Alantolactone induces apoptosis and improves chemosensitivity of pancreatic cancer cells by impairment of autophagy-lysosome pathway via targeting TFEB

He, Ruizhi; Shi, Xiuhui; Zhou, Min; Zhao, Yan; Pan, Shutao; Zhao, Chunle; Guo, Xiaomao; Wang, Min; Xu, Li; Qin, Renyi

doi:10.1016/j.taap.2018.08.003

Cited by 49 publications

(35 citation statements)

References 38 publications

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“…There are studies which have shown that ALT exerts anti-tumor effects on tumor cells alone or when combined with other anti-tumor agents The mechanisms involved included regulation of oxygen species-mediated ER stress, ROS response, and modulation of other signaling pathways, such as the Akt/GSK3β, p38 MAPK, NF-κB, STAT3 and Nrf2 signaling pathways. Currently, the function of ALT on autophagy has only been reported once by He et al who found that ALT caused the accumulation of autophagosomes due to impaired autophagic degradation, and signi cantly inhibited the activity and expression of CTSB/CTSD proteins [12]. Their data demonstrated that ALT, which impaired autophagic degradation, was a pharmacological inhibitor of autophagy in pancreatic cancer cells and markedly enhanced the chemosensitivity of pancreatic cancer cells to oxaliplatin.…”

Section: Discussionmentioning

confidence: 97%

Alantolactone inhibits cell autophagy and promotes apoptosis via AP2M1 in acute lymphoblastic leukemia

Shi

Lan

Wang

et al. 2020

Preprint

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Background: Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy that is most commonly observed in children. Alantolactone (ALT) has been reported to exhibit anti-tumor activity in different types of cancer. The aim of the present study was to investigate the anti-tumor activity and molecular mechanism of ALT in ALL. Methods: ALL cell lines were treated with 1, 5 and 10 μM ALT, and cell viability was assessed using an MTT assay and RNA sequencing. Flow cytometry, JC-1 staining and immunofluorescence staining assays were used to measure cell apoptosis and autophagy. Additionally, western blot analysis was used to detect expression of apoptosis and autophagy related proteins. Finally, the effects of ALT on tumor growth were assessed in a BV173 xenograft nude mouse model. Results: ALT inhibited the proliferation of ALL cells in a dose-dependent manner. Additionally, it was demonstrated that ALT inhibited cell proliferation, colony formation, autophagy, induced apoptosis and reduced tumor growth in vivo through upregulating the expression of adaptor related protein complex 2 subunit mu 1 (AP2M1). Moreover, the autophagy activator rapamycin, attenuated the pro-apoptotic effects of ALT on BV173 and NALM6 cell lines. Overexpression of AP2M1 decreased the expression of Beclin1 and the LC3-II/LC3-1 ratio, and increased p62 expression. Knockdown of Beclin1 increased the levels of bax, cleaved caspase 3 and cytochrome C, and decreased bcl-2 expression. Conclusions: The present study demonstrated that ALT exerts anti-tumor activity through inducing apoptosis and inhibiting autophagy by upregulating AP2M1 in ALL, highlighting a potential therapeutic strategy for treatment of ALL.

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Section: Discussionmentioning

confidence: 97%

Alantolactone inhibits cell autophagy and promotes apoptosis via AP2M1 in acute lymphoblastic leukemia

Shi

Lan

Wang

et al. 2020

Preprint

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“…Given that CQ inhibits late autophagy by preventing the autophagosome-lysosome fusion, our data suggest that the autophagic process is initiated upon treatment with the drug combination, although autophagy might not display a significant role on its antiproliferative effect. In fact, uncompleted autophagy has been related to high rates of apoptosis due to the accumulation of nonfunctional cellular structures [33,34]. Therefore, it is feasible to hypothesize that the observed strong pro-apoptotic effect induced by the drug combination (Figure 2A) might be a consequence of a blockage of the autophagic flux.…”

Section: Drug Combination Triggers Apoptosis On Caco-2 Cellsmentioning

confidence: 99%

“…We observed a time-dependent loss of acidification that correlates with lysosomal impairment. As aforementioned, drug-mediated induction of lysosome alkalization has been related to a blockage of the autophagic flux and high rates of apoptosis [33,34], and mitochondrial dysfunction is considered to be one of the main causes of the impairment of lysosomes [35]. With this in mind, changes in mitochondrial membrane potential (ψ m ) were analyzed after 24 h and 48 h incubation with the drug combination ( Table 2).…”

