Metformin sensitizes anticancer effect of dasatinib in head and neck squamous cell carcinoma cells through AMPK-dependent ER stress

Lin, Yu‐Chin; Wu, Meng-Hsuan; Wei, Tzu-Tang; Lin, Yun‐Sheng; Huang, Wen Ching; Huang, Liangyu; Lin, Yuanqing; Chen, Ching-Chow

doi:10.18632/oncotarget.1628

Cited by 43 publications

(47 citation statements)

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“…We identified 11 articles with experimental studies that were in vitro and in vivo animal studies that analyzed the effect of metformin in HNSCC [20,28,45,46,[49][50][51][52][53][54][55] 2 of these studies presented the most important and complete results. Vitale-Cross et al [46] showed that metformin reduced the growth of HNSCC cells and diminished their mTORC1 activity by both AMPK-dependent and AMPK-independent mechanisms.…”

Section: Summary Of Evidencementioning

confidence: 99%

Effects of metformin on head and neck cancer: A systematic review

et al. 2015

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Section: Summary Of Evidencementioning

confidence: 99%

Effects of metformin on head and neck cancer: A systematic review

et al. 2015

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“…Previous reports have demonstrated that metformin enhances the effect of chemotherapy and radiotherapy by promoting the AMPK-autophagy signaling pathway (15)(16)(17)(18)(19). Therefore, it is expected that metformin would potentiate the cytotoxicity of 5-ALA-PDT.…”

Section: Discussionmentioning

confidence: 97%

“…Several studies have identified that metformin enhances the cytotoxicity of chemotherapy by promoting the AMPK-autophagy pathway (15)(16)(17)(18). In addition, metformin has been demonstrated to cause cell death in radiosensitized cancer cells and radioresistant cancer stem cells by activating AMPK and suppressing mTOR (19).…”

Section: Introductionmentioning

confidence: 99%

Metformin enhances the cytotoxicity of 5-aminolevulinic acid-mediated photodynamic therapy in vitro

et al. 2017

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Abstract.The biguanide metformin is a drug widely used for the treatment of type 2 diabetes. Metformin enhances the cytotoxicity of chemotherapy by promoting the adenosine monophosphate-activated protein kinase (AMPK) autophagy signaling pathway. Photodynamic therapy (PDT) with 5-aminolevulinic acid (5-ALA), a precursor of protoporphyrin IX (PpIX), leads to apoptosis when PpIX accumulates in the mitochondria, and also leads to autophagy through activation of AMPK. In the present study, the effect of metformin in combination with 5-ALA-PDT was evaluated in vitro in KLN205 lung cancer cells. At a fluence of 5 J/cm 2 , 5-ALA-PDT in combination with 5 mM metformin exhibited significantly increased cytotoxicity compared with that observed with 0 and 0.1 mM metformin (P=0.0197 and P=0.0423, respectively). The cells treated with 5-ALA-PDT and metformin exhibited condensation of nuclear chromatin and the presence of autophagosomes. These results indicate that apoptosis and autophagy occur in KLN205 cells following combined treatment with 5-ALA-PDT and metformin. The results from the present study are the first to indicate, to the best of our knowledge, that metformin potentiates the efficacy of 5-ALA-PDT. IntroductionPhotodynamic therapy (PDT) has been developed as an effective treatment for malignant tumors. PDT involves the administration of a photosensitizer, which preferentially accumulates in malignant tissue, and its subsequent activation by light of the appropriate wavelength (1,2). The interaction of light with the intracellular photosensitizer causes the release of oxygen radicals, leading to cell death (3).5-Aminolevulinic acid (5-ALA) is a precursor of protoporphyrin IX (PpIX), a well-known photosensitizer, and is converted in situ to PpIX via the heme biosynthetic pathway (4). 5-ALA has been used successfully for photodynamic diagnosis and PDT (5,6). Although 5-ALA-PDT has been intensively studied for several decades, the mechanism underlying its cytotoxicity is not well known. It has been demonstrated that 5-ALA-PDT leads to apoptosis when PpIX accumulates in the mitochondria and to necrosis when it diffuses into the cytoplasm (7). A previous study reported that 5-ALA-PDT induced autophagic cell death through the activation of adenosine monophosphate-activated protein kinase (AMPK) (8).The biguanide metformin (N,N-dimethylimidodicarbonimidic diamide), a widely used drug for the treatment of type 2 diabetes, reduces blood glucose levels by suppressing gluconeogenesis in the liver and increasing glucose uptake by the skeletal muscle (9,10). Additionally, metformin has been demonstrated to significantly inhibit tumor growth in several types of cancer and mouse tumor models (11-13). It was reported that metformin can control the proliferation of cancer cells, and this effect was associated with a number of signaling pathways, including the activation of AMPK and mitogen-activated protein kinase (MAPK) signaling, and decreased mammalian target of rapamycin (mTOR) and epidermal growth factor signaling (14).Severa...

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“…These findings demonstrated that ER stress is elevated by the combination of metformin and FTY720. In previous studies, metformin has been found to induce ER stress in various carcinoma cells, such as liver, prostate, and head and neck squamous cell carcinoma [44][45][46]. Meanwhile, several studies determined that metformin attenuates ER-stress in pancreatic beta and cardiac epithelial cells [47,48].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Metformin and FTY720 Synergistically Induce Apoptosis in Multiple Myeloma Cells

Zhao

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Patients with multiple myeloma (MM) invariably relapse with chemotherapy-resistant disease, underscoring the need for new therapeutic options that bypass these resistance mechanisms. Metformin is a widely prescribed antidiabetic drug with direct antitumor activity against various tumor cell lines. FTY720, also known as fingolimod, is an immune-modulating agent approved by the FDA as oral medication to treat the relapsing form of multiple sclerosis (MS). In recent years, FTY720 has attracted attention due to its anti-tumor activity. To explore an optimized combinational therapy, interactions between metformin and FTY720 were examined in MM cells. Methods: MTT assays were employed to assess the viability of MM cells. An apoptotic nucleosome assay was employed to measure apoptosis. Loss of mitochondrial membrane potential (MMP, ΔΨm) and cellular levels of ROS were measured by flow cytometry. qRT-PCR was used to analyze the expression of mRNAs. Western blotting assays were applied to measure the levels of proteins involved in different signaling pathways. Results: Coadministration of metformin and FTY720 synergistically inhibited the proliferation of MM cells. Increased levels of apoptosis, activation of caspase-3 and cleavage of PARP were detected after cotreatment with metformin and FTY720. These events were associated with modulation of Bcl-2 proteins, loss of MMP, ER stress induction, and inhibition of the PI3K/AKT/mTOR signaling pathway. The metformin/FTY720 regimen markedly induced ROS generation; moreover, apoptosis, ER stress and inhibition of PI3K/AKT/ mTOR were attenuated by the ROS scavenger NAC. Conclusions: Exposure to metformin in combination with FTY720 potently induces apoptosis in MM cells in a ROS-dependent manner, suggesting that a strategy combining these agents warrants further investigation in MM.

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Metformin sensitizes anticancer effect of dasatinib in head and neck squamous cell carcinoma cells through AMPK-dependent ER stress

Cited by 43 publications

References 50 publications

Effects of metformin on head and neck cancer: A systematic review

Effects of metformin on head and neck cancer: A systematic review

Metformin enhances the cytotoxicity of 5-aminolevulinic acid-mediated photodynamic therapy in vitro

Metformin and FTY720 Synergistically Induce Apoptosis in Multiple Myeloma Cells

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