Metformin displays anti-myeloma activity and synergistic effect with dexamethasone in in vitro and in vivo xenograft models

Zi, Fu Ming; He, Jing; Li, Yang; Wu, Cai; Yang, Li; Yang, Yang; Wang, Li Juan; He, Dong Hua; Zhao, Yi; Wu, Wenjun; Zheng, Gaofeng; Han, Xiao; Huang, He; Yi, Qing; Zhang, Cai

doi:10.1016/j.canlet.2014.09.050

Cited by 57 publications

(48 citation statements)

References 46 publications

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“…Our findings are consistent with previous studies that indicated the inhibitory effects of metformin and FTY720 on the viability of various MM cell lines [37][38][39]. The combination of metformin and FTY720 dramatically inhibited cell viability in MM cells compared with the single treatment.…”

Section: Discussionsupporting

confidence: 83%

“…Apoptosis can be trigged mainly via two pathways, namely, the extrinsic pathway and the intrinsic pathway [23]. In previous studies, it has been found that metformin induces apoptosis mainly via the intrinsic pathway in MM cells [37]. Similarly, FTY720 induced apoptosis in MM cells that was dependent on the activation of the intrinsic pathway [39].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 83%

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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“…When metformin is combined with everolimus, it may exert a synergistic inhibition of cancer growth by abrogation of the phosphorylation of S6 and 4E-binding protein 1 (22). Metformin in combination with dexamethasone has been demonstrated to repress the expression of myeloid cell leukemia-1 and activate caspase 3, as well as increasing the number of cells in the G1 phase of the cell cycle (23). A previous study reported that metformin combined with vemurafenib may induce apoptosis and result in the synergistic inhibition of the growth of cancer cells, suggesting that metformin reverses the resistance of cancer cells to vemurafenib by altering the cellular energy balance (24).…”

Section: Discussionmentioning

confidence: 99%

Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer inï¿½vitro and inï¿½vivo

2017

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Abstract. Previous studies have suggested that metformin may improve the survival rate of patients with pancreatic cancer (PC) by regulating the adenosine monophosphate-activated protein kinase/mammalian target of rapamycin (mTOR) signaling pathway. Rapamycin specifically targets mTOR. In the present study, the efficacy of metformin and rapamycin in isolation and combination were investigated for the treatment of PC. The efficacy of metformin and rapamycin in reducing the proliferation of PC cell line SW1990 in vitro and in vivo was evaluated. It was revealed that metformin (10 mmol/l) + rapamycin (2 ng/ml), metformin (15 mmol/l) + rapamycin (20 ng/ml) and metformin (20 mmol/l) + rapamycin (200 ng/ml) significantly inhibited the viability of PC cells compared with untreated cells. Additionally, metformin (20 mmol/l) + rapamycin (200 ng/ml) significantly suppressed the expression of phosphorylated mTOR compared with metformin or rapamycin alone. Using a xenograft tumor model, it was revealed that combination treatment significantly inhibited the growth of PC cells compared with monotherapy. The present study revealed that a combination of metformin and rapamycin synergistically inhibited the growth of PC in vitro and in vivo and may be a potential treatment option for patients with PC.

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“…2A and B) of the MTT assay indicated that isoimperatorin significantly inhibited the proliferation of SGC-7901 cells in a dose-and time-dependent manner. Flow cytometric analysis is a common method used to investigate whether drugs can induce the apoptosis of cancer cells (28,29). In the present study, the results of the flow cytometric analysis (Fig.…”

Section: A B C D Ementioning

confidence: 73%

Isoimperatorin induces apoptosis of the SGC-7901 human gastric cancer cell line via the mitochondria-mediated pathway

2016

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Abstract. The present study was designed to investigate the antiproliferative activity of isoimperatorin against SGC-7901 cells and to examine the possible mechanisms. The antiproliferative activity of isoimperatorin against SGC-7901 cells was evaluated using an MTT assay, and the mechanisms were investigated using flow cytometry and western blot assays, which were used to determine the apoptotic rate and expression levels of mitochondria-mediated apoptosis-associated proteins, including Survivin, myeloid leukemia cell-1 (Mcl-1), B cell lymphoma-extra large (Bcl-xl), B cell lymphoma 2 (Bcl-2), second mitochondria-derived activator of caspase (Smac), Bcl-2-associated X factor (Bax), cleaved (c)-caspase-3 and c-caspase-9 in SGC-7901 cells. Additionally, a xenograft assay was used to confirm whether isoimperatorin had an inhibitory effect on SGC-7901 cell-induced tumors in vivo. The results of the MTT assay suggested that isoimperatorin significantly inhibited the proliferation of SGC-7901 cells in a dose-and time-dependent manner, and the half maximal inhibitory concentration was 18.75 µg/ml. The results of the flow cytometric analysis indicated that, following treatment with isoimperatorin, the apoptotic rate of SGC-7901 cells was significantly increased, compared with that of cells in the control group. The results of the western blot analysis indicated that, following treatment with isoimperatorin, the expression levels of the pro-apoptotic proteins, Bax, c-caspase-3 and c-caspase-9, were significantly increased and the expression levels of the anti-apoptotic proteins, Survivin and Bcl-2, were significantly reduced, compared with the control group. No alterations in expression were found in the other apoptosis-associated proteins, including Mcl-1, Bcl-xl and Smac. The results of the xenograft assay indicated that isoimperatorin significantly inhibited the growth of SGC-7901 cell-induced tumor in vivo by increasing the expression levels of pro-apoptotic proteins (Bax, c-caspase-3 and c-caspase-9) and reducing the expression levels of anti-apoptotic proteins (Survivin and Bcl-2) without adverse effects on the increasing body weight of nude mice. In conclusion, the present study revealed that isoimperatorin may be able to induce the apoptosis of SGC-7901 cells in vitro and in vivo by regulating the expression levels of mitochondria-mediated apoptosis-associated proteins.

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Metformin displays anti-myeloma activity and synergistic effect with dexamethasone in in vitro and in vivo xenograft models

Cited by 57 publications

References 46 publications

Metformin and FTY720 Synergistically Induce Apoptosis in Multiple Myeloma Cells

Metformin and FTY720 Synergistically Induce Apoptosis in Multiple Myeloma Cells

Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer inï¿½vitro and inï¿½vivo

Isoimperatorin induces apoptosis of the SGC-7901 human gastric cancer cell line via the mitochondria-mediated pathway

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