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Anand Krishnan V Iyer - One of the best experts on this subject based on the ideXlab platform.
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the biguanides metformin and Buformin in combination with 2 deoxy glucose or wzb 117 inhibit the viability of highly resistant human lung cancer cells
Stem Cells International, 2019Co-Authors: Juan Sebastian Yakisich, Neelam Azad, Vivek Kaushik, Anand Krishnan V IyerAbstract:The biguanides metformin (MET) and to a lesser extent Buformin (BUF) have recently been shown to exert anticancer effects. In particular, MET targets cancer stem cells (CSCs) in a variety of cancer types but these compounds have not been extensively tested for combination therapy. In this study, we investigated in vitro the anticancer activity of MET and BUF alone or in combination with 2-deoxy-D-glucose (2-DG) and WZB-117 (WZB), which are a glycolysis and a GLUT-1 inhibitor, respectively, in H460 human lung cancer cells growing under three different culture conditions with varying degrees of stemness: (1) routine culture conditions (RCCs), (2) floating lung tumorspheres (LTSs) that are enriched for stem-like cancer cells, and (3) adherent cells under prolonged periods (8-12 days) of serum starvation (PPSS). These cells are highly resistant to conventional anticancer drugs such as paclitaxel, hydroxyurea, and colchicine and display an increased level of stemness markers. As single agents, MET, BUF, 2-DG, and WZB-117 potently inhibited the viability of cells growing under RCCs. Both MET and BUF showed a strong synergistic effect when used in combination with 2-DG. A weak potentiation was observed when used with WZB-117. Under RCCs, H460 cells were more sensitive to MET and BUF and WZB-117 compared to nontumorigenic Beas-2B cells. While LTSs were less sensitive to each single drug, both MET and BUF in combination with 2-DG showed a strong synergistic effect and reduced cell viability to similar levels compared to the parental H460 cells. Adherent cells growing under PPSS were also less sensitive to each single drug, and MET and BUF showed a strong synergistic effect on cell viability in combination with 2-DG. Overall, our data demonstrates that the combination of BGs with either 2-DG or WZB-117 has “broad-spectrum” anticancer activities targeting cells growing under a variety of cell culture conditions with varying degrees of stemness. These properties may be useful to overcome the chemoresistance due to intratumoral heterogeneity found in lung cancer.
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abstract 277 broad spectrum anticancer activities of the biguanides metformin and Buformin in combination with 2 deoxy glucose or wzb 117 in human lung cancer cells
Cancer Research, 2016Co-Authors: Juan Sebastian Yakisich, Neelam Azad, Anand Krishnan V IyerAbstract:Purpose: The biguanides Metformin (MET) and to a lesser extent Buformin (BUF) have recently been shown to exert anticancer effects. In particular MET targets cancer stem cells (CSCs) in a variety of cancer types. These compounds have not been extensively tested for combination therapy. Objectives: In this study we investigated in vitro the anticancer activity of MET and BUF alone or in combination with 2-deoxy-D-glucose (2-DG), or WZB-117 (WZB), which are a glycolysis and a GLUT-1 inhibitor, respectively, in H460 human lung cancer cells growing under three different culture conditions with varying degrees of stemness: 1) Routine Culture Conditions (RCCs), 2) Floating Lung Tumorspheres (LTSs) that are enriched for stem-like cancer cells and 3) Adherent cells under prolonged periods (8-12 days) of serum starvation (PPSS): These cells are highly resistant to conventional anticancer drugs such as Paclitaxel, Hydroxyurea and Colchicine and display increased level of stemnes markers. Experimental setup: For cells growing under RCCs and under PPSS, cell viability was measured by the MTT assay. Viability of LTS was evaluated by the CCK assay. Clonogenicity was evaluated by the colony formation assays. Results: As single agents MET, BUF, 2-DG and WZB-117 potently inhibited the viability of cells growing under RCCs. These results were confirmed by the colony forming assay. Both MET and BUF showed a strong synergistic effect when used in combination with 2-DG. A weak potentiation was observed when used with WZB-117. Under RCCs H460 cells were more sensitive to MET and BUF and WZB-117 compared to non-tumorigenic Beas-2B cells. While LTSs were less sensitive to each single drug, both MET or BUF in combination with 2-DG showed a strong synergistic effect and reduced cell viability to similar levels compared to the parental H460 cells. Adherent cells growing under PPSS were also less sensitive to each single drug and MET and BUF showed a strong synergistic effect on cell viability in combination with 2-DG. We are currently evaluating the generation of reactive oxygen species (ROS) and the signaling pathways involved in the antiproliferative effects of these agents as single drugs as well as in combination. Conclusions: Overall our data demonstrates that combination of BGs with either 2-DG or WZB-117 have a “Broad - spectrum” anticancer activities targeting cells growing under a variety of cell culture conditions with varying degrees of stemness. These properties may be useful to overcome the chemoresistance due to intratumoral heterogeneity found in lung cancer. Citation Format: Juan Sebastian Yakisich, Neelam Azad, Anand V. Iyer. Broad-spectrum anticancer activities of the biguanides metformin and Buformin in combination with 2-deoxy-glucose or WZB-117 in human lung cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 277.
