Differential Response of Lung Cancer Cells, with Various Driver Mutations, to Plant Polyphenol Resveratrol and Vitamin D Active Metabolite PRI-2191

Maj, Ewa; Maj, Beata; Bobak, Klaudia; Gos, Michalina; Chodyński, Michał; Kutner, Andrzej; Wietrzyk, Joanna

doi:10.3390/ijms22052354

Cited by 13 publications

(9 citation statements)

References 82 publications

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“…In our study, we first evaluated the activity of RES against A549 and H1299 cells, which are the most commonly used cell lines in antilung cancer studies (Bian et al, 2022; Fan et al, 2020; J. Li et al, 2022; Y. H. Lin, Zhu, et al, 2021; Maj et al, 2021). Consistent with previous studies (Y. H. Lin, Zhu, et al, 2021), we also demonstrated that RES inhibited the growth and induced apoptosis of NSCLC cells.…”

Section: Discussionmentioning

confidence: 99%

“…However, many tumors, including lung cancer, can hijack and overactivate the Nrf2/ARE antioxidant system (Sanchez-Ortega et al, 2021;Tian et al, 2016). Importantly, some studies have confirmed that different lung cancer cells respond differently to RES treatment (Maj et al, 2021;Takashina et al, 2017). It is important to understand whether RES inhibits lung cancer by modulating the Nrf2-mediated signaling pathway.…”

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confidence: 99%

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Destruction of the cellular antioxidant pool contributes to resveratrol‐induced senescence and apoptosis in lung cancer

Liang

Zhou

et al. 2023

Phytotherapy Research

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Resveratrol (RES) has various pharmacological bioactivities and its anticancer effects in lung cancer have been proven. However, the underlying mechanisms of action of RES in lung cancer remain unclear. This study focused on Nrf2-mediated antioxidant systems in RES-treated lung cancer cells. A549 and H1299 cells were treated with various concentrations of RES at different times. RES decreased cell viability, inhibited cell proliferation, and increased the number of senescent and apoptotic cells in a concentration-and time-dependent manner. Moreover, RES-induced lung cancer cell arrest at the G1 phase was accompanied by changes in apoptotic proteins (Bax, Bcl-2, and cleaved caspase 3). Furthermore, RES induced a senescent phenotype along with changes in senescence-related markers (senescence-associated β-galactosidase activity, p21, and p-γH2AX). More importantly, with prolonged exposure time and increased exposure concentration, intracellular reactive oxygen species (ROS) continuously accumulated, resulting in a decrease in Nrf2 and its downstream antioxidant response elements, including CAT, HO-1, NQO1, and SOD1. Meanwhile, RES-induced ROS accumulation and cell apoptosis were reversed by N-acetyl-Lcysteine treatment. Taken together, these results suggest that RES disturb lung cancer cellular homeostasis by destroying the intracellular antioxidant pool to increase ROS production. Our findings provide a new perspective on RES intervention in lung cancer.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Destruction of the cellular antioxidant pool contributes to resveratrol‐induced senescence and apoptosis in lung cancer

Liang

Zhou

et al. 2023

Phytotherapy Research

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“…In lung cancer, PRI-219, a vitamin D3 active metabolite (24R-1,24-dihdroxycholecalciferol), in combination with a hydroxystilbene, RSV (3,5,4′-trihydroxystilbene), induced a significant increase in PD-L1 mRNA expression in NCIH358, A549, and HCC827 cells when compared to PRI-2191 treatment alone [ 50 ]. RSV alone also had a non-significant tendency to upregulate PD-L1 expression in HCC827 cells [ 50 ]. Similarly, RSV was able to increase PD-L1 expression in two lung adenocarcinoma cell lines (A549 and H1299) [ 51 ].…”

Section: Polyphenols As Adjuvants To Enhance Anti-pd-1/anti-pd-l1 Immunotherapiesmentioning

confidence: 99%

PD-1/PD-L1 Checkpoints and Resveratrol: A Controversial New Way for a Therapeutic Strategy

