MG-2477, a new tubulin inhibitor, induces autophagy through inhibition of the Akt/mTOR pathway and delayed apoptosis in A549 cells

Viola, Giampietro; Bortolozzi, Roberta; Hamel, Ernest; Moro, Stefano; Brun, Paola; Castagliuolo, Ignazio; Ferlin, María Grazia; Basso, Giuseppe

doi:10.1016/j.bcp.2011.09.017

Cited by 101 publications

(79 citation statements)

References 47 publications

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“…Majewski et al (29) reported that phosphorylated Akt inhibits caspase activity, resulting in the inhibition of apoptosis, whereas inhibition of the phosphorylation of Akt may increase autophagy (30). In our study, DHL-TauZnNa did not significantly alter the phosphorylation of Akt in HT-29 cells.…”

Section: Discussioncontrasting

confidence: 49%

DHL-TauZnNa, a newly synthesized α-lipoic acid derivative, induces autophagy in human colorectal cancer cells

et al. 2013

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Abstract. In recent years, several antioxidant substances have been found to have an antiproliferative effect on various types of carcinomas. α-lipoic acid (ALA) induces apoptosis in several types of cancer cell lines, but it is difficult to apply α-lipoic acid in clinical use as it is easily oxidized and unstable. Recently, we succeeded in synthesizing the α-lipoic acid derivative sodium N-[6,8-dimercaptooctanoyl]-2-aminoethanesulfonate zinc complex (DHL-TauZnNa), which has highly stable antioxidant effects. We investigated whether DHL-TauZnNa elicits its antiproliferative effects in vivo and in vitro by inducing apoptosis, autophagy or cell cycle arrest, and we analyzed the expression of proteins related to these phenomena and their phosphorylation in HT-29 human colon cancer cells. Subcutaneously administered DHL-TauZnNa treatment applied daily for 41 days significantly inhibited tumor growth by 43% in a xenograft mouse model (P=0.0271). DHL-TauZnNa significantly reduced cell viability over that of controls in the trypan-blue exclusion test in a time-and dose-dependent manner (P<0.05). DHL-TauZnNa increased the proportion of cells in S phase and decreased that of cells in G0/G1 phase in the cell cycle analysis of HT-29 cells. Although DHL-TauZnNa did not increase caspase-3/7 activity and DNA fragmentation in flow cytometry analysis, it increased the expression of microtubule-associated protein light chain 3-II. Autophagosomes and autolysosomes were observed by electron microscopy in the cytoplasm of HT-29 cells treated with DHL-TauZnNa. These results suggest that DHL-TauZnNa inhibited the proliferation of HT-29 cells through the mechanisms of G2/M cell cycle arrest and autophagy but not that of apoptosis. The newly synthesized ALA derivative DHL-TauZnNa may be expected to become a novel cancer therapeutic strategy through its induction of autophagy.

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Section: Discussioncontrasting

confidence: 49%

DHL-TauZnNa, a newly synthesized α-lipoic acid derivative, induces autophagy in human colorectal cancer cells

et al. 2013

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“…srB was subsequently solubilized with 10 mM tris (pH 10.5), and the absorbance was read at 570 nM on a microplate reader (Multiskan MK3; thermo scientific). the Mtt assay was carried out as previously described (14).…”

Section: Antibodies and Reagentsmentioning

confidence: 99%

Honokiol exhibits enhanced antitumor effects with chloroquine by inducing cell death and inhibiting autophagy in human non-small cell lung cancer cells

