Synergistic Effect of Phenformin in Non-Small Cell Lung Cancer (NSCLC) Ionizing Radiation Treatment

Wang, Jia; Xia, Shi’an; Zhu, Zhizhen

doi:10.1007/s12013-014-0283-z

Cited by 18 publications

(17 citation statements)

References 17 publications

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“…However, there is controversy regarding the role of AMPK in the anti-tumor activity of phenformin. It was reported that phenformin displays AMPK-independent effects on cancer cell proliferation and metabolism [ 29 ], whereas others have shown that the anti-tumor effect of phenformin is dependent, at least partially, on AMPK signaling [ 7 , 10 , 30 ]. Our results demonstrated that AMPK phosphorylation increases in breast cancer cells treated with phenformin.…”

Section: Discussionmentioning

confidence: 99%

Phenformin Induces Cell Cycle Change, Apoptosis, and Mesenchymal-Epithelial Transition and Regulates the AMPK/mTOR/p70s6k and MAPK/ERK Pathways in Breast Cancer Cells

et al. 2015

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Breast cancer remains a world-wide challenge, and additional anti-cancer therapies are still urgently needed. Emerging evidence has demonstrated the potent anti-tumor effect of biguanides, among which phenformin was reported to potentially be a more active anti-cancer agent than metformin. However, little attention has been given to the role of phenformin in breast cancer. In this study, we reveal the role of phenformin in cell death of the MCF7, ZR-75-1, MDA-MB-231 and SUM1315 breast cancer cell lines. The respective IC50 values of phenformin in MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells were 1.184±0.045 mM, 0.665±0.007 mM, 2.347±0.010 mM and 1.885±0.015 mM (mean± standard error). Phenformin induced cell cycle change and apoptosis in breast cancer cells via the AMPK/mTOR/p70s6k and MAPK/ERK pathways. Interestingly, phenformin induced MET (mesenchymal-epithelial transition) and decreased the migration rate in breast cancer cell lines. Furthermore, our results suggest that phenformin inhibits breast cancer cell metastasis after intracardiac injection into nude mice. Taken together, our study further confirms the potential benefit of phenformin in breast cancer treatment and provides novel mechanistic insight into its anti-cancer activity in breast cancer.

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Section: Discussionmentioning

confidence: 99%

Phenformin Induces Cell Cycle Change, Apoptosis, and Mesenchymal-Epithelial Transition and Regulates the AMPK/mTOR/p70s6k and MAPK/ERK Pathways in Breast Cancer Cells

et al. 2015

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“…Met has been used in the clinic for over 50 years and has a very good safety profile (diabetic patients tolerate daily doses of 2-3 g) (1-4). Efforts to improve and enhance efficacy of Met involved modification of structure by attaching alkyl or aromatic groups (e.g., butformin, phenformin) (17) (Fig. 1A).…”

Section: Introductionmentioning

confidence: 99%

“…Mito-Met 10 inhibited mitochondrial complex I, stimulating superoxide generation and AMPK activation, more potently than Met in MiaPaCa-2 cells. Reports suggest that Met (1 mM) pretreatment followed by radiation resulted in enhanced cancer cell killing (17-19). In this study, we show that Mito-Met 10 enhanced radiation sensitivity in PDAC to the same extent as did Met (1 mM) but at a 1,000-fold lower concentration (1 μM).…”

Section: Introductionmentioning

confidence: 99%

Mitochondria-Targeted Analogues of Metformin Exhibit Enhanced Antiproliferative and Radiosensitizing Effects in Pancreatic Cancer Cells

