Cytotoxicity of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-carboxamide in multidrug-resistant cancer cells through activation of PERK/eIF2α/ATF4 pathway

Lu, Xiaohua; Yan, Ge; Klauck, Sabine M.; Fleischer, Edmond; Klinger, Anette; Sugimoto, Yoshikazu; Shan, Letian; Efferth, Thomas

doi:10.1016/j.bcp.2021.114788

Cited by 5 publications

(2 citation statements)

References 67 publications

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“…Following that, 24 h post-tumor growth, the success of the established model was verified with a fluorescent microscope (AZ100, Nikon, Tokyo, Japan). The zebrafish bearing the labelled CCRF-CEM cells were then subjected to different adapalene concentrations, or the positive control cis-platinum for 24 h. The fluorescence intensity (Fi) of the tumor mass was measured in each single zebrafish and the inhibitory rate was determined using the following equation [ 37 ]: % inhibitory rate = [1 − (Fi treated group /Fi negative control group )] × 100% …”

Section: Methodsmentioning

confidence: 99%

In Silico, In Vitro, and In Vivo Investigations on Adapalene as Repurposed Third Generation Retinoid against Multiple Myeloma and Leukemia

Boulos,

Chatterjee,

Shan

et al. 2023

Cancers

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The majority of hematopoietic cancers in adults are incurable and exhibit unpredictable remitting-relapsing patterns in response to various therapies. The proto-oncogene c-MYC has been associated with tumorigenesis, especially in hematological neoplasms. Therefore, targeting c-MYC is crucial to find effective, novel treatments for blood malignancies. To date, there are no clinically approved c-MYC inhibitors. In this study, we virtually screened 1578 Food and Drug Administration (FDA)-approved drugs from the ZINC15 database against c-MYC. The top 117 compounds from PyRx-based screening with the best binding affinities to c-MYC were subjected to molecular docking studies with AutoDock 4.2.6. Retinoids consist of synthetic and natural vitamin A derivatives. All-trans-retinoic acid (ATRA) were highly effective in hematological malignancies. In this study, adapalene, a third-generation retinoid usually used to treat acne vulgaris, was selected as a potent c-MYC inhibitor as it robustly bound to c-MYC with a lowest binding energy (LBE) of −7.27 kcal/mol, a predicted inhibition constant (pKi) of 4.69 µM, and a dissociation constant (Kd value) of 3.05 µM. Thus, we examined its impact on multiple myeloma (MM) cells in vitro and evaluated its efficiency in vivo using a xenograft tumor zebrafish model. We demonstrated that adapalene exerted substantial cytotoxicity against a panel of nine MM and two leukemic cell lines, with AMO1 cells being the most susceptible one (IC50 = 1.76 ± 0.39 µM) and, hence, the focus of this work. Adapalene (0.5 × IC50, 1 × IC50, 2 × IC50) decreased c-MYC expression and transcriptional activity in AMO1 cells in a dose-dependent manner. An examination of the cell cycle revealed that adapalene halted the cells in the G2/M phase and increased the portion of cells in the sub-G0/G1 phase after 48 and 72 h, indicating that cells failed to initiate mitosis, and consequently, cell death was triggered. Adapalene also increased the number of p-H3(Ser10) positive AMO1 cells, which is a further proof of its ability to prevent mitotic exit. Confocal imaging demonstrated that adapalene destroyed the tubulin network of U2OS cells stably transfected with a cDNA coding for α-tubulin-GFP, refraining the migration of malignant cells. Furthermore, adapalene induced DNA damage in AMO1 cells. It also induced apoptosis and autophagy, as demonstrated by flow cytometry and western blotting. Finally, adapalene impeded tumor growth in a xenograft tumor zebrafish model. In summary, the discovery of the vitamin A derivative adapalene as a c-MYC inhibitor reveals its potential as an avant-garde treatment for MM.

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Section: Methodsmentioning

confidence: 99%

In Silico, In Vitro, and In Vivo Investigations on Adapalene as Repurposed Third Generation Retinoid against Multiple Myeloma and Leukemia

Boulos,

Chatterjee,

Shan

et al. 2023

Cancers

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“…MCC1734, a derivative of coumarin, showed varying degrees of cytotoxicity against five multidrug-resistant cell lines expressing different resistance mechanisms and could not be pumped out of resistant cancer cells; thus, this compound shows promise in killing multidrug-resistant tumors. MCC1734 possibly exerts antitumor effects by upregulating the p-PERK, eIF2α, ATF4, and CHOP proapoptotic pathways in tumor cells ( Lu et al, 2021 ). Similarly, lobaplatin promotes apoptosis and inhibits the proliferation of HCC by upregulating the PERK-eIF2α-ATF4-CHOP pathway ( Li et al, 2019 ).…”

Section: Links Between Ers and Multidrug Resistant Tumorsmentioning

confidence: 99%

Crosstalk between endoplasmic reticulum stress and multidrug-resistant cancers: hope or frustration

Qing,

Wang,

et al. 2023

Front. Pharmacol.

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Endoplasmic reticulum stress (ERS) is a kind of cell response for coping with hypoxia and other stresses. Pieces of evidence show that continuous stress can promote the occurrence, development, and drug resistance of tumors through the unfolded protein response. Therefore, the abnormal ac-tivation of ERS and its downstream signaling pathways not only can regulate tumor growth and metastasis but also profoundly affect the efficacy of antitumor therapy. Therefore, revealing the molecular mechanism of ERS may be expected to solve the problem of tumor multidrug resistance (MDR) and become a novel strategy for the treatment of refractory and recurrent tumors. This re-view summarized the mechanism of ERS and tumor MDR, reviewed the relationship between ERS and tumor MDR, introduced the research status of tumor tissue and ERS, and previewed the prospect of targeting ERS to improve the therapeutic effect of tumor MDR. This article aims to provide researchers and clinicians with new ideas and inspiration for basic antitumor treatment.

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Artemisinin derivative FO-ARS-123 as a novel VEGFR2 inhibitor suppresses angiogenesis, cell migration, and invasion

Elbadawi

Blatt

et al. 2022

Chemico-Biological Interactions

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Cytotoxicity of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-carboxamide in multidrug-resistant cancer cells through activation of PERK/eIF2α/ATF4 pathway

Cited by 5 publications

References 67 publications

In Silico, In Vitro, and In Vivo Investigations on Adapalene as Repurposed Third Generation Retinoid against Multiple Myeloma and Leukemia

In Silico, In Vitro, and In Vivo Investigations on Adapalene as Repurposed Third Generation Retinoid against Multiple Myeloma and Leukemia

Crosstalk between endoplasmic reticulum stress and multidrug-resistant cancers: hope or frustration

Artemisinin derivative FO-ARS-123 as a novel VEGFR2 inhibitor suppresses angiogenesis, cell migration, and invasion

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