Adding a combination of hydroxycitrate and lipoic acid (METABLOC™) to chemotherapy improves effectiveness against tumor development: experimental results and case report.

Altered metabolism of cancer first highlighted by Otto Warburg has a long history. Although ignored for a considerable amount of time, it is now receiving substantial attention. We recently published results obtained with a combination of two drugs, lipoic acid and hydroxycitrate, targeting metabolic enzymes particularly affected in cancer: ATP citrate lyase and pyruvate dehydrogenase kinase. This treatment was as efficient as chemotherapy in the three mouse cancer models that were tested. In this work, we asked if our drug combination could be used in conjunction with standard cytotoxic chemotherapy, in particular cisplatin, to improve basic protocol efficacy. A combination of lipoic acid and hydroxycitrate was administered to mice implanted with syngeneic cancer cells, LL/2 lung carcinoma and MBT-2 bladder carcinoma, concommitantly with classical chemotherapy (cisplatin or methotrexate). We demonstrate that the triple combination lipoic acid + hydroxycitrate + cisplatin or methotrexate is more efficient than cisplatin or methotrexate used individually or the combination of lipoic acid and hydroxycitrate administered alone. Of particular note are the results obtained in the treatment of an 80 year-old female who presented with ductal adenocarcinoma of the pancreas accompanied by liver metastases. A treatment course using gemcitabine plus α-lipoic acid and hydroxycitrate gave highly promising results. The in vivo data, coupled with the case study results, suggest a possible advantage in using a treatment targeted at cancer metabolism in association with classical chemotherapy.

Screening of well-established drugs targeting cancer metabolism: reproducibility of the efficacy of a highly effective drug combination in mice.

Alterations in metabolic pathways are known to characterize cancer. In order to suppress cancer growth, however, multiple proteins involved in these pathways have to be targeted simultaneously. We have developed a screening method to assess the best drug combination for cancer treatment based on targeting several factors implicated in tumor specific metabolism. Following a review of the literature, we identified those enzymes known to be deregulated in cancer and established a list of sixty-two drugs targeting them. These molecules are used routinely in clinical settings for diseases other than cancer. We screened a first library in vitro against four cell lines and then evaluated the most promising binary combinations in vivo against three murine syngeneic cancer models, (LL/2, Lewis lung carcinoma; B16-F10, melanoma; and MBT-2, bladder cancer). The optimum result was obtained using a combination of α-lipoic acid and hydroxycitrate (METABLOC(TM)). In this study, a third agent was added by in vivo evaluation of a large number of combinations. The addition of octreotide strongly reduced tumor development (T/C% value of 30.2 to 34.5%; P < 0.001) in the same models and prolonged animal survival (P < 0.001) as compared to cisplatin. These results were confirmed in a different laboratory setting using a human xenograft model (NCI-H69, small cell lung cancer). None of these three molecules are known to target DNA. The effectiveness of this combination in several animal models, as well as the low toxicity of these inexpensive drugs, emphasizes the necessity of rapidly setting up a clinical trial.

Ion fluxes, transmembrane potential, and osmotic stabilization: a new dynamic electrophysiological model for eukaryotic cells.

Survival of mammalian cells is achieved by tight control of cell volume, while transmembrane potential has been known to control many cellular functions since the seminal work of Hodgkin and Huxley. Regulation of cell volume and transmembrane potential have a wide range of implications in physiology, from neurological and cardiac disorders to cancer and muscle fatigue. Therefore, understanding the relationship between transmembrane potential, ion fluxes, and cell volume regulation has become of great interest. In this paper we derive a system of differential equations that links transmembrane potential, ionic concentrations, and cell volume. In particular, we describe the dynamics of the cell within a few seconds after an osmotic stress, which cannot be done by the previous models in which either cell volume was constant or osmotic regulation instantaneous. This new model demonstrates that both membrane potential and cell volume stabilization occur within tens of seconds of changes in extracellular osmotic pressure. When the extracellular osmotic pressure is constant, the cell volume varies as a function of transmembrane potential and ion fluxes, thus providing an implicit link between transmembrane potential and cell volume. Experimental data provide results that corroborate the numerical simulations of the model in terms of time-related changes in cell volume and dynamics of the phenomena. This paper can be seen as a generalization of previous electrophysiological results, since under restrictive conditions they can be derived from our model.

Tour de France, Giro, Vuelta, and classic European races show a unique progression of road cycling speed in the last 20 years.

