and in a SKOV3 xenograft mouse model in vivo. The cell proliferation and invasion ability were measured using MTT, EdU, and transwell assays, respectively. The cell apoptosis was examined by flow cytometry and JC-1 assays. The expression levels of the Bcl-2 family and the PI3K/AKT/mTOR/NF-κB pathway-related proteins were analyzed by Western blot. Results. The in vivo and in vitro studies showed that FJD administration could significantly inhibit cell proliferation and promote cell apoptosis in two OC cell lines SKOV3 and 3AO and partially decreased the tumor volumes and weights. In addition, FJD could significantly downregulate the protein levels of p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, NF-κB, p38, and Bcl-2 and upregulate the Bax, Cyt-C, and cleaved caspase-3 in OC tumor tissues and cells. FJD cotreatment increased the efficacy of cisplatin, including inhibiting OC cell proliferation and invasion, promoting cell apoptosis, and inhibiting the PI3K/AKT/mTOR signaling pathway, while this enhancement was suppressed by IGF-1. Similarly, LY also enhanced the anticancer efficacy of cisplatin. Conclusions. This study indicated that FJD could improve the efficacy of cisplatin by inhibiting the PI3K/AKT/mTOR/NF-κB signaling pathway. It is suggested that FJD may be a valuable adjuvant drug for the treatment of OC.

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“…Therefore, the development of more effective and safer antitumor agents has become the focus of drug discovery. In general, natural products are advantageous due to the easy availability and relative safety, and chalcone derivatives have good cytotoxic activity towards several tumor cells(Tsai et al, 2014; Yan et al, 2016; Makhdoumi et al, 2017; Wang et al, 2018; Jung et al, 2019), which has led to the increasing consideration of chalcone derivatives as the anti-tumor treatment (Bommareddy et al, 2018; Kim and Kim, 2018). Based on the skeleton of chalcone, the hydrogens on the benzene ring were replaced by various substituents (electron-acceptor groups: –Br, –Cl, and –F; electron-donor groups: –OCH 3 , –CH 3 ) to explore the effects of electronegativity on the inhibitory activities of the compounds against the tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Synthesis of Chalcone Derivatives: Inducing Apoptosis of HepG2 Cells via Regulating Reactive Oxygen Species and Mitochondrial Pathway

et al. 2019

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Chalcone derivatives, as a hot research field, exhibit a variety of physiological bioactivities and target multiple biological receptors. Based on the skeleton of (E)-1,3-diphenyl-2-propene-1-one, 14 chalcone derivatives were designed and synthesized, and evaluated as the antitumor candidates agents against four human cancer cell lines (A549, Hela, HepG2, and HL-60) as well as one normal cell line (WI-38). Among the title compounds, compound a14 showed better inhibitory activity against HepG2 cells (IC50 = 38.33 µM) and had relatively weak cytotoxicity towards normal cells WI-38 (IC50 = 121.29 µM). In this study, apoptosis, cycle arrest, assessment of reactive oxygen species (ROS) level, and measurement of mitochondrial membrane potential were adopted to explore the inhibitory mechanism of a14 towards HepG2. Compound a14 could effectively block the division of HepG2 cell lines in the G2/M phase and robustly induced generation of ROS, demonstrating that the generation of ROS induced by a14 was the main reason for resulting in the apoptosis of HepG2 cells. Moreover, the mitochondrial membrane potential (MMP) of HepG2 cells treated with a14 was significantly decreased, which was closely related to the enhanced ROS level. Furthermore, based on Western blot experiment, cell apoptosis induced by a14 also involved the expression of B-cell lymphoma-2 (Bcl-2) family and Caspase 3 protein. In summary, compound a14 could contribute to the apoptosis of HepG2 cells through regulating ROS-mitochondrial pathway, which provides valuable hints for the discovery of novel anti-tumor drug candidates.

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Overcoming Multidrug Resistance by Activating Unfolded Protein Response of the Endoplasmic Reticulum in Cisplatin-Resistant A2780/CisR Ovarian Cancer Cells

Cited by 14 publications

References 24 publications

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

Fuzheng Jiedu Decoction Induces Apoptosis and Enhances Cisplatin Efficacy in Ovarian Cancer Cells In Vitro and In Vivo through Inhibiting the PI3K/AKT/mTOR/NF-κB Signaling Pathway

Synthesis of Chalcone Derivatives: Inducing Apoptosis of HepG2 Cells via Regulating Reactive Oxygen Species and Mitochondrial Pathway

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