The Role of Autophagy in Pancreatic Cancer: From Bench to the Dark Bedside

Görgülü, Kıvanç; Diakopoulos, Kalliope N.; Kaya-Aksoy, Ezgi; Ciecielski, Katrin J.; Ai, Jiaoyu; Lesina, Marina; Algül, Hana

doi:10.3390/cells9041063

Cited by 31 publications

(25 citation statements)

References 123 publications

(165 reference statements)

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“…Autophagy promotes invasion of cancer stem cells through TGF-1β dependent epithelial-mesenchymal transition ( 85 ). However, autophagy inhibitors have not yet shown survival improvements in clinical trials ( 86 ). Further studies require to clarify mechanisms by which benzimidazole anthelmintics induce autophagy.…”

Section: Antitumorigenic Effects Of Benzimidazole Anthelmintics In Camentioning

confidence: 99%

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

2020

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The development of refractory tumor cells limits therapeutic efficacy in cancer by activating mechanisms that promote cellular proliferation, migration, invasion, metastasis, and survival. Benzimidazole anthelmintics have broad-spectrum action to remove parasites both in human and veterinary medicine. In addition to being antiparasitic agents, benzimidazole anthelmintics are known to exert anticancer activities, such as the disruption of microtubule polymerization, the induction of apoptosis, cell cycle (G2/M) arrest, anti-angiogenesis, and blockage of glucose transport. These antitumorigenic effects even extend to cancer cells resistant to approved therapies and when in combination with conventional therapeutics, enhance anticancer efficacy and hold promise as adjuvants. Above all, these anthelmintics may offer a broad, safe spectrum to treat cancer, as demonstrated by their long history of use as antiparasitic agents. The present review summarizes central literature regarding the anticancer effects of benzimidazole anthelmintics, including albendazole, parbendazole, fenbendazole, mebendazole, oxibendazole, oxfendazole, ricobendazole, and flubendazole in cancer cell lines, animal tumor models, and clinical trials. This review provides valuable information on how to improve the quality of life in patients with cancers by increasing the treatment options and decreasing side effects from conventional therapy.

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Section: Antitumorigenic Effects Of Benzimidazole Anthelmintics In Camentioning

confidence: 99%

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

2020

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“…Autophagy induced by chemotherapy drugs can not only promote the apoptosis of tumor cells, but also serve as the survival mechanism of anti-apoptosis of tumor cells (58). Radiotherapy can activate autophagy of pancreatic cancer cells and induce autophagy apoptosis (59).…”

Section: Discussionmentioning

confidence: 99%

Oridonin induces autophagy-mediated cell death in pancreatic cancer by activating the c-Jun N-terminal kinase pathway and inhibiting phosphoinositide 3-kinase signaling

Zhao¹,

Zhang²,

Wang³

et al. 2021

Ann Transl Med

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Background: Oridonin is a diterpenoid isolated from Rabdosia rubescens that has potent anticancer activity.This study set out to investigate the antitumor effects of oridonin in pancreatic carcinoma (PC) and their underlying mechanisms.Methods: To investigate the antitumor effects of oridonin, we developed an orthotopic C57BL/6 mouse model of PC. After successful establishment of the model, the mice were given a daily intraperitoneal injection of phosphate-buffered saline containing 0.1% dimethyl sulfoxide or oridonin for 2 weeks. In vitro experiments including MTT assay and flow cytometry were performed to examine cell viability and apoptosis. Panc-1 and Panc02 cells were transfected with a green fluorescent protein (GFP)-LC3 plasmid.After the cells had been treated with or without 20 μM oridonin and 10 μM 3-MA, the formation of GFP-LC3 puncta was detected by fluorescence microscopy. The levels of the autophagy-related proteins Beclin-1, LC3, and p62 were measured by western blotting.Results: Oridonin inhibited the proliferation of PC cells and induced their apoptosis in vitro and in vivo.Treatment with oridonin also led to an increase in the quantity of LC3B II protein and upregulation of the p62 and Beclin-1 levels in PC cells. The effects of oridonin on PC cell proliferation, apoptosis, and autophagy were mediated via the simultaneous inhibition of the phosphoinositide 3-kinase pathway and activation of the c-Jun N-terminal kinase pathway. Conclusions:Our study is the first to confirm the antitumor and autophagy-activating effects of oridonin on PC cells. In light of these results, oridonin may be a promising therapeutic agent for PC.

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“…Indeed, increased autophagy or mitophagy levels are observed in various types of pancreatic cancer (46)(47)(48). However, autophagy plays a dual role in various cancer (including PDAC), depending on many factors, such as tumor stage, tumor microenvironment, gene mutation status involving oncogenes and tumor suppressor genes, and metabolic reprogramming (49)(50)(51)(52)(53)(54). PDAC is a heterogeneous disease and can be morphologically classified into four types: conventional, tubulopapillary, squamous, and "composite", which exhibit different molecular and genetic characteristics (55).…”

Section: Mitophagy In Pancreatic Cancermentioning

confidence: 99%

Mitophagy in Pancreatic Cancer

et al. 2021

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Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive solid malignancies, is characterized by the presence of oncogenic KRAS mutations, poor response to current therapies, prone to metastasis, and a low 5-year overall survival rate. Macroautophagy (herein referred to as autophagy) is a lysosome-dependent degradation system that forms a series of dynamic membrane structures to engulf, degrade, and recycle various cargoes, such as unused proteins, damaged organelles, and invading pathogens. Autophagy is usually upregulated in established cancers, but it plays a dual role in the regulation of the initiation and progression of PDAC. As a type of selective autophagy, mitophagy is a mitochondrial quality control mechanism that uses ubiquitin-dependent (e.g., the PINK1-PRKN pathway) and -independent (e.g., BNIP3L/NIX, FUNDC1, and BNIP3) pathways to regulate mitochondrial turnover and participate in the modulation of metabolism and cell death. Genetically engineered mouse models indicate that the loss of PINK1 or PRKN promotes, whereas the depletion of BNIP3L inhibits oncogenic KRAS-driven pancreatic tumorigenesis. Mitophagy also play a dual role in the regulation of the anticancer activity of certain cytotoxic agents (e.g., rocaglamide A, dichloroacetate, fisetin, and P. suffruticosa extracts) in PDAC cells or xenograft models. In this min-review, we summarize the latest advances in understanding the complex role of mitophagy in the occurrence and treatment of PDAC.

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The Role of Autophagy in Pancreatic Cancer: From Bench to the Dark Bedside

Cited by 31 publications

References 123 publications

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

Oridonin induces autophagy-mediated cell death in pancreatic cancer by activating the c-Jun N-terminal kinase pathway and inhibiting phosphoinositide 3-kinase signaling

Mitophagy in Pancreatic Cancer

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