Road cycling ranks among the most intense endurance exercises. Previous studies and mathematical models describing road cycling have not analysed performances per se. We describe the evolution of road cycling performance over the past 116 years. We studied the top ten cyclists' mean speeds in eight famous classic races and three European Grand Tours, using a previously published multi-exponential model that highlights the different progression periods of an event during the century. In addition, we measured an indicator of difficulty for the Tour de France by calculating the climbing index (i.e. the total altitude climbed over total distance). The eleven races' mean speed increased progressively from 23.13 km . h(-1) in 1892 to 41.19 +/- 2.03 km . h(-1) in 2008. Road cycling development, like other quantifiable disciplines, fits a piecewise progression pattern that follows three periods: before, between, and after the two World Wars. However, a fourth period begins after 1993, providing a speed progression of 6.38% from the third one. The Tour de France's climbing index also provided insight into a recent paradoxical relationship with speeds: when the climbing index increased, the winner's speed also increased. Our results show a major improvement (6.38%) in road cycling performance in the last 20 years and question the role of extra-physiological parameters in this recent progression.

A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: preliminary results.

The impact of metabolic dysregulation on tumor development has long been established. We have targeted two enzymes that are altered during carcinogenesis: pyruvate dehydrogenase (PDH), which is down-regulated, and ATP citrate lyase, which is overexpressed in cancer cells. Alpha lipoic acid is a cofactor of PDH, while hydroxycitrate is a known inhibitor of ATP citrate lyase. Our hypothesis is that a combination of these drugs may have antitumoral potential. The efficacy of these molecules was screened in vitro by treatment of different human cancer and murine cell lines. Lipoic acid reduced the cell number by 10-50% depending on concentrations (0.1-10 microM) and cell types. Calcium hydroxycitrate reduced the cell number by 5-60% at different concentrations (10-500 microM). When hydroxycitrate and lipoic acid were used together, there was a major cytotoxic effect: complete cell death was seen following 8 microM lipoic acid and 300 microM hydroxycitrate treatment for 72 h. The combination of alpha lipoic acid and hydroxycitrate was administered to healthy mice, at doses currently utilized for other indications than cancer; no demonstrable toxicity was observed. The combination was used to treat mouse syngenic cancer models: MBT-2 bladder transitional cell carcinoma, B16-F10 melanoma and LL/2 Lewis lung carcinoma. The efficacy of this combination appears similar to conventional chemotherapy (cisplatin or 5-fluorouracil) as it resulted in significant tumor growth retardation and enhanced survival. This preliminary study suggests that this combination of drugs is efficient against cancer cell proliferation both in vitro and in vivo. A clinical trial is warranted.

Relationship between %HRmax, %HR reserve, %VO2max, and %VO2 reserve in elite cyclists.

PURPOSE: To evaluate the relations between %HRmax, %HRR, %VO2max, and %VO2R in elite cyclists and to check whether the intensity scale recommended by ACSM in its 1998 position stand is also applicable to this specific population. METHODS: Twenty-six male elite road cyclists (25.1 +/- 0.7 yr, 71.0 +/- 1.2 kg, 70.9 +/- 1.2 mL x kg(-1) x min(-1), 433.9 +/- 9.8 W) performed an incremental maximal exercise test (50 W x 3 min(-1)). Individual linear regressions based on HR and VO2 values measured at rest, end of each stage, and maximum, were used to calculate slopes and intercepts, and to predict %HRmax, %HRR, %VO2max, or %VO2R for a given exercise intensity. RESULTS: Below 85% VO2max or VO2R, predicted %HRmax values were significantly higher (P < 0.001) than the ACSM intensity scale (58, 65, 73, and 87% vs 55, 62, 70, and 85% HRmax at 40, 50, 60, and 80% VO2max, and 48, 61, 74% vs 35, 55, and 70% HRmax at 20, 40, and 60% VO2R). The %HRR versus %VO2max regression mean slope (1.069 +/- 0.01) and intercept (-5.747 +/- 0.80) were significantly different (P < 0.0001) from 1 and 0, respectively. Conversely, the %HRR versus %VO2R regression was indistinguishable from the line of identity (mean slope = 1.003 +/- 0.01; mean intercept = 0.756 +/- 0.7). Predicted %VO2R values were equivalent to %HRR in the 35-95%HRR range. %VO2max was equivalent to %HRR at and above 75%HRR, and it was significantly higher at (P < 0.05) and below 65%HRR (P < 0.001). CONCLUSION: The intensity scale recommended by ACSM underestimates exercise intensity in elite cyclists. Prediction of %HRR by %VO2R is better than by %VO2max. Thus, elite cyclists should use %HRR in relation to %VO2R rather than in relation to %VO2max.