Victoria L Baejump - One of the best experts on this subject based on the ideXlab platform.
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Buformin exhibits anti proliferative and anti invasive effects in endometrial cancer cells
American Journal of Translational Research, 2016Co-Authors: Joshua Kilgore, Amanda L Jackson, Leslie H Clark, Hui Guo, Lu Zhang, Hannah M Jones, Timothy P Gilliam, Paola A Gehrig, Chunxiao Zhou, Victoria L BaejumpAbstract:Objective: Biguanides are anti-diabetic drugs that are thought to have anti-tumorigenic effects. Most pre-clinical studies have focused on metformin for cancer treatment and prevention; however, Buformin may be potentially more potent than metformin. Given this, our goal was to evaluate the effects of Buformin on cell growth, adhesion and invasion in endometrial cancer cell lines. Methods: The ECC-1 and Ishikawa endometrial cancer cell lines were used. Cell proliferation was assessed by MTT assay. Apoptosis and cell cycle analysis was performed by FITC Annexin V assay and propidium iodide staining, respectively. Adhesion was analyzed using the laminin adhesion assay. Invasion was assessed using the transwell invasion assay. The effects of Buformin on the AMPK/mTOR pathway were determined by Western immunoblotting. Results: Buformin and metformin inhibited cell proliferation in a dose-dependent manner in both endometrial cancer cell lines. IC50s were 1.4-1.6 mM for metformin and 8-150 μM for Buformin. Buformin induced cell cycle G1 phase arrest in the ECC-1 cells and G2 phase arrest in the Ishikawa cells. For both ECC-1 and Ishikawa cells, treatment with Buformin resulted in induction of apoptosis, reduction in adhesion and invasion, activation of AMPK and inhibition of phosphorylated-S6. Buformin potentiated the anti-proliferative effects of paclitaxel in both cell lines. Conclusion: Buformin has significant anti-proliferative and anti-metastatic effects in endometrial cancer cells through modulation of the AMPK/mTOR pathway. IC50 values were lower for Buformin than metformin, suggesting that Buformin may be more potent for endometrial cancer treatment and worthy of further investigation.
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abstract 1312 Buformin an anti diabetic biguanide inhibits proliferation invasion and adhesion and acts synergistically with paclitaxel in endometrial cancer cell lines
Cancer Research, 2014Co-Authors: Joshua Kilgore, Amanda L Jackson, Paola A Gehrig, Chunxiao Zhou, Haifeng Qiu, Victoria L BaejumpAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Objectives: Epidemiologic and pre-clinical studies suggest that anti-diabetic biguanide drugs, such as metformin and Buformin, may have anti-tumorigenic effects and behave as chemosensitizers. Thus, we evaluated the effects of Buformin alone and in combination with paclitaxel on proliferation in human endometrial cancer (EC) cell lines as well as the impact of Buformin on apoptosis and adhesion/invasion. Methods: The ECC-1 and Ishikawa EC cell lines were treated with varying doses of Buformin alone and in combination with paclitaxel. Cell growth was determined by MTT assay. Cell cycle progression was assessed by Cellometer. Apoptosis was evaluated by Annexin V-FITC assay. Invasion was demonstrated by transwell invasion assay. Adhesion was assessed by ELISA. Effects on AMPK and S6 expression were documented by Western blotting. Results: Buformin inhibited proliferation in a dose-dependent manner in the EC cell lines (IC50 1000 μM for ECC-1, 10μM for Ishikawa, p=0.00001-0.0010). Treatment with Buformin resulted in G1 arrest in the ECC-1 cell line and G2 arrest in the Ishikawa cell line. Buformin induced apoptosis in the Ishikawa cell