Section: Drug Combination Disrupts Redox Homeostasis Which Induces Mmentioning

confidence: 99%

A Combination of Rosa Canina Extracts and Gold Complex Favors Apoptosis of Caco-2 Cells by Increasing Oxidative Stress and Mitochondrial Dysfunction

et al. 2019

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Given the alarming increase in colorectal cancer (CRC) worldwide, novel therapies are urgently needed. Plant-derived extracts have gained considerable interest in the last years due to their strong anticancer effect mediated by their unique bioactive compounds. Specifically, rosehips from Rosa canina have been successfully tested against several cancer models, including colon cancer. Moreover, gold derivatives are a promising alternative to the current platinum-based drugs commonly used in CRC chemotherapy due to their lack of affinity for DNA. Herein we have investigated the antitumor potential of a drug combination made of acidic polyphenols extracted from R. canina and the gold complex (Au(C≡C-2-NC5H4) (PTA)) in Caco-2 cell line as a model of CRC. The combination triggered strong apoptosis mediated by a blockage of the autophagic flux, which might be a consequence of a reactive oxygen species (ROS) increase and mitochondrial dysfunctionality. Our results suggest that the clinical application of plant polyphenols might enhance the anticancer effect of metallodrugs and reduce drug exposure time and therefore its side effects.

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“…ALT regulates the p38 MAPK and NF-κB pathways. ALT inhibits TrxR1 activity and activates a ROS-mediated p38 MAPK signaling pathway [12]. Additionally, ALT impairs the autophagy-lysosome pathway by targeting TFEB [12].…”

mentioning

confidence: 99%

“…ALT inhibits TrxR1 activity and activates a ROS-mediated p38 MAPK signaling pathway [12]. Additionally, ALT impairs the autophagy-lysosome pathway by targeting TFEB [12]. Finally, ALT enhances the sensitivity of cancer cells to EGFR inhibitors through inhibition of STAT3 signaling [11].…”

mentioning

confidence: 99%

Alantolactone inhibits cell autophagy and promotes apoptosis via AP2M1 in acute lymphoblastic leukemia

et al. 2020

View full text Add to dashboard Cite

Background Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy that is most commonly observed in children. Alantolactone (ALT) has been reported to exhibit anti-tumor activity in different types of cancer. The aim of the present study was to investigate the anti-tumor activity and molecular mechanism of ALT in ALL. Methods ALL cell lines were treated with 1, 5 and 10 μM ALT, and cell viability was assessed using an MTT assay and RNA sequencing. Flow cytometry, JC-1 staining and immunofluorescence staining assays were used to measure cell apoptosis and autophagy. Additionally, western blot analysis was used to detect expression of apoptosis and autophagy related proteins. Finally, the effects of ALT on tumor growth were assessed in a BV173 xenograft nude mouse model. Results ALT inhibited the proliferation of ALL cells in a dose-dependent manner. Additionally, it was demonstrated that ALT inhibited cell proliferation, colony formation, autophagy, induced apoptosis and reduced tumor growth in vivo through upregulating the expression of adaptor related protein complex 2 subunit mu 1 (AP2M1). Moreover, the autophagy activator rapamycin, attenuated the pro-apoptotic effects of ALT on BV173 and NALM6 cell lines. Overexpression of AP2M1 decreased the expression of Beclin1 and the LC3-II/LC3-1 ratio, and increased p62 expression. Knockdown of Beclin1 increased the levels of bax, cleaved caspase 3 and cytochrome C, and decreased bcl-2 expression. Conclusions The present study demonstrated that ALT exerts anti-tumor activity through inducing apoptosis and inhibiting autophagy by upregulating AP2M1 in ALL, highlighting a potential therapeutic strategy for treatment of ALL.

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Alantolactone induces apoptosis and improves chemosensitivity of pancreatic cancer cells by impairment of autophagy-lysosome pathway via targeting TFEB

Cited by 49 publications

References 38 publications

Alantolactone inhibits cell autophagy and promotes apoptosis via AP2M1 in acute lymphoblastic leukemia

Alantolactone inhibits cell autophagy and promotes apoptosis via AP2M1 in acute lymphoblastic leukemia

A Combination of Rosa Canina Extracts and Gold Complex Favors Apoptosis of Caco-2 Cells by Increasing Oxidative Stress and Mitochondrial Dysfunction

Alantolactone inhibits cell autophagy and promotes apoptosis via AP2M1 in acute lymphoblastic leukemia

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