et al. 2016

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Metformin (Met) is an approved antidiabetic drug currently being explored for repurposing in cancer treatment based on recent evidence of its apparent chemopreventive properties. Met is weakly cationic and targets the mitochondria to induce cytotoxic effects in tumor cells, albeit not very effectively. We hypothesized that increasing its mitochondria-targeting potential by attaching a positively-charged lipophilic substituent would enhance the antitumor activity of Met. In pursuit of this question, we synthesized a set of mitochondria-targeted Met analogs (Mito-Mets) with varying alkyl chain lengths containing a triphenylphosphonium cation (TPP+). In particular, the analog Mito-Met10, synthesized by attaching TPP+ to Met via a 10-carbon aliphatic side chain, was nearly 1,000 times more efficacious than Met at inhibiting cell proliferation in pancreatic ductal adenocarcinoma (PDAC). Notably, in PDAC cells Mito-Met10 potently inhibited mitochondrial complex I, stimulating superoxide and AMPK activation, but had no effect in non-transformed control cells. Moreover, Mito-Met10 potently triggered G1 cell cycle phase arrest in PDAC cells, enhanced their radiosensitivity and more potently abrogated PDAC growth in preclinical mouse models, compared to Met. Collectively, our findings show how improving the mitochondrial targeting of Met enhances its anticancer activities, including in aggressive cancers like PDAC in great need of more effective therapeutic options.

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“…The biguanides metformin (METF) and phenformin (PHEN) are anti-diabetic drugs, but intriguingly, biguanides decrease cancer incidence and cancer-related mortality 1 , 2 . Preclinical studies have demonstrated that biguanides inhibit cancer cell proliferation 3 – 5 , and may potentiate conventional treatment 4 , 6 – 9 . METF has an excellent safety profile and is the first-line drug for managing type 2 diabetes, and exploring its significance in oncology is appealing.…”

Section: Introductionmentioning

confidence: 99%

Results from 11C-metformin-PET scans, tissue analysis and cellular drug-sensitivity assays questions the view that biguanides affects tumor respiration directly

Iversen

Horsman

Jakobsen

et al. 2017

Sci Rep

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The anti-diabetic biguanide drugs metformin (METF) and phenformin (PHEN) may have anti-cancer effects. Biguanides suppress plasma growth factors, but nonetheless, the view that these mitochondrial inhibitors accumulate in tumor tissue to an extent that leads to severe energetic stress or alleviation of hypoxia-induced radioresistance is gaining ground. Our cell studies confirm that biguanides inhibits cell proliferation by targeting respiration, but only at highly suprapharmacological concentrations due to low drug retention. Biodistribution/PET studies of 11C-labeled metformin (11C-METF) revealed that plasma bioavailability remained well below concentrations with metabolic/anti-proliferative in vitro effects, following a high oral dose. Intraperitoneal administration resulted in higher drug concentrations, which affected metabolism in normal organs with high METF uptake (e.g., kidneys), but tumor drug retention peaked at low levels comparable to plasma levels and hypoxia was unaffected. Prolonged intraperitoneal treatment reduced tumor growth in two tumor models, however, the response did not reflect in vitro drug sensitivity, and tumor metabolism and hypoxia was unaffected. Our results do not support that direct inhibition of tumor cell respiration is responsible for reduced tumor growth, but future studies using 11C-METF-PET are warranted, preferably in neoplasia’s originating from tissue with high drug transport capacity, to investigate the controversial idea of direct targeting.

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Synergistic Effect of Phenformin in Non-Small Cell Lung Cancer (NSCLC) Ionizing Radiation Treatment

Cited by 18 publications

References 17 publications

Phenformin Induces Cell Cycle Change, Apoptosis, and Mesenchymal-Epithelial Transition and Regulates the AMPK/mTOR/p70s6k and MAPK/ERK Pathways in Breast Cancer Cells

Phenformin Induces Cell Cycle Change, Apoptosis, and Mesenchymal-Epithelial Transition and Regulates the AMPK/mTOR/p70s6k and MAPK/ERK Pathways in Breast Cancer Cells

Mitochondria-Targeted Analogues of Metformin Exhibit Enhanced Antiproliferative and Radiosensitizing Effects in Pancreatic Cancer Cells

Results from 11C-metformin-PET scans, tissue analysis and cellular drug-sensitivity assays questions the view that biguanides affects tumor respiration directly

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