line, but not in the ECC-1 cell line. Treatment with Buformin resulted in inhibition of adhesion (p=0.42-0.0009) and invasion (p=0.00001-0.227) in both EC cell lines. Western blotting analysis demonstrated that Buformin increased phosphorylation of AMPK and decreased phosphorylation of S6. Paclitaxel inhibited proliferation in a dose-dependent manner in both cell lines with IC50 values of 0.1-0.5 nM and 1-5 nM for Ishikawa and ECC-1 cells, respectively. To assess synergy of paclitaxel and Buformin, the combination index (CI) was calculated by the method of Chou and Talalay. Simultaneous exposure of cells to various doses of paclitaxel in combination with Buformin (0.1-1 μM) resulted in a significant synergistic anti-proliferative effect (CI <1, range 0.009-0.85). Conclusions: Buformin inhibited proliferation in EC cell lines, via AMPK activation and mTOR pathway inhibition. Inhibition of adhesion/invasion was also seen with Buformin. Buformin acted synergistically with paclitaxel to inhibit cell proliferation. More work is needed to determine if Buformin and other biguanides alone or in combination with cytotoxic agents will be beneficial in the treatment of women with EC. Citation Format: Joshua Kilgore, Amanda Jackson, Haifeng Qiu, Chunxiao Zhou, Paola Gehrig, Victoria Bae-Jump. Buformin, an anti-diabetic biguanide, inhibits proliferation, invasion and adhesion, and acts synergistically with paclitaxel in endometrial cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1312. doi:10.1158/1538-7445.AM2014-1312
Yuichi Sugiyama - One of the best experts on this subject based on the ideXlab platform.
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involvement of organic cation transporter 1 in the lactic acidosis caused by metformin
Molecular Pharmacology, 2003Co-Authors: Desheng Wang, Hiroyuki Kusuhara, Yukio Kato, Johan W Jonker, Alfred H Schinkel, Yuichi SugiyamaAbstract:Biguanides are a class of drugs widely used as oral antihyperglycemic agents for the treatment of type 2 diabetes mellitus, but they are associated with lactic acidosis, a lethal side effect. We reported previously that biguanides are good substrates of rat organic cation transporter 1 (Oct1; Slc22a1 ) and, using Oct1(−/−) mice, that mouse Oct1 is responsible for the hepatic uptake of a biguanide, metformin. In the present study, we investigated whether the liver is the key organ for the lactic acidosis. When mice were given metformin, the blood lactate concentration significantly increased in the wild-type mice, whereas only a slight increase was observed in Oct1(−/−) mice. The plasma concentration of metformin exhibited similar time profiles between the wild-type and Oct1(−/−) mice, suggesting that the liver is the key organ responsible for the lactic acidosis. Furthermore, the extent of the increase in blood lactate caused by three different biguanides (metformin, Buformin, and phenformin) was compared with the abilities to reduce oxygen consumption in isolated rat hepatocytes. When rats were given each of these biguanides, the lactate concentration increased significantly. This effect was dose-dependent, and the EC50 values of metformin, Buformin, and phenformin were 734, 119, and 4.97 μM, respectively. All of these biguanides reduced the oxygen consumption by isolated rat hepatocytes in a concentration-dependent manner. When the concentration required to reduce the oxygen consumption to 75% of the control value (from 0.40 to 0.29 μmol/min/mg protein) was compared with the EC50 value obtained in vivo, a clear correlation was observed among the three biguanides, suggesting that oxygen consumption in isolated rat hepatocytes can be used as an index of the incidence of lactic acidosis.
