Flavokavain C Suppresses Breast Cancer Cell Viability and Induces Cell Apoptosis by Triggering DNA Damage

Lin, Xiaoyu; Xing, Sunhui; Chen, Kejie; Yang, Huamao; Hu, Xiaoqu

doi:10.1248/bpb.b22-00760

Cited by 4 publications

(6 citation statements)

References 33 publications

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“…Previous research indicates that natural chalcones, including butein, xanthohumol, isoliquiritigenin, chalcotanina, and flavokawains, may exhibit cytotoxic effects, particularly inducing apoptosis in breast cancer (BC) cells [17,28,43,45]. However, prior to this study, there was no evidence demonstrating the simultaneous induction of both apoptosis and autophagy in BC cells by flavokawains (FKC).…”

Section: Discussionmentioning

confidence: 70%

Differential Induction of Autophagy and Mitochondrial Apoptosis by 2′, 4-Dihydroxy-4′, 6′-Dimethoxy Chalcone Isolated from Chromolaena tacotana, in Breast Cancer Cells

Mendez-Callejas,

Piñeros-Avila,

Celis

et al. 2023

Preprint

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Breast cancer (BC) ranks among the most prevalent cancers diagnosed in women. Its treatment necessitates precision tailored to the cancer's genetic makeup for enhanced efficacy. Research has been directed towards natural compounds for their anti-BC properties, aiming to augment existing treatment modalities. Chromolaena tacotana (Klatt) R.M. King and H. Rob, commonly referred to as Ch. tacotana, is a notable source of bioactive hydroxy-methylated flavonoids. However, the specific anti-BC mechanisms of these flavonoids, particularly those present in the plant's inflorescences, remain partly undefined. This study focuses on assessing a chalcone derivative extracted from Ch. tacotana inflorescences for its potential to concurrently activate regulated autophagy and intrinsic apoptosis in Luminal A and triple-negative BC cells. We determined the chemical composition of the chalcone using ultraviolet (UV) and nuclear magnetic resonance (NMR) spectroscopy. Its selective cytotoxicity against BC cell lines was assessed using the MTT assay. Flow cytometry and western blot analysis were employed to examine the modulation of proteins governing autophagy and the intrinsic apoptosis pathway. Additionally, in silico simulations were conducted to predict interactions between the chalcone and various anti-apoptotic proteins, including the mTOR protein. The chalcone was identified as 2',4-dihydroxy-4',6'-dimethoxy-chalcone (DDC), also known as Flavokavain C (FKC). This compound demonstrated selective inhibition of BC cell proliferation and triggered autophagy and intrinsic apoptosis. It induced cell cycle arrest in the G0/G1 phase and altered mitochondrial outer membrane potential (∆ψm). The study observed the activation of autophagic LC3-II and mitochondrial pro-apoptotic proteins in both BC cell lines. The regulation of Bcl-XL and Bcl-2 proteins varied according to BC subtype, yet they showed promising molecular interactions with DDC. Among the examined pro-survival proteins, mTOR and Mcl-1 exhibited the most favorable binding energies and were downregulated in MCF-7 and MDA-MB-231 cell lines. Further research is needed to fully understand the molecular dynamics involved in the activation and interaction of autophagy and apoptosis pathways in cancer cells in response to potential anticancer agents like the hydroxy-methylated flavonoids from Ch. tacotana.

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Section: Discussionmentioning

confidence: 70%

Differential Induction of Autophagy and Mitochondrial Apoptosis by 2′, 4-Dihydroxy-4′, 6′-Dimethoxy Chalcone Isolated from Chromolaena tacotana, in Breast Cancer Cells

Mendez-Callejas,

Piñeros-Avila,

Celis

et al. 2023

Preprint

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“…Previous research indicates that natural chalcones, including butein, xanthohumol, isoliquiritigenin, chalcotanina, and flavokawains, may exhibit cytotoxic effects, particularly inducing apoptosis in breast cancer (BC) cells [ 17 , 28 , 43 , 45 ]. However, prior to this study, there was no evidence demonstrating the simultaneous induction of both apoptosis and autophagy in BC cells by flavokawains (FKCs).…”

Section: Discussionmentioning

confidence: 99%

“…These compounds have demonstrated anticancer properties against MCF-7 and MDA-MB-231 breast cancer cell lines, inducing apoptosis and causing G2/M-phase cell cycle arrest. They also influence the processes of cell migration and invasion [ 15 , 16 , 17 ]. Specifically, FKB has been observed to induce cell death through p21-mediated cell cycle arrest and p38 activation in HeLa cervical cancer cells.…”

Section: Introductionmentioning

confidence: 99%

“…It induces cell cycle arrest and promotes apoptosis, which is associated with endoplasmic reticulum stress and the regulation of MAPK and Akt signaling pathways [ 19 ]. Recent studies have shown that breast cancer cells treated with synthetic FKC exhibit suppressed colony formation, G2/M phase cell cycle arrest, apoptosis, and DNA damage in a dose-dependent manner [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Natural 2′,4-Dihydroxy-4′,6′-dimethoxy Chalcone Isolated from Chromolaena tacotana Inhibits Breast Cancer Cell Growth through Autophagy and Mitochondrial Apoptosis

