FAK and S6K1 Inhibitor, Neferine, Dually Induces Autophagy and Apoptosis in Human Neuroblastoma Cells

Pham, Dinh‐Chuong; Chang, Yu‐Chuan; Lin, Shian-Ren; Fuh, Yuh-Ming; Tsai, Ming-Tzu; Weng, Ching‐Feng

doi:10.3390/molecules23123110

Cited by 33 publications

(21 citation statements)

References 52 publications

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“…According to our data, Survivin protein is more strongly expressed in CD44 + CSCs than Induction of apoptosis is a useful vehicle of targeted cancer therapy (Philchenkov, Zavelevich, Kroczak, & Los, 2004). Previous reports have shown that neferine causes apoptosis in various cancer cells, such as liver cancer (Poornima, Quency, et al, 2013), GIST (Xue et al, 2019), glioma (Liang et al, 2019), neuroblastoma (Pham et al, 2018), lung (Sivalingam et al, 2017), and cervical cancer cells (Eid & Abdel-Rehim, 2017) through enhancing the expression of Bax, caspase-3, -9, Bad, and downregulating Bcl-2. Thus we assessed the apoptotic effect of neferine treatment in PC3 and CD44 + CSCs.…”

Section: Iscus I Onmentioning

confidence: 99%

Neferine inhibits proliferation and migration of human prostate cancer stem cells through p38 MAPK/JNK activation

Erdoğan

Turkekul

2020

J Food Biochem

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Cancer stem cells (CSCs) are one of the significant causes of cancer treatment failure and metastasis, as they have significant chemo‐and radio‐resistance leading to tumor recurrence. Here we investigated the possible anticancer properties of neferine, a natural alkaloid, on human prostate cancer (PCa) cells and their stem cells. CD44+ CSCs were isolated from androgen‐insensitive PC3 cells by magnetic‐activated cell sorting system (MACS). Neferine dose‐and time‐dependently inhibited the viability of PC3 and CSCs as well as androgen‐sensitive LNCaP cells through inducing apoptosis and cell cycle arrest at G1 phase. Neferine was shown to downregulate the expression of Bcl‐2 and CDK4, and upregulate caspase 3, clePARP, p21, p27, and p53. The treatment significantly inhibits the migration of CSCs. Neferine induces JNK and p38 MAPK phosphorylation, and downregulates PI3K and NF‐ĸβ signaling. In conclusion, neferine may have a therapeutic effect inhibiting the PCa cell proliferation as well as by eliminating CSCs. Practical applications Neferine is an alkaloid found in the seed embryo of Nelumbo nucifera and has recently been shown to have anticancer effects on various human cancer cells. More than 90% of cancer‐related deaths develop after metastasis, and CSCs are considered to be largely responsible for the cell migration and invasion. It has been shown that treatment of neferine kills not only PCa cells but also CSCs, and may contribute to the prevention of progression of PCa and metastasis by inhibiting cell proliferation and migration.

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Section: Iscus I Onmentioning

confidence: 99%

Neferine inhibits proliferation and migration of human prostate cancer stem cells through p38 MAPK/JNK activation

Erdoğan

Turkekul

2020

J Food Biochem

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“…In case of cancer, Nef was demonstrated to induce reactive oxygen species (ROS)‐dependent mitochondrial‐mediated apoptosis in liver, lung, breast, cervical, and osteosarcoma cancer cells (Eid & Abdel‐Rehim, 2017; Poornima, Quency, et al, 2013; Poornima, Weng, et al, 2013; Yang et al, 2016; Zhang et al, 2012). Although previous studies have reported Nef regulated autophagy and apoptosis mediated cell death involving ROS in cancers such as lung, ovarian cancer, and neuroblastoma (Pham et al, 2018; Poornima, Quency, & Padma, 2013; Xu et al, 2016), the exact anti‐cancer mechanism of Nef is yet to be clearly defined. ROS plays an important role in cell survival, cell death, and the maintenance of the cellular homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Neferine, an alkaloid from lotus seed embryo targets HeLa and SiHa cervical cancer cells via pro‐oxidant anticancer mechanism