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involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin
Journal of Pharmacology and Experimental Therapeutics, 2002Co-Authors: Desheng Wang, Hiroyuki Kusuhara, Yukio Kato, Johan W Jonker, Alfred H Schinkel, Yuichi SugiyamaAbstract:Metformin, a biguanide, is widely used as an oral hypoglycemic agent for the treatment of type 2 diabetes mellitus. The purpose of the present study was to investigate the role of organic cation transporter 1 (Oct1) in the disposition of metformin. Transfection of rat Oct1 cDNA results in the time-dependent and saturable uptake of metformin by the Chinese hamster ovary cell line with K m and V maxvalues of 377 μM and 1386 pmol/min/mg of protein, respectively. Buformin and phenformin, two other biguanides, were also transported by rOct1 with a higher affinity than metformin: their K m values were 49 and 16 μM, respectively. To investigate the role of Oct1 in the disposition of metformin, the tissue distribution of metformin was determined in Oct1 gene-knockout mice after i.v. administration. Distribution of metformin to the liver in Oct1(−/−) mice was more than 30 times lower than that in Oct1(+/+) mice, and can be accounted for by the extracellular space. Distribution to the small intestine was also decreased in Oct1(−/−) mice, whereas that to the kidney as well as the urinary excretion profile showed only minimal differences. In conclusion, the present findings suggest that Oct1 is responsible for the hepatic uptake as well as playing a role in the intestinal uptake of metformin, whereas the renal distribution and excretion are mainly governed by other transport mechanism(s).
Yuan Wang - One of the best experts on this subject based on the ideXlab platform.
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Buformin increases radiosensitivity in cervical cancer cells via cell cycle arrest and delayed dna damage repair
Experimental Biology and Medicine, 2018Co-Authors: Ling Chen, Qiuli Liu, Mei Tang, Yuan Wang, Ting Zhang, Yue Yang, Haifeng QiuAbstract:Cervical cancer is the most common malignancy of the female reproductive system. It is estimated that there were as many as 98,900 newly diagnosed cases of cervical cancer and 30,500 cervical cancer-related deaths in China in 2015.1,2 Surgery alone or combined with radiotherapy may be used to treat early cervical cancer, but advanced disease is mainly treated with radiotherapy with or without chemotherapy.3,4 Some patients still develop metastasis and recurrence after radical radiotherapy. Therefore, research efforts should focus on predicting the radiosensitivity of cervical cancer and determining how other agents can improve the efficacy of radiotherapy in the treatment of cervical cancer. The commonly used biguanides include metformin, phenformin, and Buformin, which have been widely used to treat type 2 diabetes mellitus.5,6 Evans et al.7 first proposed biguanides to reduce cancer incidence in patients with type 2 diabetes in 2015; biguanides have since become a research focus in the field of malignant tumor treatment. As research progresses, the pharmacological action and mechanism of metformin are gradually being elucidated. Biguanides can inhibit tumorigenic activity by activating AMPK, inhibiting the mTOR pathway and inducing cell cycle arrest in tumors such as endometrial cancer, ovarian cancer, and breast cancer.8–11 To date, most studies have focused mainly on metformin, whereas there is a lack of research on the anticancer effect of Buformin. Nonetheless, a previous report showed that Buformin has a better anticancer effect than metformin in endometrial cancer,10 and another study found that Buformin can reduce the development of breast cancer by regulating stem cell function in mice.11 Our previous research showed that Buformin can restrain the proliferation of cervical cancer cells and enhance their chemosensitivity by activating AMPK signaling and inhibiting its downstream targets. Based on the results of these studies, we aimed to investigate the effects and mechanism of biguanide combined with radiotherapy in cervical cancer cells.
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Buformin suppresses proliferation and invasion via ampk s6 pathway in cervical cancer and synergizes with paclitaxel
Cancer Biology & Therapy, 2018Co-Authors: Ling Chen, Qiuli Liu, Mei Tang, Yuan WangAbstract:Buformin is an old anti-diabetic agent and manifests potent anti-tumor activities in several malignancies. In the present study, we aimed to explore the functions of Buformin in human cervical canc...
Juan Sebastian Yakisich - One of the best experts on this subject based on the ideXlab platform.