Liu

Shang

et al. 2015

Oncology Reports

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Abstract. Honokiol (HNK), a potential antitumor compound, has been widely studied in recent years. It induces apoptosis and affects autophagy in cancer cells, yet the mechanism of its antitumor efficacy remains obscure. Chloroquine (CQ), an autophagy inhibitor, is often applied to sensitize antitumor drugs in clinical trials. Here, we investigated the antitumor effect of HNK or CQ alone or in combination in non-small cell lung cancer (NSCLC) cells. Using an experimental approach, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) or sulforhodamine B (SRB) was used to determine the cytotoxicity of the agents. The expression levels of proteins were detected by western blotting. Apoptosis was examined via Annexin V-FITC and PI staining. H460 cell xenografts in nude mice were used to study the effects of HNK and/or CQ in vivo. Transfection with siRNA was applied to knock down cathepsin D. The results demonstrated the enhanced effects of HNK combined with CQ on the inhibition of proliferation, induction of apoptosis in vitro and the reduction in growth in vivo. It was confirmed that HNK and/or CQ triggered apoptosis via a caspase-dependent manner. Furthermore, HNK significantly increased the expression of p62 and LC3-Ⅱ in the A549 and H460 cells and inhibited autophagy and induced apoptosis in a cathepsin D-involved manner. In conclusion, an enhanced antitumor effect was demonstrated following treatment with HNK combined with CQ by inhibiting autophagy and inducing apoptosis via a caspase-dependent and cathepsin D-involved manner. This combination may be a novel and useful antitumor approach for chemotherapy in NSCLC. IntroductionHonokiol (HNK) (Fig. 1A), a biphenolic compound isolated from the leaves, bark, and root of Magnolia officinalis is used in traditional Chinese and Japanese medicine (1). It was reported that HNK effectively reduces the growth of cancer in vitro and in vivo in cell and animal xenograft models (2). It also induces caspase-dependent apoptosis of cancer cells through downregulation of survivin, c-FLIP, Bcl-xL and upregulation of . Recent studies have demonstrated that HNK increases the expression levels of the two hallmarks of autophagy, Beclin-1 and LC3-II, and induces autophagy in glioblastoma multiforme (GBM) DBTRG-05MG cells, yet the role of autophagy in the anti-GBM effects requires further research (6). In addition, HNK was found to induce autophagy in prostate cancer cells (7). However, another study indicated that w007B, a newly synthesized derivative of honokiol, exerted neuroprotective effects through inhibition of autophagy (8). As suggested above, the role of autophagy in the antitumor effects of HNK requires further research and combined treatment of HNK with an autophagy inhibitor or activator may result in enhanced antitumor effects.Autophagy is a conserved, lysosomal-dependent membrane process to maintain cellular homeostasis under metabolic stress. During this process, autophagosomes engulf damaged proteins and defective organelles and then fuse with lysosomes f...

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“…Recent studies have demonstrated that autophagy, including mitophagy, is often stimulated in tumor cells in response to multiple forms of cellular stress induced by chemotherapeutic agents [16][17][18] . In fact, the mode of action of some anticancer drugs from natural materials such as paclitaxel and camptothecin [19,20] involves the induction of autophagy, which is important for the regulation of cancer development and progression and for determining the response of tumor cells to anticancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Retigeric acid B-induced mitophagy by oxidative stress attenuates cell death against prostate cancer cells in vitro

Liu

et al. 2013

Acta Pharmacol Sin

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Aim: Retigeric acid B (RAB), a pentacyclic triterpenic acid from Lobaria kurokawae Yoshim, has been found to induce apoptosis in prostate cancer cells. The aim of this study was to investigate the roles of mitochondrial damage-caused mitophagy in RAB-induced prostate cancer cell death in vitro. Methods: Human prostate cancer PC3 and LNCaP cells were tested. Cell viability was analyzed with MTT assay. Cell apoptosis, ROS level and mitochondrial transmembrane potential (mtΔψ) were measured with flow cytometry. Autophagy-and apoptosis-related proteins were studied using Western blotting. GFP-LC3B puncta, mitochondrial swelling and mitophagy were examined morphologically. Quantitative RT-PCR was used to measure LC3B mRNA level, and siRNA was used to knock down LC3BII. Results: In both PC3 and LNCaP cells, RAB (15 µmol/L) increased ROS accumulation and decreased mtΔψ in a time-dependent manner. Furthermore, RAB induced mitochondrial swelling and mitophagy, significantly increased LC3B expression and conversion of LC3BI to LC3BII, and the elimination of mitochondria by LC3BII-containing autophagolysosomes. In addition, RAB suppressed the PI3K/Akt/mTOR pathway activation. Pretreatment of PC3 cells with autophagy inhibitor 3-MA (5 mmol/L) or the lysosomal protease inhibitor CQ (10 µmol/L) significantly increased RAB-induced apoptosis. Similar results were obtained in RAB-treated PC3 cells with LC3B knocked down. Conclusion: RAB induces mitochondrial damage and mitophagy that attenuates RAB-induced prostate cancer cell death. Thus, suppression of mitophagy might be a potential strategy for improving the chemotherapeutic effects of RAB.

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MG-2477, a new tubulin inhibitor, induces autophagy through inhibition of the Akt/mTOR pathway and delayed apoptosis in A549 cells

Cited by 101 publications

References 47 publications

DHL-TauZnNa, a newly synthesized α-lipoic acid derivative, induces autophagy in human colorectal cancer cells

DHL-TauZnNa, a newly synthesized α-lipoic acid derivative, induces autophagy in human colorectal cancer cells

Honokiol exhibits enhanced antitumor effects with chloroquine by inducing cell death and inhibiting autophagy in human non-small cell lung cancer cells

Retigeric acid B-induced mitophagy by oxidative stress attenuates cell death against prostate cancer cells in vitro

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