N-Desmethyldauricine Induces Autophagic Cell Death in Apoptosis-Defective Cells via Ca2+ Mobilization

Law, Betty Yuen Kwan; Mok, Simon Wing Fai; Chen, Juan; Michelangeli, Francesco; Jiang, Zhi‐Hong; Han, Yu; Qu, Yuan Qing; Qiu, Alena Cong Ling; Xu, Su-Wei; Xue, Weiwei; Yao, Xiaojun; Gao, Jiajia; Javed, Masood-Ul-Hassan; Coghi, Paolo; Liu, Liang

doi:10.3389/fphar.2017.00388

Cited by 25 publications

(15 citation statements)

References 67 publications

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“…Anticancer treatment induces robust autophagy of cancer cells to self-digestion until death (Simonet et al, 2020;Ganesher et al, 2020). Many natural compounds and synthetic agents exhibit their anticancer effects through triggering autophagic cell death (Law et al, 2017;Xu et al, 2019;Kiruthiga et al, 2020;Pellerito et al, 2020). Moreover, the activation of autophagy-related signaling may implicate the suppression of certain other cancer therapeutic target to help against cancer, such as tumor invasion and migration and tumor angiogenesis Jiang et al, 2019;Song et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Combination of an Autophagy Inducer and an Autophagy Inhibitor: A Smarter Strategy Emerging in Cancer Therapy

Liu

Zhang

et al. 2020

Front. Pharmacol.

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Autophagy is considered a cytoprotective function in cancer therapy under certain conditions and is a drug resistance mechanism that represents a clinical obstacle to successful cancer treatment and leads to poor prognosis in cancer patients. Because certain clinical drugs and agents in development have cytoprotective autophagy effects, targeting autophagic pathways has emerged as a potential smarter strategy for cancer therapy. Multiple preclinical and clinical studies have demonstrated that autophagy inhibition augments the efficacy of anticancer agents in various cancers. Autophagy inhibitors, such as chloroquine and hydroxychloroquine, have already been clinically approved, promoting drug combination treatment by targeting autophagic pathways as a means of discovering and developing more novel and more effective cancer therapeutic approaches. We summarize current studies that focus on the antitumor efficiency of agents that induce cytoprotective autophagy combined with autophagy inhibitors. Furthermore, we discuss the challenge and development of targeting cytoprotective autophagy as a cancer therapeutic approach in clinical application. Thus, we need to facilitate the exploitation of appropriate autophagy inhibitors and coadministration delivery system to cooperate with anticancer drugs. This review aims to note optimal combination strategies by modulating autophagy for therapeutic advantage to overcome drug resistance and enhance the effect of antitumor therapies on cancer patients.

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Section: Introductionmentioning

confidence: 99%

Combination of an Autophagy Inducer and an Autophagy Inhibitor: A Smarter Strategy Emerging in Cancer Therapy

Liu

Zhang

et al. 2020

Front. Pharmacol.

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“…However, studies that address ACD induction in MEFs have so far remained scarce 69 . Whereas two studies reported the induction of ACD upon treatment of MEFs with N-desmethyldauricine or upon radiation 70,71 , other studies performed with MEFs focused on the induction of ACD under basal conditions in Puma −/− , Bid −/− and Bax −/− Bak −/− KO MEFs 69,72 .…”

Section: Discussionmentioning

confidence: 99%

STF-62247 and pimozide induce autophagy and autophagic cell death in mouse embryonic fibroblasts

