Gemcitabine induces apoptosis and autophagy via the AMPK/mTOR signaling pathway in pancreatic cancer cells

Zhu, Jinhui; Chen, Yan; Ji, Yun; Yu, Yuanquan; Yun, Jimmy; Zhang, Xiaoxiao; Zhou, Jiale

doi:10.1002/bab.1657

Cited by 34 publications

(27 citation statements)

References 50 publications

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“…IHC staining also showed that Gem induced CC3 and CC8 expression in vivo. These observations are consistent with those presented in our previous report [ 8 ] and those of others [ 7 , 15 ]. Gem induces apoptosis more potently than other basic agents, such as methotrexate, doxorubicin, cisplatin, and ifosfamide, and may therefore be a key drug for treating OS through the induction of apoptosis.…”

Section: Discussionsupporting

confidence: 94%

“…Since then, several clinical trials using Gem have been conducted and recently, additional clinical studies on Gem in combination with docetaxel have been evaluated in various adult sarcomas, including OS [ 9 , 10 , 11 , 12 ]. We also reported that Gem strongly induces apoptosis in OS cells in vitro and in vivo [ 8 ]; however, several other reports have shown that Gem induces autophagic cell death [ 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 98%

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Gemcitabine and Rapamycin Exhibit Additive Effect against Osteosarcoma by Targeting Autophagy and Apoptosis

Ando

Ichikawa

Fujimaki

et al. 2020

Cancers

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The overall prognosis for sarcoma-based cancer patients has remained largely unchanged over the past 10 years. Because there is no effective anticancer drug for patients with chemoresistant osteosarcoma (OS), novel approaches are needed to improve the prognosis. Here, we investigated whether rapamycin (Rapa) could enhance the anti-tumor effects of gemcitabine (Gem) in OS. Gem dose-dependently killed the OS cells, but exhibited much lower cytotoxicity on osteoblasts. Treatment with a combination Gem and Rapa was much more effective than that of either single agent with respect to reducing cell viability, cell invasion, cell migration, and vascular endothelial growth factor production in vitro. Moreover, the combination of these agents suppressed tumor growth, angiogenesis, and lung metastasis in allograft and xenograft murine models of OS with minimal adverse effects. Overall, the combination therapy prolonged the overall survival of tumor-bearing mice. Mechanistically, Gem induced apoptosis and increased the levels of cleaved caspases, while Rapa induced autophagy and microtubule-associated protein light chain 3 (LC3)-I/LC3-II expression both in vitro and in vivo. Our findings suggest that chemotherapy using Gem combined with Rapa may be a novel and promising therapeutic approach for the treatment of OS.

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Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 98%

Gemcitabine and Rapamycin Exhibit Additive Effect against Osteosarcoma by Targeting Autophagy and Apoptosis

Ando

Ichikawa

Fujimaki

et al. 2020

Cancers

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“…The mTOR pathway is considered as one of regulating mechanisms responsible for cell sensitivity to GEM. Such relation was already proved in various cancers including breast and pancreatic 33 , 34 , 35 . Yang et al investigated the mechanism of resistance to GEM in breast cancer model, they noted hyperactivation of mTOR pathway in cells insensitive to treatment with GEM.…”

Section: Discussionmentioning

confidence: 71%

“…The most important is using only 2D models of uterine sarcomas and carcinosarcoma, such models are easily reproducible and allow to perform isobolographic analysis of relations between tested substances, but on the other hand do not fully reflect behaviour of tumours in vivo . Secondly, the reported project do not include any mechanistic research, partially the activity mechanisms of used compounds were previously described 4 , 5 , 5 , 7 , 26 , 29 , 30 , 33 , 35 but further studies aimed to describe mechanisms of cellular response to combined treatment are strongly indicated.…”

Section: Discussionmentioning

confidence: 99%

Gemcitabine and Selected mTOR Inhibitors in Uterine Sarcomas and Carcinosarcoma Cells- an Isobolographic Analysis

Bobinski¹,

Okła²,

Łuszczki³

et al. 2020

Int. J. Med. Sci.

