Ketogenic diets are low in carbohydrates and high in fat, which forces cells to rely more heavily upon mitochondrial oxidation of fatty acids for energy. Relative to normal cells, cancer cells are ...believed to exist under a condition of chronic mitochondrial oxidative stress that is compensated for by increases in glucose metabolism to generate reducing equivalents. In this study we tested the hypothesis that a ketogenic diet concurrent with radiation and chemotherapy would be clinically tolerable in locally advanced non-small cell lung cancer (NSCLC) and pancreatic cancer and could potentially exploit cancer cell oxidative metabolism to improve therapeutic outcomes. Mice bearing MIA PaCa-2 pancreatic cancer xenografts were fed either a ketogenic diet or standard rodent chow, treated with conventionally fractionated radiation (2 Gy/fraction), and tumor growth rates were assessed daily. Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)-modfied proteins as a marker of oxidative stress. Based on this and another previously published preclinical study, phase 1 clinical trials in locally advanced NSCLC and pancreatic cancer were initiated, combining standard radiation and chemotherapy with a ketogenic diet for six weeks (NSCLC) or five weeks (pancreatic cancer). The xenograft experiments demonstrated prolonged survival and increased 4HNE-modfied proteins in animals consuming a ketogenic diet combined with radiation compared to radiation alone. In the phase 1 clinical trial, over a period of three years, seven NSCLC patients enrolled in the study. Of these, four were unable to comply with the diet and withdrew, two completed the study and one was withdrawn due to a dose-limiting toxicity. Over the same time period, two pancreatic cancer patients enrolled in the trial. Of these, one completed the study and the other was withdrawn due to a dose-limiting toxicity. The preclinical experiments demonstrate that a ketogenic diet increases radiation sensitivity in a pancreatic cancer xenograft model. However, patients with locally advanced NSCLC and pancreatic cancer receiving concurrent radiotherapy and chemotherapy had suboptimal compliance to the oral ketogenic diet and thus, poor tolerance.
Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the ...autoxidation of ascorbate leading to increased steady-state levels of H
O
; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O
and H
O
are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H
O
. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.
Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the ...autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2⋅− and H2O2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.
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•High-dose ascorbate sensitizes NSCLC and GBM cells to radio-chemotherapy•O2⋅− and H2O2 increase labile iron causing cancer cell-selective ascorbate toxicity•Therapeutic levels of ascorbate are achievable and well tolerated in GBM and NSCLC•Cancer cell oxidative metabolism can be targeted with ascorbate for cancer therapy
Schoenfeld et al. show that cancer cells are selectively sensitive to ascorbate due to their altered redox-active iron metabolism. They present preclinical and clinical data demonstrating the feasibility, tolerability, and potential efficacy of pharmacological ascorbate for treating glioblastoma and non-small cell lung cancer.
P-AscH– radiosensitizes pancreatic cancer (PDAC) in vitro and in vivo. The purpose of this Phase I trial is to determine the safety and tolerability of P-AscH- when combined with gemcitabine and ...radiation. Patients with locally advanced PDAC who were to undergo gemcitabine and radiotherapy were enrolled (Clinical Trials.gov NCT0152890). Patients were given P-AscH– (50-100 g/daily), 5 days/week and Gemcitabine as prescribed per standard of care guidelines. Intensity modulated radiation therapy was also administered at either 50.4 Gy in 28 fractions or 50 Gy in 25 fractions. The primary endpoints were safety and tolerability of P-AscH– other co-primary endpoints were dose-limiting toxicity and maximum tolerated dose. Since June, 2014, 14 patients have enrolled and 11 have completed therapy. Both 75 gram and 100 gram infusions achieved plasma ascorbate levels of 20 mM. The adverse event most commonly attributable to P-AscH– was dry mouth during infusion. No other adverse events were observed to be greater in intensity or frequency than with gemcitabine and radiation alone. Grade 3 or greater adverse events were hematologic in nature which occurred in all patients to varying severity. One P-AscH–-related toxicity was reported with non-cardiac chest pain which did not alter ongoing treatment. Common grade 1 and 2 adverse events included chills, abdominal pain, dry mouth, fatigue, nausea, vomiting, and thrombocytopenia, all in similar frequency and intensity to chemoradiotherapy alone. Progression Free and overall survival is 10.8 months and 13.1 months, respectively, compared to 6.0 months and 11.1 months, for historical controls. Our preliminary results demonstrate that P-AscH– in combination with gemcitabine/radiation is safe and tolerable.
Permeable reactive barrier (PRB) technology, in which sulfate-reducing bacteria (SRB) facilitate precipitation of metal sulfides, is a promising approach for remediation of sulfate- and metal-laden ...mine drainage. While PRBs are easily established, they often decline for reasons not well understood. SRB depend on or compete with multiple dynamic microbial populations within a PRB; as a result, performance depends on the changing PRB chemical composition and on succession and competition within the microbial community. To investigate these interactions, we constructed and monitored eight bench-scale PRBs to define periods of establishment, performance, and decline. We then conducted short-term batch studies, using substrate-supplemented column materials, on Days 0 (pre-establishment), 27 (establishment), 41 (performance), and 99 (decline) to reveal potential activities of cellulolytic bacteria,
fermenters
+
anaerobic
respirers, SRB, and methanogens. PRBs showed active sulfate reduction, with sulfate removal rates (SRR) of ∼1–3
mol/m
3/d, as well as effective removal of Zn
2+. Potential activities of
fermentative
+
anaerobic
respiratory bacteria were initially high but diminished greatly during establishment and dropped further during performance and decline. In contrast, potential SRB activity rose during establishment, peaked during performance, and diminished as performance declined. Potential methanogen activity was low; in addition, SRB-methanogen substrate competition was shown not to limit SRB activity. Cellulolytic bacteria showed no substrate limitation at any time. However, fermenters experienced substrate limitation by Day 0, SRB by Day 27, and methanogens by Day 41, showing the dependence of each group on upstream populations to provide substrates. All potential activities, except methanogenesis, were ultimately limited by cellulose hydrolysis; in addition, all potential activities except methanogenesis declined substantially by Day 99, showing that long-term substrate deprivation strongly diminished the intrinsic capacity of the PRB community to perform.
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