Pub Date : 2018-01-01Epub Date: 2018-03-21DOI: 10.4172/2476-2261.1000129
R S Wahdan-Alaswad, S M Edgerton, H S Salem, A D Thor
Metformin is the most widely administered anti-diabetic agent worldwide. In patients receiving metformin for metabolic syndrome or diabetes, it reduces the incidence and improves the survival of breast cancer (BC) patients. We have previously shown that metformin is particularly potent against triple negative breast cancer (TNBC), with a reduction of proliferation, oncogenicity and motility, inhibition of pro-oncogenic signaling pathways and induction of apoptosis. These BCs are well recognized to be highly dependent on glucose/glucosamine (metabolized through anaerobic glycolysis) and lipids, which are metabolized for the production of energy and cellular building blocks to sustain a high rate of proliferation. We have previously demonstrated that metformin inhibits lipid metabolism, specifically targeting fatty acid synthase (FASN), cholesterol biosynthesis and GM1 lipid rafts in TNBC. We also reported that glucose promotes phenotypic aggression and reduces metformin efficacy. We now show that metformin inhibits several key enzymes requisite to glucose metabolism in TNBC, providing additional insight into why metformin is especially toxic to this subtype of BC. Our data suggests that the use of metformin to target key metabolic defects in lipid and carbohydrate metabolism in cancer may be broadly applicable, especially against highly aggressive malignant cells.
{"title":"Metformin Targets Glucose Metabolism in Triple Negative Breast Cancer.","authors":"R S Wahdan-Alaswad, S M Edgerton, H S Salem, A D Thor","doi":"10.4172/2476-2261.1000129","DOIUrl":"https://doi.org/10.4172/2476-2261.1000129","url":null,"abstract":"<p><p>Metformin is the most widely administered anti-diabetic agent worldwide. In patients receiving metformin for metabolic syndrome or diabetes, it reduces the incidence and improves the survival of breast cancer (BC) patients. We have previously shown that metformin is particularly potent against triple negative breast cancer (TNBC), with a reduction of proliferation, oncogenicity and motility, inhibition of pro-oncogenic signaling pathways and induction of apoptosis. These BCs are well recognized to be highly dependent on glucose/glucosamine (metabolized through anaerobic glycolysis) and lipids, which are metabolized for the production of energy and cellular building blocks to sustain a high rate of proliferation. We have previously demonstrated that metformin inhibits lipid metabolism, specifically targeting fatty acid synthase (FASN), cholesterol biosynthesis and GM1 lipid rafts in TNBC. We also reported that glucose promotes phenotypic aggression and reduces metformin efficacy. We now show that metformin inhibits several key enzymes requisite to glucose metabolism in TNBC, providing additional insight into why metformin is especially toxic to this subtype of BC. Our data suggests that the use of metformin to target key metabolic defects in lipid and carbohydrate metabolism in cancer may be broadly applicable, especially against highly aggressive malignant cells.</p>","PeriodicalId":91759,"journal":{"name":"Journal of oncology translational research","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4172/2476-2261.1000129","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36115482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-01DOI: 10.4172/2476-2261.1000108
A. Zahra, Tangel Chang, T. A. Hejleh, M. Furqan, G. Clamon, S. Bhatia, J. Watkins, S. Mott, Logan Ahmann, K. Bodeker, D. Spitz, J. Buatti, B. Allen
BACKGROUND To investigate outcomes and prognostic factors in patients treated with once daily high-dose (≥60 Gy) radiation therapy (HDRT) and concurrent platinum-based chemotherapy in limited stage small cell lung cancer (LS-SCLC). While we await current phase III trials to determine optimal radiation dose fractionation schemes in LS-SCLC, we report our experience in LS-SCLC with once daily HDRT. We hypothesized that HDRT would achieve similar efficacy and tolerability as twice daily therapy. METHODS We conducted a single institution retrospective review of all patients with LS-SCLC who underwent curative intent treatment from 2005-2013. Patients treated with HDRT (≥60 Gy) and concurrent chemotherapy (cisplatin or carboplatin and etoposide) were included in our analysis. Clinicopathologic variables assessed include gender, performance status, time to treatment, response to treatment, toxicity, volumetric tumor response at 3 months, and use of prophylactic cranial irradiation (PCI). RESULTS 42 patients with LS-SCLC who initiated concurrent chemoradiation from 2005 to 2013 were included in the analysis. 