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Introduction: mTOR inhibitors are anticancer agents affecting mTOR/AKT/PI3K pathway that is one of the most important in human cancer cells. Hyperactivation of mTOR/AKT/PI3K and overexpression of this pathway members are frequently reported in uterine sarcoma and carcinosarcoma. Present study is aimed to assess the activity of the two mTOR inhibitors (rapamycin - RAP and sapanisertib - MLN) as a single agent and combined with gemcitabine (GEM, one of substances commonly used in systemic anticancer treatment) in uterine sarcoma and carcinosarcoma in vitro models. Material and methods: SK-UT-1 and SK-UT1-B (uterine carcinosarcoma), MES-SA (leiomyosarcoma) and ESS-1 (endometrial stromal sarcoma) cell lines were used. An MTT assay was performed to examine the cytotoxicity of RAP, MLN and mixtures: RAP+MLN, RAP+GEM, MLN+GEM against these cells. The interactions between tested compounds were assessed in isobolographic analysis. Results and conclusions: Carcinosarcoma cell lines (both SK-UT-1 and SK-UT-1B) do not respond to RAP and respond relatively weakly to MLN treatment. Additive and supraadditive effects were noted for combined treatment with GEM and MLN. Endometrial stromal sarcoma cell line (ESS-1) occured to be sensitive to both RAP and MLN, but the response was stronger for MLN. Additive effect of all tested drug combinations was observed for ESS-1. Leiomyosarcoma cell line (MES-SA) was found sensitive to both mTOR inhibitors. Additive effects in combinations of GEM, RAP and MLN were observed, what makes them promising for future preclinical and clinical trials. Additivity with slight tendency towards antagonism between GEM and MLN observed in MES-SA cell line is unexpected finding and might prompt the mechanistic research aimed to explain this phenomenon.

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“…Zyflamend treatment induced ER stress, autophagy, MAP kinases and apoptosis in pancreatic β-TC6 Cells. Previous studies have shown that activation of AMPK in pancreatic cancer cells by chemotherapeutic agens induces apoptosis and autophagy via the AMPK/mTOR signaling pathway (dotted lines) [ 47 ]. Similarly, activation of the JNK/SAPK pathway [ 48 ] by stressors and chemotherapeutic agents can lead to apoptotic cell death of pancreatic cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Zyflamend induces apoptosis in pancreatic cancer cells via modulation of the JNK pathway

et al. 2020

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Background: Current pharmacological therapies and treatments targeting pancreatic neuroendocrine tumors (PNETs) have proven ineffective, far too often. Therefore, there is an urgent need for alternative therapeutic approaches. Zyflamend, a combination of anti-inflammatory herbal extracts, that has proven to be effective in various in vitro and in vivo cancer platforms, shows promise. However, its effects on pancreatic cancer, in particular, remain largely unexplored. Methods: In the current study, we investigated the effects of Zyflamend on the survival of beta-TC-6 pancreatic insulinoma cells (β-TC6) and conducted a detailed analysis of the underlying molecular mechanisms. Results: Herein, we demonstrate that Zyflamend treatment decreased cell proliferation in a dose-dependent manner, concomitant with increased apoptotic cell death and cell cycle arrest at the G2/M phase. At the molecular level, treatment with Zyflamend led to the induction of ER stress, autophagy, and the activation of c-Jun N-terminal kinase (JNK) pathway. Notably, pharmacological inhibition of JNK abrogated the pro-apoptotic effects of Zyflamend. Furthermore, Zyflamend exacerbated the effects of streptozotocin and adriamycin-induced ER stress, autophagy, and apoptosis. Conclusion: The current study identifies Zyflamend as a potential novel adjuvant in the treatment of pancreatic cancer via modulation of the JNK pathway.

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Gemcitabine induces apoptosis and autophagy via the AMPK/mTOR signaling pathway in pancreatic cancer cells

Cited by 34 publications

References 50 publications

Gemcitabine and Rapamycin Exhibit Additive Effect against Osteosarcoma by Targeting Autophagy and Apoptosis

Gemcitabine and Rapamycin Exhibit Additive Effect against Osteosarcoma by Targeting Autophagy and Apoptosis

Gemcitabine and Selected mTOR Inhibitors in Uterine Sarcomas and Carcinosarcoma Cells- an Isobolographic Analysis

Zyflamend induces apoptosis in pancreatic cancer cells via modulation of the JNK pathway

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