Kinzler

Zielke

Kardo

et al. 2020

Sci Rep

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Induction of autophagy can have beneficial effects in several human diseases, e.g. cancer and neurodegenerative diseases (ND). Here, we therefore evaluated the potential of two novel autophagyinducing compounds, i.e. STF-62247 and pimozide, to stimulate autophagy as well as autophagic cell death (ACD) using mouse embryonic fibroblasts (MEFs) as a cellular model. Importantly, both STF-62247 and pimozide triggered several hallmarks of autophagy in MEFs, i.e. enhanced levels of LC3B-II protein, its accumulation at distinct cytosolic sites and increase of the autophagic flux. Intriguingly, autophagy induction by STF-62247 and pimozide resulted in cell death that was significantly reduced in ATG5-or ATG7-deficient MEFs. Consistent with ACD induction, pharmacological inhibitors of apoptosis, necroptosis or ferroptosis failed to protect MEFs from STF-62247-or pimozide-triggered cell death. Interestingly, at subtoxic concentrations, pimozide stimulated fragmentation of the mitochondrial network, degradation of mitochondrial proteins (i.e. mitofusin-2 and cytochrome c oxidase IV (COXIV)) as well as a decrease of the mitochondrial mass, indicative of autophagic degradation of mitochondria by pimozide. In conclusion, this study provides novel insights into the induction of selective autophagy as well as ACD by STF-62247 and pimozide in MEFs.Besides bulk autophagy, mitophagy is known as one of the best-characterized forms of selective autophagy. During mitophagy, distinct receptors selectively recognize mitochondria and bridge them to LC3 proteins, which enables lysosomal degradation of the entire organelles 9 . To date, several receptors have been reported to selectively bind to mitochondria, among these are B-cell lymphoma 2 nineteen kilodalton interacting protein 3 (BNIP3), Nix, BCL-2-like protein 13 (BCL2-L-13), FUN14 domain-containing protein 1 (FUNDC1), p62, Optineurin, Calcium-binding and coiled-coil domain-containing protein 2 (NDP52), Protein NBR1 homolog (NBR1) and TAX1-binding protein 1 (TAX1BP1) 10 . A well-characterized model of mitophagy is Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase (PTEN)-induced kinase 1 (PINK1)/ Parkin-mediated mitophagy, in which Parkin becomes phosphorylated by the E3 ligase PINK1 and subsequently builds up ubiquitin chains on mitochondria, which are in turn recognized by selective autophagy receptors 11 .Autophagy is induced in response to starvation, oxidative stress and accumulation of misfolded proteins 12-14 and can serve to provide novel building blocks in response to high energy demands or as a protein quality control mechanism to remove protein aggregates or damaged organelles 15 . Depending on the cellular context, autophagy may exert dual roles in the regulation of programmed cell death, i.e. lethal and/or cytoprotective. Stimulation of autophagy can promote cell death referred to as ACD [16][17][18][19] . Although the molecular signals that trigger ACD are not yet fully understood, there are well-acknowledged criteria to class...

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“…In addition, we also demonstrated that inhibition of autophagy promoted apoptotic activity and sensitized TBMS1 cytotoxicity in breast cancer cells. Autophagy can cause either cell death or survival depending on different stimuli and the intracellular environment [5]. A better understanding of the exact roles that autophagy plays in tumor cells subjected to therapeutic stress would be beneficial to explore autophagy as a therapeutic strategy against cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Autophagy is associated with pathogenesis of various human diseases, including cancer, cardiac disease, and neurodegeneration [2]. Autophagy suppresses tumor initiation and development by eliminating damaged proteins and organelles and by preventing genomic instability [3][4][5]. Once cancer is established, this catabolic process can provide nutrients and energy to allow cancer cells to survive against a variety of stresses, including nutrient deprivation, hypoxia, chemotherapy, or radiation, thereby contributing to tumor progression and therapeutic resistance [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Tubeimoside-1, a triterpenoid saponin, induces cytoprotective autophagy in human breast cancer cells in vitro via Akt-mediated pathway

et al. 2018

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Autophagy, a form of cellular self-digestion by lysosome, is associated with various disease processes including cancers, and modulating autophagy has shown promise in the treatment of various malignancies. A number of natural products display strong antitumor activity, yet their mechanisms of action remain unclear. To gain a better understanding of how traditional Chinese medicine agents exert antitumor effects, we screened 480 natural compounds for their effects on autophagy using a high content screening assay detecting GFP-LC3 puncta in HeLa cells. Tubeimoside-1 (TBMS1), a triterpenoid saponin extracted from Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae), was identified as a potent activator of autophagy. The activation of autophagy by TBMS1 was evidenced by increased LC3-II amount and GFP-LC3 dots, observation of autophagosomes under electron microscopy, and enhanced autophagic flux. To explore the mechanisms underlying TBMS1-activated autophagy, we performed cheminformatic analyses and surface plasmon resonance (SPR) binding assay that showed a higher likelihood of the binding between Akt protein and TBMS1. In three human breast cancer cell lines, we demonstrated that Akt-mTOR-eEF-2K pathway was involved in TBMS1-induced activation of autophagy, while Akt-mediated downregulations of Mcl-1, Bcl-xl, and Bcl-2 led to the activation of apoptosis of the breast cancer cells. Inhibition of autophagy enhanced the cytotoxic effect of TBMS1 via promoting apoptosis. Our results demonstrate the role and mechanism of TBMS1 in activating autophagy, suggesting that inhibition of cytoprotective autophagy may act as a therapeutic strategy to reinforce the activity of TBMS1 against cancers.

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N-Desmethyldauricine Induces Autophagic Cell Death in Apoptosis-Defective Cells via Ca2+ Mobilization

Cited by 25 publications

References 67 publications

Combination of an Autophagy Inducer and an Autophagy Inhibitor: A Smarter Strategy Emerging in Cancer Therapy

Combination of an Autophagy Inducer and an Autophagy Inhibitor: A Smarter Strategy Emerging in Cancer Therapy

STF-62247 and pimozide induce autophagy and autophagic cell death in mouse embryonic fibroblasts

Tubeimoside-1, a triterpenoid saponin, induces cytoprotective autophagy in human breast cancer cells in vitro via Akt-mediated pathway

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