Inhibition of JNK-Mediated Autophagy Promotes Proscillaridin A- Induced Apoptosis via ROS Generation, Intracellular Ca+2 Oscillation and Inhibiting STAT3 Signaling in Breast Cancer Cells

Saleem, Muhammad Zubair; Alshwmi, Mohammed; Zhang, He; Din, Syed Riaz Ud; Nisar, Muhammad Azhar; Khan, Muhammad Noman; Alam, Shahid; Alam, Gulzar; Jin, Lingling; Ma, Tonghui

doi:10.3389/fphar.2020.01055

Cited by 17 publications

(13 citation statements)

References 54 publications

(74 reference statements)

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“…Current findings also indicate that the induction of autophagy facilitates IL-6 secretion, suggesting a positive feedback loop for the IL-6/STAT3 pathway underlying the survival and drug resistance mechanisms, while inhibiting apoptosis [58,59]. In addition, inhibited autophagy activation by CQ, leading to the blockage of autophagic flux, thereby decreased the amount of IL-6, and inhibited STAT3 expression, which caused the shift from autophagy to apoptosis and increased the sensitivity of cells to cancer therapy [60]. Our results are similar to previous findings showing that PT combined with CQ significantly inhibited autophagy, decreased cell viability, and sensitized the cells to PT-induced apoptosis via downregulation of the RAGE/STAT3 pathways in PDAC cells.…”

Section: Discussionmentioning

confidence: 81%

Chloroquine Potentiates the Anticancer Effect of Pterostilbene on Pancreatic Cancer by Inhibiting Autophagy and Downregulating the RAGE/STAT3 Pathway

et al. 2021

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The treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, because pro-survival signaling pathways—such as the receptor for advanced glycation end products (RAGE)/signal transducer and activator of transcription 3 (STAT3) pathway—are overexpressed in PDAC cells. Moreover, PDAC cells are highly resistant to chemotherapeutic agents because of autophagy induction. Therefore, autophagy and its modulated signaling pathways are attractive targets for developing novel therapeutic strategies for PDAC. Pterostilbene is a stilbenoid chemically related to resveratrol, and has potential for the treatment of cancers. Accordingly, we investigated whether the autophagy inhibitor chloroquine could potentiate the anticancer effect of pterostilbene in the PDAC cell lines MIA PaCa-2 and BxPC-3, as well as in an orthotopic animal model. The results indicated that pterostilbene combined with chloroquine significantly inhibited autophagy, decreased cell viability, and sensitized the cells to pterostilbene-induced apoptosis via downregulation of the RAGE/STAT3 and protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways in PDAC cells. The results of the orthotopic animal model showed that pterostilbene combined with chloroquine significantly inhibited pancreatic cancer growth, delayed tumor quadrupling times, and inhibited autophagy and STAT3 in pancreatic tumors. In summary, the present study suggested the novel therapeutic strategy of pterostilbene combined with chloroquine against the growth of pancreatic ductal adenocarcinoma by inhibiting autophagy and downregulating the RAGE/STAT3 signaling pathways.

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Section: Discussionmentioning

confidence: 81%

Chloroquine Potentiates the Anticancer Effect of Pterostilbene on Pancreatic Cancer by Inhibiting Autophagy and Downregulating the RAGE/STAT3 Pathway

et al. 2021

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“…Fifty nM of proscillaridin A induces autophagy in human cells derived from hepatocarcinoma (MHCC97H, and Huh7) after 24 h of treatment (LC3-II increase, inhibition of mTOR) [ 111 ]. As confirmed by Saleem et al [ 112 ], proscillaridin A could be combined with autophagy inhibitors to increase its anticancer potential. In breast cancer, proscillaridin A induces both apoptosis and autophagy.…”