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the biguanides metformin and Buformin in combination with 2 deoxy glucose or wzb 117 inhibit the viability of highly resistant human lung cancer cells
Stem Cells International, 2019Co-Authors: Juan Sebastian Yakisich, Neelam Azad, Vivek Kaushik, Anand Krishnan V IyerAbstract:The biguanides metformin (MET) and to a lesser extent Buformin (BUF) have recently been shown to exert anticancer effects. In particular, MET targets cancer stem cells (CSCs) in a variety of cancer types but these compounds have not been extensively tested for combination therapy. In this study, we investigated in vitro the anticancer activity of MET and BUF alone or in combination with 2-deoxy-D-glucose (2-DG) and WZB-117 (WZB), which are a glycolysis and a GLUT-1 inhibitor, respectively, in H460 human lung cancer cells growing under three different culture conditions with varying degrees of stemness: (1) routine culture conditions (RCCs), (2) floating lung tumorspheres (LTSs) that are enriched for stem-like cancer cells, and (3) adherent cells under prolonged periods (8-12 days) of serum starvation (PPSS). These cells are highly resistant to conventional anticancer drugs such as paclitaxel, hydroxyurea, and colchicine and display an increased level of stemness markers. As single agents, MET, BUF, 2-DG, and WZB-117 potently inhibited the viability of cells growing under RCCs. Both MET and BUF showed a strong synergistic effect when used in combination with 2-DG. A weak potentiation was observed when used with WZB-117. Under RCCs, H460 cells were more sensitive to MET and BUF and WZB-117 compared to nontumorigenic Beas-2B cells. While LTSs were less sensitive to each single drug, both MET and BUF in combination with 2-DG showed a strong synergistic effect and reduced cell viability to similar levels compared to the parental H460 cells. Adherent cells growing under PPSS were also less sensitive to each single drug, and MET and BUF showed a strong synergistic effect on cell viability in combination with 2-DG. Overall, our data demonstrates that the combination of BGs with either 2-DG or WZB-117 has “broad-spectrum” anticancer activities targeting cells growing under a variety of cell culture conditions with varying degrees of stemness. These properties may be useful to overcome the chemoresistance due to intratumoral heterogeneity found in lung cancer.
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abstract 277 broad spectrum anticancer activities of the biguanides metformin and Buformin in combination with 2 deoxy glucose or wzb 117 in human lung cancer cells
Cancer Research, 2016Co-Authors: Juan Sebastian Yakisich, Neelam Azad, Anand Krishnan V IyerAbstract:Purpose: The biguanides Metformin (MET) and to a lesser extent Buformin (BUF) have recently been shown to exert anticancer effects. In particular MET targets cancer stem cells (CSCs) in a variety of cancer types. These compounds have not been extensively tested for combination therapy. Objectives: In this study we investigated in vitro the anticancer activity of MET and BUF alone or in combination with 2-deoxy-D-glucose (2-DG), or WZB-117 (WZB), which are a glycolysis and a GLUT-1 inhibitor, respectively, in H460 human lung cancer cells growing under three different culture conditions with varying degrees of stemness: 1) Routine Culture Conditions (RCCs), 2) Floating Lung Tumorspheres (LTSs) that are enriched for stem-like cancer cells and 3) Adherent cells under prolonged periods (8-12 days) of serum starvation (PPSS): These cells are highly resistant to conventional anticancer drugs such as Paclitaxel, Hydroxyurea and Colchicine and display increased level of stemnes markers. Experimental setup: For cells growing under RCCs and under PPSS, cell viability was measured by the MTT assay. Viability of LTS was evaluated by the CCK assay. Clonogenicity was evaluated by the colony formation assays. Results: As single agents MET, BUF, 2-DG and WZB-117 potently inhibited the viability of cells growing under RCCs. These results were confirmed by the colony forming assay. Both MET and BUF showed a strong synergistic effect when used in combination with 2-DG. A weak potentiation was observed when used with WZB-117. Under RCCs H460 cells were more sensitive to MET and BUF and WZB-117 compared to non-tumorigenic Beas-2B cells. While LTSs were less sensitive to each single drug, both MET or BUF in combination with 2-DG showed a strong synergistic effect and reduced cell viability to similar levels compared to the parental H460 cells. Adherent cells growing under PPSS were also less sensitive to each single drug and MET and BUF showed a strong synergistic effect on cell viability in combination with 2-DG. We are currently evaluating the generation of reactive oxygen species (ROS) and the signaling pathways involved in the antiproliferative effects of these agents as single drugs as well as in combination. Conclusions: Overall our data demonstrates that combination of BGs with either 2-DG or WZB-117 have a “Broad - spectrum” anticancer activities targeting cells growing under a variety of cell culture conditions with varying degrees of stemness. These properties may be useful to overcome the chemoresistance due to intratumoral heterogeneity found in lung cancer. Citation Format: Juan Sebastian Yakisich, Neelam Azad, Anand V. Iyer. Broad-spectrum anticancer activities of the biguanides metformin and Buformin in combination with 2-deoxy-glucose or WZB-117 in human lung cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 277.
