<i>N</i>‐acetyl‐<scp>L</scp>‐cysteine enhances fisetin‐induced cytotoxicity via induction of ROS‐independent apoptosis in human colonic cancer cells

Wu, Ming; Lien, Gi Shih; Shen, Shing Chuan; Yang, Liang; Chen, Yen Chou

doi:10.1002/mc.22053

Cited by 34 publications

(28 citation statements)

References 39 publications

(44 reference statements)

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“…We speculate that lower ROS levels in fisetin treated cells may predispose to inhibited cell growth due to decreased signaling mediated by pro-survival pathways such as PI3K/AKT/ mTOR, or the NF-KB. This notion is corroborated from recent studies where it was shown that NAC in non-toxic concentrations can enhance fisetin-mediated apoptosis in colon cancer cells (35). Similar results were seen in A375 melanoma cells that were pre-incubated with NAC prior to treatment with fisetin (SFig.2).…”

Section: Discussionsupporting

confidence: 73%

Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma

Syed

Lall

Chamcheu

et al. 2014

Archives of Biochemistry and Biophysics

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The prognosis of malignant melanoma remains poor in spite of recent advances in therapeutic strategies for the deadly disease. Fisetin, a dietary flavonoid is currently being investigated for its growth inhibitory properties in various cancer models. We previously showed that fisetin inhibited melanoma growth in vitro and in vivo. Here, we evaluated the molecular basis of fisetin induced cytoxicity in metastatic human melanoma cells. Fisetin treatment induced endoplasmic reticulum (ER) stress in highly aggressive A375 and 451Lu human melanoma cells, as revealed by up- regulation of ER stress markers including IRE1α, XBP1s, ATF4 and GRP78. Time course analysis indicated that the ER stress was associated with activation of the extrinsic and intrinsic apoptotic pathways. Fisetin treated 2-D melanoma cultures displayed autophagic response concomitant with induction of apoptosis. Prolonged treatment (16 days) with fisetin in a 3-D reconstituted melanoma model resulted in inhibition of melanoma progression with significant apoptosis, as evidenced by increased staining of cleaved Caspase-3 in the treated constructs. However, no difference in the expression of autophagic marker LC-3 was noted between treated and control groups. Fisetin treatment to 2-D melanoma cultures resulted in phosphorylation and activation of the multifunctional AMPK-activated protein kinase (AMPK) involved in the regulation of diverse cellular processes, including autophagy and apoptosis. Silencing of AMPK failed to prevent cell death indicating that fisetin induced cytotoxicity is mediated through both AMPK-dependent and -independent mechanisms. Taken together, our studies confirm apoptosis as the primary mechanism through which fisetin inhibits melanoma cell growth and that activation of both extrinsic and intrinsic pathways contributes to fisetin induced cytotoxicity.

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Section: Discussionsupporting

confidence: 73%

Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma

Syed

Lall

Chamcheu

et al. 2014

Archives of Biochemistry and Biophysics

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“…Fisetin was shown to reduce the levels of intracellular ROS generated by γ-irradiation thereby protecting cells against radiation-induced membrane lipid peroxidation, DNA damage, and protein carbonylation [81]. Remarkably, in a recent study, the known antioxidant N-acetyl-L-cysteine (NAC) was found to enhance fisetin-induced cytotoxicity via induction of ROS-independent apoptosis in human colon cancer cells [40]. However, taking into account the recently identified role of NAC as an antagonist of proteasome inhibitors, data interpretation might not be straightforward in studies where NAC is utilized as an antioxidant to validate ROS involvement in fisetin-induced cell death.…”

Section: Anti-cancer Activity Of Fisetinmentioning

confidence: 99%

Exploring the molecular targets of dietary flavonoid fisetin in cancer

Syed

Adhami

Khan

et al. 2016

Seminars in Cancer Biology

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The last few decades have seen a resurgence of interest among the scientific community in exploring the efficacy of natural compounds against various human cancers. Compounds of plant origin belonging to different groups such as alkaloids, flavonoids and polyphenols evaluated for their cancer preventive effects have yielded promising data, thereby offering a potential therapeutic alternative against this deadly disease. The flavonol fisetin (3,3′,4′,7-tetrahydroxyflavone), present in fruits and vegetables such as strawberries, apple, cucumber, persimmon, grape and onion, was shown to possess anti-microbial, anti-inflammatory, anti-oxidant and more significantly anti-carcinogenic activity when assessed in diverse cell culture and animal model systems. The purpose of this review is to update and discuss key findings obtained till date from in vitro and in vivo studies on fisetin, with special focus on its anti-cancer role. The molecular mechanism(s) described in the observed growth inhibitory effects of fisetin in different cancer cell types is also summarized. Moreover, an attempt is made to analyze the direction required for future studies that could lead to the development of fisetin as a potent chemopreventive/chemotherapeutic agent against cancer.

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“…Previous studies have shown that NAC is able to induce apoptosis in vascular smooth muscle cells, in colorectal carcinoma cell lines, in cardiomyocyte cells and murine embryonic fibroblasts [26][27][28]. In our study, we determined the apoptotic effect of NAC on DU145 prostate cancer cells.…”

Section: Discussionmentioning

confidence: 92%

Cytotoxic effect of N-acetyl cysteine in DU145 human prostate cancer cells

Çakir¹,

Alhasan²,

Çakir³

et al. 2019

Sanat

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Prostate cancer is one of the most common types of cancer in men all over the world. Chemotherapy, radiotherapy and surgery are conventional cancer treatment modalities. However, these modalities have many complications and side effects. Therefore, it is very important to support the treatment with compounds that will reduce the side effects and increase the effectiveness of the treatment. The aim of this study is to investigate the cytotoxic effects of N-acetyl cysteine (NAC), an antioxidant, on human prostate cancer cells. This study was performed on DU145 human prostate cancer cells. The cells were divided into 7 groups (control and 0.2, 0.5, 1, 2, 5 and 10 mM NAC groups). Cell index was determined using real time monitoring of electrical impedance in all groups. Apoptotic activity was determined using flow cytometry. Apoptotic activity was measured only 5 and 10 mM NAC groups. The cell index increased significantly at lower doses of NAC (0.2, 0.5, 1, 2 mM) but decreased at higher doses (5 and 10 mM). NAC significantly increased percentage of early and late apoptotic cells at 10 mM concentration. Percentage of necrotic cell significantly increased at 5 and 10 mM concentrations. Our data showed that NAC could significantly inhibit the proliferation of DU145 human prostate cancer cells in high doses. In addition, in this study for the first time, we report that NAC enhances apoptotic activity of human prostate DU145 cancer cells. These findings denote the antitumor properties of NAC.

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N‐acetyl‐L‐cysteine enhances fisetin‐induced cytotoxicity via induction of ROS‐independent apoptosis in human colonic cancer cells

Cited by 34 publications

References 39 publications

Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma

Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma

Exploring the molecular targets of dietary flavonoid fisetin in cancer

Cytotoxic effect of N-acetyl cysteine in DU145 human prostate cancer cells

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