Dasari

Bakthavachalam

Chinnapaka

et al. 2020

Phytotherapy Research

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Apoptosis and autophagy are important processes that control cellular homeostasis and have been highlighted as promising targets for novel anticancer drugs. This study aims to investigate the inhibitory effects and mechanisms of Neferine (Nef), an alkaloid from the lotus seed embryos of Nelumbo nucifera (N. nucifera), as a dual inducer of apoptosis and autophagy through the reactive oxygen species (ROS) activation in cervical cancer cells. Nef and N. nucifera extract suppressed the cell viability of HeLa and SiHa cells in a dose‐dependent manner. Importantly, Nef showed minimal toxicity to normal cells. Furthermore, Nef inhibited anchorage‐independent growth, colony formation and migration ability of cervical cancer cells. Nef induces mitochondrial apoptosis by increasing pro‐apoptotic protein bax, cytochrome‐c, cleaved caspase‐3 and caspase‐9, poly‐ADP ribose polymerase (PARP) cleavage, DNA damage (pH2AX) while downregulating Bcl‐2, procaspase‐3 and procaspase‐9, and TCTP. Of note, apoptotic effect by Nef was significantly attenuated in the presence of N‐acetylcysteine (NAC), suggesting pro‐oxidant activity of this compound. Nef also promoted autophagy induction through increasing beclin‐1, atg‐4, atg‐5 and atg‐12, LC‐3 activation, and P62/SQSTM1 as determined by western blot analysis. Collectively, these results demonstrate that Nef is a potent anticancer compound against cervical cancer cells through inducing apoptosis and autophagic pathway involving ROS.

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“…Previous studies have revealed that neferine inhibits progression of multiple malignancies, through cell cycle arrest, although this effect varies ( 12 ). For instance, Pham et al revealed that neferine hindered proliferation of human neuroblastoma by blocking G 2 /M cell cycle progression ( 9 ), while Xu et al revealed that it could cause G1-phase arrest in ovarian carcinoma cells by upregulating p21 and p27 ( 11 ). In the present study, it was observed that neferine treatment increased the G 2 /M phase in ESCC cells by downregulating the expression of cyclin B1 while upregulating that of p21.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Neferine (Fig. 1A), an alkaloid extracted from Nelumbo nucifera (lotus), has been revealed to actively reduce blood lipid levels and anti-inflammation, and recently it was reported to exert antitumor effects in multiple tumor cells (9,10). Xu et al (11) revealed that neferine suppressed the proliferation of ovarian carcinoma cells by provoking autophagy.…”

Section: Introductionmentioning

confidence: 99%

Neferine induces apoptosis by modulating the ROS‑mediated JNK pathway in esophageal squamous cell carcinoma

Zhang

Liu

et al. 2020

Oncol Rep

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Current treatments for esophageal squamous cell carcinoma (ESCC) have limited efficacy. Therefore, the development of novel therapeutic targets to effectively manage the disease and boost survival rates is imperative Neferine, a natural product extracted from Nelumbo nucifera (lotus) leaves, has been revealed to inhibit the growth of hepatocarcinoma, breast cancer and lung cancer cells. However, its effect on ESCC is unknown. In the present study, it was revealed that neferine exerted anti-proliferative effects in ESCC. It was also revealed that it triggered arrest of the G 2 /M phase and enhanced apoptosis of ESCC cell lines. Moreover, its ability to trigger accumulation of reactive oxygen species (ROS) and activate the c-Jun N-terminal kinase (JNK) pathway was demonstrated. Further study revealed how N-acetyl cysteine (NAC), a ROS inhibitor, attenuated these effects, demonstrating that ROS and JNK inhibitors mediated a marked reversal of neferine-triggered cell cycle arrest and apoptosis in ESCC cells. Finally, it was revealed that neferine was involved in the inhibition of Nrf2, an antioxidant factor. Collectively, these findings demonstrated the antitumor effect of neferine in ESCC, through the ROS-mediated JNK pathway and inhibition of Nrf2, indicating its potential as a target for development of novel and effective therapeutic agents against ESCC.

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FAK and S6K1 Inhibitor, Neferine, Dually Induces Autophagy and Apoptosis in Human Neuroblastoma Cells

Cited by 33 publications

References 52 publications

Neferine inhibits proliferation and migration of human prostate cancer stem cells through p38 MAPK/JNK activation

Neferine inhibits proliferation and migration of human prostate cancer stem cells through p38 MAPK/JNK activation

Neferine, an alkaloid from lotus seed embryo targets HeLa and SiHa cervical cancer cells via pro‐oxidant anticancer mechanism

Neferine induces apoptosis by modulating the ROS‑mediated JNK pathway in esophageal squamous cell carcinoma

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