Delmas

Hermetet

Aires

2021

Cancers

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Immune checkpoints refer to a range of immunoregulatory molecules that modulate the immune response. For example, proteins expressed at the surface of T-cells (including PD-1 and CTLA-4) and their ligands (PD-L1 and B7-1/B7-2, respectively), expressed by cancer cells and antigen-presenting cells, are needed to prevent excessive immune responses. However, they dampen anti-tumor immunity by limiting T-cell activity, making them promising therapeutic targets in cancer. Although immunotherapies using checkpoint blocking/neutralizing antibodies targeting PD-L1 or PD-1 have proven their superiority over conventional chemotherapies or targeted therapies by enhancing T-cell-mediated anti-tumor immunity, some limitations have emerged. These include a relatively low rate of “responders” (<50%; irrespective of cancer type), the high cost of injections, and a rare risk of hyper-progression. For clinicians, the current challenge is thus to improve the existing therapies, potentially through combinatory approaches. Polyphenols such as resveratrol (RSV), a trihydroxystilbene found in various plants and an adjuvant in numerous nutraceuticals, have been proposed as potential therapeutic targets. Beyond its well-known pleiotropic effects, RSV affects PD-L1 and PD-1 expression as well as PD-L1 subcellular localization and post-translational modifications, which we review here. We also summarize the consequences of PD-1/PD-L1 signaling, the modalities of their blockade in the context of cancer, and the current status and limitations of these immunotherapies. Finally, we discuss their potential use in combination with chemotherapies, and, using RSV as a model, we propose polyphenols as adjuvants to enhance the efficacy of anti-PD-1/anti-PD-L1 immunotherapies.

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“…They also have a low resistance to vitamin D metabolizing enzymes [ 10 ]. The current search is for vitamin D analogs of therapeutic potential against leukemia [ 7 , 11 , 12 ] and solid tumors, including breast [ 13 ], lung [ 14 ], prostate [ 15 ], colorectal [ 16 , 17 ], skin [ 18 ], and ovarian cancer [ 19 ]. We have developed analogs of 1,25D that exceed the potency of the parent 1,25D against cancer cells in vitro and in vivo, and that are less calcaemic and more enzymatically stable [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

In Silico Prediction of the Metabolic Resistance of Vitamin D Analogs against CYP3A4 Metabolizing Enzyme

Żołek

Yasuda

Brown

et al. 2022

IJMS

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The microsomal cytochrome P450 3A4 (CYP3A4) and mitochondrial cytochrome P450 24A1 (CYP24A1) hydroxylating enzymes both metabolize vitamin D and its analogs. The three-dimensional (3D) structure of the full-length native human CYP3A4 has been solved, but the respective structure of the main vitamin D hydroxylating CYP24A1 enzyme is unknown. The structures of recombinant CYP24A1 enzymes have been solved; however, from studies of the vitamin D receptor, the use of a truncated protein for docking studies of ligands led to incorrect results. As the structure of the native CYP3A4 protein is known, we performed rigid docking supported by molecular dynamic simulation using CYP3A4 to predict the metabolic conversion of analogs of 1,25-dihydroxyvitamin D2 (1,25D2). This is highly important to the design of novel vitamin D-based drug candidates of reasonable metabolic stability as CYP3A4 metabolizes ca. 50% of the drug substances. The use of the 3D structure data of human CYP3A4 has allowed us to explain the substantial differences in the metabolic conversion of the side-chain geometric analogs of 1,25D2. The calculated free enthalpy of the binding of an analog of 1,25D2 to CYP3A4 agreed with the experimentally observed conversion of the analog by CYP24A1. The metabolic conversion of an analog of 1,25D2 to the main vitamin D hydroxylating enzyme CYP24A1, of unknown 3D structure, can be explained by the binding strength of the analog to the known 3D structure of the CYP3A4 enzyme.

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Differential Response of Lung Cancer Cells, with Various Driver Mutations, to Plant Polyphenol Resveratrol and Vitamin D Active Metabolite PRI-2191

Cited by 13 publications

References 82 publications

Destruction of the cellular antioxidant pool contributes to resveratrol‐induced senescence and apoptosis in lung cancer

Destruction of the cellular antioxidant pool contributes to resveratrol‐induced senescence and apoptosis in lung cancer

PD-1/PD-L1 Checkpoints and Resveratrol: A Controversial New Way for a Therapeutic Strategy

In Silico Prediction of the Metabolic Resistance of Vitamin D Analogs against CYP3A4 Metabolizing Enzyme

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