Mendez-Callejas,

Piñeros-Avila,

Celis

et al. 2024

Plants

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Breast cancer (BC) is one of the most common cancers among women. Effective treatment requires precise tailoring to the genetic makeup of the cancer for improved efficacy. Numerous research studies have concentrated on natural compounds and their anti-breast cancer properties to improve the existing treatment options. Chromolaena tacotana (Klatt) R.M. King and H. Rob (Ch. tacotana) is a notable source of bioactive hydroxy-methylated flavonoids. However, the specific anti-BC mechanisms of these flavonoids, particularly those present in the plant’s inflorescences, remain partly undefined. This study focuses on assessing a chalcone derivative extracted from Ch. tacotana inflorescences for its potential to concurrently activate regulated autophagy and intrinsic apoptosis in luminal A and triple-negative BC cells. We determined the chemical composition of the chalcone using ultraviolet (UV) and nuclear magnetic resonance (NMR) spectroscopy. Its selective cytotoxicity against BC cell lines was assessed using the MTT assay. Flow cytometry and Western blot analysis were employed to examine the modulation of proteins governing autophagy and the intrinsic apoptosis pathway. Additionally, in silico simulations were conducted to predict interactions between chalcone and various anti-apoptotic proteins, including the mTOR protein. Chalcone was identified as 2′,4-dihydroxy-4′,6′-dimethoxy-chalcone (DDC). This compound demonstrated a selective inhibition of BC cell proliferation and triggered autophagy and intrinsic apoptosis. It induced cell cycle arrest in the G0/G1 phase and altered mitochondrial outer membrane potential (∆ψm). The study detected the activation of autophagic LC3-II and mitochondrial pro-apoptotic proteins in both BC cell lines. The regulation of Bcl-XL and Bcl-2 proteins varied according to the BC subtype, yet they showed promising molecular interactions with DDC. Among the examined pro-survival proteins, mTOR and Mcl-1 exhibited the most favorable binding energies and were downregulated in BC cell lines. Further research is needed to fully understand the molecular dynamics involved in the activation and interaction of autophagy and apoptosis pathways in cancer cells in response to potential anticancer agents, like the hydroxy-methylated flavonoids from Ch. tacotana.

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“…Furthermore, the fundamental anticancer mechanisms underlying flavokawain A and B primarily center around the ROS signaling pathway (Pinner et al 2016 ; Chang et al 2017 ; Hseu et al 2019 ; Hseu et al 2020a , b ; Hseu et al 2020a , b ), the mTOR signaling pathway (Liu et al 2017 ), and the PI3K/AKT signaling pathway (Hua et al 2020 ). In contrast to flavokawain A and B, limited research has shown that flavokawain C exhibits anticancer effects specifically against colon cancer (Phang et al 2017 , 2021 ) and breast cancer (Lin et al 2023 ). The potential of flavokawain C as a prospective drug for liver cancer treatment, along with its associated anticancer mechanisms, remains uncertain and warrants thorough investigation.…”

Section: Introductionmentioning

confidence: 99%

Flavokawain C inhibits proliferation and migration of liver cancer cells through FAK/PI3K/AKT signaling pathway

Wang,

Li,

Yang

et al. 2024

J Cancer Res Clin Oncol

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Purpose This study investigated the potential applicability and the underlying mechanisms of flavokawain C, a natural compound derived from kava extracts, in liver cancer treatment. Methods Drug distribution experiment used to demonstrate the preferential tissues enrichment of flavokawain C. Cell proliferation, apoptosis and migration effect of flavokawain C were determined by MTT, colony formation, EdU staining, cell adhesion, transwell, flow cytometry and western blot assay. The mechanism was explored by comet assay, immunofluorescence assay, RNA-seq-based Kyoto encyclopedia of genes and genomes analysis, molecular dynamics, bioinformatics analysis and western blot assay. The anticancer effect of flavokawain C was further confirmed by xenograft tumor model. Results The studies first demonstrated the preferential enrichment of flavokawain C within liver tissues in vivo. The findings demonstrated that flavokawain C significantly inhibited proliferation and migration of liver cancer cells, induced cellular apoptosis, and triggered intense DNA damage along with strong DNA damage response. The findings from RNA-seq-based KEGG analysis, molecular dynamics, bioinformatics analysis, and western blot assay mechanistically indicated that treatment with flavokawain C notably suppressed the FAK/PI3K/AKT signaling pathway in liver cancer cells. This effect was attributed to the induction of gene changes and the binding of flavokawain C to the ATP sites of FAK and PI3K, resulting in the inhibition of their phosphorylation. Additionally, flavokawain C also displayed the strong capacity to inhibit Huh-7-derived xenograft tumor growth in mice with minimal adverse effects. Conclusions These findings identified that flavokawain C is a promising anticancer agent for liver cancer treatment.

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Flavokavain C Suppresses Breast Cancer Cell Viability and Induces Cell Apoptosis by Triggering DNA Damage

Cited by 4 publications

References 33 publications

Differential Induction of Autophagy and Mitochondrial Apoptosis by 2′, 4-Dihydroxy-4′, 6′-Dimethoxy Chalcone Isolated from Chromolaena tacotana, in Breast Cancer Cells

Differential Induction of Autophagy and Mitochondrial Apoptosis by 2′, 4-Dihydroxy-4′, 6′-Dimethoxy Chalcone Isolated from Chromolaena tacotana, in Breast Cancer Cells

Natural 2′,4-Dihydroxy-4′,6′-dimethoxy Chalcone Isolated from Chromolaena tacotana Inhibits Breast Cancer Cell Growth through Autophagy and Mitochondrial Apoptosis

Flavokawain C inhibits proliferation and migration of liver cancer cells through FAK/PI3K/AKT signaling pathway

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