38 patients (90%) completed definitive treatment to the lung; 16 (38%) also completed PCI. Median failure free survival (FFS) and overall survival (OS) were 11.9 and 23.1 months, respectively. Two-year and 5-year OS rates were 47% (CI=30-62%) and 21% (CI=7-38%), respectively. On univariate analysis, PCI was associated with improved FFS but this was not significant (p=0.18). Gender was the only co-variate significantly associated with statistical differences in FFS (p=0.03) and OS (p=0.02). Grade 3 and 4 esophagitis were 10.5% and 2.6%, respectively. Pre-HDRT tumor volume and 3-month post-treatment tumor volume were both associated with FFS (p<0.01) but not OS. CONCLUSIONS In this single institution series, daily HDRT demonstrated a 2-year OS of 47% in LS-SCLC. This compares well to the historical survival of daily fractionation (47%) from INT 0096 reported by Turrisi et. al. Male gender was predictive of significantly worse FFS and OS. Once daily HDRT has similar OS to twice-daily radiation schemes; however, further studies assessing once daily HDRT for LS-SCLC are warranted.
{"title":"Once Daily High-dose Radiation (≥60 Gy) Treatment in Limited Stage Small Cell Lung Cancer.","authors":"A. Zahra, Tangel Chang, T. A. Hejleh, M. Furqan, G. Clamon, S. Bhatia, J. Watkins, S. Mott, Logan Ahmann, K. Bodeker, D. Spitz, J. Buatti, B. Allen","doi":"10.4172/2476-2261.1000108","DOIUrl":"https://doi.org/10.4172/2476-2261.1000108","url":null,"abstract":"BACKGROUND To investigate outcomes and prognostic factors in patients treated with once daily high-dose (≥60 Gy) radiation therapy (HDRT) and concurrent platinum-based chemotherapy in limited stage small cell lung cancer (LS-SCLC). While we await current phase III trials to determine optimal radiation dose fractionation schemes in LS-SCLC, we report our experience in LS-SCLC with once daily HDRT. We hypothesized that HDRT would achieve similar efficacy and tolerability as twice daily therapy. METHODS We conducted a single institution retrospective review of all patients with LS-SCLC who underwent curative intent treatment from 2005-2013. Patients treated with HDRT (≥60 Gy) and concurrent chemotherapy (cisplatin or carboplatin and etoposide) were included in our analysis. Clinicopathologic variables assessed include gender, performance status, time to treatment, response to treatment, toxicity, volumetric tumor response at 3 months, and use of prophylactic cranial irradiation (PCI). RESULTS 42 patients with LS-SCLC who initiated concurrent chemoradiation from 2005 to 2013 were included in the analysis. 38 patients (90%) completed definitive treatment to the lung; 16 (38%) also completed PCI. Median failure free survival (FFS) and overall survival (OS) were 11.9 and 23.1 months, respectively. Two-year and 5-year OS rates were 47% (CI=30-62%) and 21% (CI=7-38%), respectively. On univariate analysis, PCI was associated with improved FFS but this was not significant (p=0.18). Gender was the only co-variate significantly associated with statistical differences in FFS (p=0.03) and OS (p=0.02). Grade 3 and 4 esophagitis were 10.5% and 2.6%, respectively. Pre-HDRT tumor volume and 3-month post-treatment tumor volume were both associated with FFS (p<0.01) but not OS. CONCLUSIONS In this single institution series, daily HDRT demonstrated a 2-year OS of 47% in LS-SCLC. This compares well to the historical survival of daily fractionation (47%) from INT 0096 reported by Turrisi et. al. Male gender was predictive of significantly worse FFS and OS. Once daily HDRT has similar OS to twice-daily radiation schemes; however, further studies assessing once daily HDRT for LS-SCLC are warranted.","PeriodicalId":91759,"journal":{"name":"Journal of oncology translational research","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87598382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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