TW01001, a novel piperazinedione compound, induces mitotic arrest and autophagy in non-small cell lung cancer A549 cells

Chen, Mei Chuan; Chen, Chun Han; Liu, Yi Nan; Wang, Hui Po; Pan, Shiow Lin; Teng, Che-Ming

doi:10.1016/j.canlet.2013.03.028

Cited by 13 publications

(14 citation statements)

References 56 publications

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“…1). Our findings with asbestos are in accord with others showing that various toxins cause autophagy in A549 cells, an alveolar type 2-like epithelial lung cancer cell line with wild-type p53 function [4, 33–36]. Although we focused on human A549 cells in this study, we previously reported that amosite asbestos-induced mitochondrial dysfunction, DNA damage, p53 activation and mitochondria-regulated apoptosis are all comparable in A549 and primary isolated rat alveolar type 2 cells [37, 38].…”

Section: Discussionsupporting

confidence: 92%

AKT/mTOR and c-Jun N-terminal kinase signaling pathways are required for chrysotile asbestos-induced autophagy

Lin

Kamp

et al. 2014

Free Radical Biology and Medicine

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Chrysotile asbestos is closely associated with excess mortality from pulmonary diseases such as lung cancer, mesothelioma, and asbestosis. Although multiple mechanisms in which chrysotile asbestos fibers induce pulmonary disease have been identified, the role of autophagy in human lung epithelial cells has not been examined. In the present study, we evaluated whether chrysotile asbestos induces autophagy in A549 human lung epithelial cells, and then analyzed the possible underlying molecular mechanism. Chrysotile asbestos-induced autophagy in A549 cells based on a series of biochemical and microscopic autophagy markers. We observed that asbestos increased A549 cell microtubule-associated protein 2 light chains 3 (LC3-II) expression, an autophagy marker, in conjunction with dephosphorylation of phospho-AKT, phospho-mTOR, and phospho-P70s6k. Notably, AKT1/AKT2 double knockout (AKT DKO) murine embryonic fibroblasts (MEFs) had negligible asbestos-induced LC3-II expression supporting a crucial role for AKT signaling. Chrysotile asbestos also led to the phosphorylation/activation of Jun N-terminal kinase (JNK) and p38 MAPK. Pharmacologic inhibition of JNK, but not p38 MAPK, dramatically inhibited the protein expression of LC3-II. Moreover, JNK2−/− MEFs but not JNK1−/− MEFs blocked LC3-II levels induced by chrysotile asbestos. In addition, NAC, an antioxidant, attenuated chrysotile asbestos-induced dephosphorylation of p-AKT and completely abolished phosphorylation/activation of JNK. Finally, we demonstrated that chrysotile asbestos-induced apoptosis was not affected by the presence of the autophagy inhibitors 3-methyladenine (3-MA) or ATG5 (autophagy-related gene 5) siRNA, indicating that chrysotile asbestos-induced autophagy may be adaptive rather than prosurvival. Our findings demonstrate that AKT/mTOR and JNK2 signaling pathways are required for chrysotile asbestos-induced autophagy. These data provide a mechanistic basis for possible future clinical applications targeting these signaling pathways in the management of asbestos-induced lung disease.

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Section: Discussionsupporting

confidence: 92%

AKT/mTOR and c-Jun N-terminal kinase signaling pathways are required for chrysotile asbestos-induced autophagy

Lin

Kamp

et al. 2014

Free Radical Biology and Medicine

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“…In addition to apoptosis‐dependent cancer cell death, autophagic cell death is increasingly being valued as a novel mechanism for cancer cell death induced by chemotherapeutics [8–10]. Previous studies have suggested that the pro‐survival functions of autophagy decrease drug efficacy after cancer therapeutic use [11,21,27].…”

Section: Discussionmentioning

confidence: 99%

Gambogic acid improves non‐small cell lung cancer progression by inhibition of mTOR signaling pathway

Zhao

Wang

Zhao

et al. 2017

The Kaohsiung J of Med Scie

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Gambogic acid (GA) has been shown to inhibit cancer cell proliferation, induce apoptosis, and enhance reactive oxygen species accumulation. However, whether GA could improve multidrug resistance through modulating autophagy has never been explored. We demonstrated that the combination of GA and cisplatin (CDDP) resulted in a stronger growth inhibition effect on A549 and NCI-H460 cells using the MTT assay. Furthermore, treatment with GA significantly increased autophagy in these cells. More importantly, GA-induced cell death could be largely abolished by 3-methyladenine (3-MA) or chloroquine (CQ) treatment, suggesting that GA-induced cell death was dependent on autophagy. Western blot analysis showed that GA treatment suppressed the activation of Akt, mTOR, and S6. In addition, using a GA and rapamycin combination induced more cell death compared to either GA or rapamycin alone. In summary, GA may have utility as an adjunct therapy for non-small cell lung cancer (NSCLC) patients through autophagy-dependent cell death, even when cancer cells have developed resistance to apoptosis.

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“…In addition to apoptosis-dependent cancer cell death, autophagic cell death has been greatly valued as a novel mechanism for cancer cell death induced by chemotherapeutics (6,7,9). Certain studies suggest that the pro-survival functions of autophagy decrease the efficacy of cancer therapeutics (20,25).…”

Section: Discussionmentioning

confidence: 99%

“…At the initial development phase, autophagy functions as a tumor suppressor mechanism (4,5). However, it prompts the malignant progression of tumors in hypoxic microenvironments (6,7). When autophagy is initiated, cytosolic light chain (LC)3 (LC3-I) loses a small polypeptide during enzymatic hydrolysis and is transformed into the membrane type of LC3, LC3-II, thereby enhancing the formation of an autophagosome.…”

Section: Introductionmentioning

confidence: 99%

Allicin activates autophagic cell death to alleviate the malignant development of thyroid cancer

Xiang

Zhao

et al. 2018

Exp Ther Med

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Abstract. Allicin has been reported to inhibit cancer cell proliferation, induce cell apoptosis and enhance the accumulation of reactive oxygen species. However, it has remained elusive whether allicin improves multidrug resistance in thyroid cancer cells through modulating autophagy. The present study demonstrated that combined use of allicin and cisplatin or carboplatin resulted in an enhanced growth inhibitory effect on SW1736 and HTh-7 cells. Furthermore, treatment with allicin significantly increased SW1736 and HTh-7 cell autophagy. Of note, allicin-induced cell death was largely abolished by 3-methyladenine or chloroquine treatment, suggesting that allicin-induced A549 cell death was dependent on autophagy. Western blot analysis demonstrated that allicin treatment inhibited the activation of Akt, mammalian target of rapamycin and S6. Furthermore, it was demonstrated that combined use of allicin and rapamycin induced more cell death compared with that induced by allicin or rapamycin alone. In conclusion, allicin may serve as an adjunctive therapy for thyroid cancer, as it induces autophagy-dependent cell death even when cancer cells have developed apoptosis resistance.

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TW01001, a novel piperazinedione compound, induces mitotic arrest and autophagy in non-small cell lung cancer A549 cells

Cited by 13 publications

References 56 publications

AKT/mTOR and c-Jun N-terminal kinase signaling pathways are required for chrysotile asbestos-induced autophagy

AKT/mTOR and c-Jun N-terminal kinase signaling pathways are required for chrysotile asbestos-induced autophagy

Gambogic acid improves non‐small cell lung cancer progression by inhibition of mTOR signaling pathway

Allicin activates autophagic cell death to alleviate the malignant development of thyroid cancer

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