Section: Cardiac Glycosides As Autophagy Modulatorsmentioning

confidence: 84%

Cardiac Glycosides as Autophagy Modulators

Škubník

Pavlíčková

Psotová

et al. 2021

Cells

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Drug repositioning is one of the leading strategies in modern therapeutic research. Instead of searching for completely novel substances and demanding studies of their biological effects, much attention has been paid to the evaluation of commonly used drugs, which could be utilized for more distinct indications than they have been approved for. Since treatment approaches for cancer, one of the most extensively studied diseases, have still been very limited, great effort has been made to find or repurpose novel anticancer therapeutics. One of these are cardiac glycosides, substances commonly used to treat congestive heart failure or various arrhythmias. Recently, the antitumor properties of cardiac glycosides have been discovered and, therefore, these compounds are being considered for anticancer therapy. Their mechanism of antitumor action seems to be rather complex and not fully uncovered yet, however, autophagy has been confirmed to play a key role in this process. In this review article, we report on the up-to-date knowledge of the anticancer activity of cardiac glycosides with special attention paid to autophagy induction, the molecular mechanisms of this process, and the potential employment of this phenomenon in clinical practice.

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“…Although it is no longer used clinically, Pro A was reported to have anti-tumor effects on several cancers. Pro A can inhibit STAT3 signaling in breast cancer cells ( 32 ) and trigger the activation of endoplasmic reticulum stress to slow the prostate cancer progression ( 33 ). Previous study has shown that Pro A at micro-molar concentrations can induce PC cell apoptosis ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

Proscillaridin A induces mitochondrial damage and autophagy in pancreatic cancer and reduces the stability of SMAD4 in Panc-1 cells

Jia¹,

Kang²,

Liu³

et al. 2022

Ann Transl Med

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Background Pancreatic cancer (PC) is a highly metastatic and lethal cancer with a very low overall 5-year survival rate. There is an urgent need for identifying new therapeutic agents for this deadly disease. Cardiac glycosides (CGs) have been traditionally used for their potent cardiovascular activities and have also recently been reported to exhibit anti-tumor effects. Proscillaridin A (Pro A), a natural CG, has been shown to display anti-tumor effects on multiple cancer types. Methods The cytotoxic effect of Pro A on PC cells was determined using cell viability assay, colony formation assay and transwell assay in vitro . Cell apoptosis, cell cycle, reactive oxygen species (ROS) generation, intracellular Ca 2+ levels and mitochondrial membrane potential (MMP) were assayed by flow cytometry. Panc-1-xenografted mice model was used to evaluate Pro A’s effect in tumor growth. Mitochondria morphology was observed by transmission electron microscopy. LC3 aggregation was assessed by GFP-LC3 fluorescence microscopy. Gene expression was assayed by western blot or real-time quantitative polymerase chain reaction (qPCR). Results Pro A inhibits the proliferation, migration and invasion of Panc-1, BxPC-3 and AsPC-1 PC cells in vitro , and Panc-1 cells display the highest sensitivity with an IC50 at the nano-molar level. In vivo , Pro A treatment inhibits tumor progression in Panc-1 xenograft nude mice. Pro A treatment promotes both cell apoptosis and autophagy, and Pro A-treated PC cells display characteristics of mitochondrial damage including increased ROS generation, intracellular Ca 2+ levels and disruption of MMP. In addition, high sensitivity towards Pro A of Panc-1 cells compared to BxPC-3 and AsPC-1 cells could be partially attributed to the loss of endogenous SMAD4 expression in the latter. Conclusions Our findings suggest that Pro A constitutes a promising therapeutic candidate for certain types of PC.

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Inhibition of JNK-Mediated Autophagy Promotes Proscillaridin A- Induced Apoptosis via ROS Generation, Intracellular Ca+2 Oscillation and Inhibiting STAT3 Signaling in Breast Cancer Cells

Cited by 17 publications

References 54 publications

Chloroquine Potentiates the Anticancer Effect of Pterostilbene on Pancreatic Cancer by Inhibiting Autophagy and Downregulating the RAGE/STAT3 Pathway

Chloroquine Potentiates the Anticancer Effect of Pterostilbene on Pancreatic Cancer by Inhibiting Autophagy and Downregulating the RAGE/STAT3 Pathway

Cardiac Glycosides as Autophagy Modulators

Proscillaridin A induces mitochondrial damage and autophagy in pancreatic cancer and reduces the stability of SMAD4 in Panc-1 cells

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