The HK2 Dependent "Warburg Effect" and Mitochondrial Oxidative Phosphorylation in Cancer:Targets for Effective Therapy with 3-Bromopyruvate

This review summarizes the current state of knowledge about the metabolism of cancer cells, especially with respect to the “Warburg” and “Crabtree” effects. This work also summarizes two key discoveries, one of which relates to hexokinase-2 (HK2), a major player in both the “Warburg effect” and cancer cell immortalization. The second discovery relates to the finding that cancer cells, unlike normal cells, derive as much as 60% of their ATP from glycolysis via the “Warburg effect”, and the remaining 40% is derived from mitochondrial oxidative phosphorylation. Also described are selected anticancer agents which generally act as strong energy blockers inside cancer cells. Among them, much attention has focused on 3-bromopyruvate (3BP). This small alkylating compound targets both the “Warburg effect”, i.e., elevated glycolysis even in the presence oxygen, as well as mitochondrial oxidative phosphorylation in cancer cells. Normal cells remain unharmed. 3BP rapidly kills cancer cells growing in tissue culture, eradicates tumors in animals, and prevents metastasis. In addition, properly formulated 3BP shows promise also as an effective anti-liver cancer agent in humans and is effective also toward cancers known as “multiple myeloma”. Finally, 3BP has been shown to significantly extend the life of a human patient for which no other options were available. Thus, it can be stated that 3BP is a very promising new anti-cancer agent in the process of undergoing clinical development

The Antitumor Effect and Hepatotoxicity of a Hexokinase II Inhibitor 3-Bromopyruvate: In Vivo Investigation of Intraarterial Administration in a Rabbit VX2 Hepatoma Model

Objective: The purpose of this study was to compare the antitumor effect and hepatotoxicity of an intraarterial delivery of low-dose and high-dose 3-bromopyruvate (3-BrPA) and those of a conventional Lipiodol-doxorubicin emulsion in a rabbit VX2 hepatoma model. Materials and Methods: This experiment was approved by the animal care committee at our institution. VX2 carcinoma was implanted in the livers of 36 rabbits. Transcatheter intraarterial administration was performed using low dose 3-BrPA (25 mL in a 1 mM concentration, n = 10), high dose 3-BrPA (25 mL in a 5 mM concentration, n = 10) and Lipiodol-doxorubicin emulsion (1.6 mg doxorubicin/0.4 mL Lipiodol, n = 10), and six rabbits were treated with normal saline alone as a control group. One week later, the proportion of tumor necrosis was calculated based on histopathologic examination. The hepatotoxicity was evaluated by biochemical analysis. The differences between these groups were statistically assessed with using Mann-Whitney U tests and Kruskal-Wallis tests. Results: The tumor necrosis rate was significantly higher in the high dose group (93% +/- 7.6 [mean +/- SD]) than that in the control group (48% +/- 21.7) (p = 0.0002), but the tumor necrosis rate was not significantly higher in the low dose group (62% +/- 20.0) (p = 0.2780). However, the tumor necrosis rate of the high dose group was significantly lower than that of the Lipiodol-doxorubicin treatment group (99% +/- 2.7) (p = 0.0015). The hepatotoxicity observed in the 3-BrPA groups was comparable to that of the Lipiodol-doxorubicin group. Conclusion: Even though intraarterial delivery of 3-BrPA shows a dose-related antitumor effect, single session treatment seems to have limited efficacy when compared with the conventional method.Vali M, 2008, J PHARMACOL EXP THER, V327, P32, DOI 10.1124/jpet.108.141093Park HS, 2007, KOREAN J RADIOL, V8, P216Vali M, 2007, J VASC INTERV RADIOL, V18, P95, DOI 10.1016/j.jvir.2006.10.019Shin SW, 2006, ACTA RADIOL, V47, P1036, DOI 10.1080/02841850600977752Gwak GY, 2005, J HEPATOL, V42, P358, DOI 10.1016/j.jhep.2004.11.020Ko YH, 2004, BIOCHEM BIOPH RES CO, V324, P269, DOI 10.1016/j.bbrc.2004.09.047Llovet JM, 2003, LANCET, V362, P1907Yoon CJ, 2003, RADIOLOGY, V229, P126, DOI 10.1148/radio.2291021029Pedersen PL, 2002, BBA-BIOENERGETICS, V1555, P14Geschwind JFH, 2002, CANCER RES, V62, P3909Ko YH, 2001, CANCER LETT, V173, P83Smith TAD, 2000, BRIT J BIOMED SCI, V57, P170Pedersen PL, 1999, J BIOENERG BIOMEMBR, V31, P291Dang CV, 1999, TRENDS BIOCHEM SCI, V24, P68Bosch FX, 1999, SEMIN LIVER DIS, V19, P271Bruix J, 1997, HEPATOLOGY, V25, P259Rempel A, 1996, CANCER RES, V56, P2468Stuart KE, 1996, CANCER, V77, P2217MATHUPALA SP, 1995, J BIOL CHEM, V270, P16918OKADA M, 1995, BRIT J CANCER, V71, P518WATANABE D, 1995, ONCOLOGY, V52, P76REMPEL A, 1994, BBA-GENE STRUCT EXPR, V1219, P660BRUIX J, 1992, J HEPATOL, V15, P350OKUDA K, 1992, HEPATOLOGY, V15, P948SHINOHARA Y, 1991, FEBS LETT, V291, P55KO YH, 1990, ARCH BIOCHEM BIOPHYS, V278, P373BISMUTH H, 1986, WORLD J SURG, V10, P311JOHANSSON T, 1985, BIOCHEM BIOPH RES CO, V133, P608VIITANEN PV, 1984, J BIOL CHEM, V259, P9679BUSTAMANTE E, 1981, J BIOL CHEM, V256, P8699PEDERSEN PL, 1978, PROGR EXPT TUMOR RES, V22, P190WEINHOUS.S, 1972, CANCER RES, V32, P2007

On the asymptotic and practical complexity of solving bivariate systems over the reals

This paper is concerned with exact real solving of well-constrained, bivariate polynomial systems. The main problem is to isolate all common real roots in rational rectangles, and to determine their intersection multiplicities. We present three algorithms and analyze their asymptotic bit complexity, obtaining a bound of \sOB(N^{14}) for the purely projection-based method, and \sOB(N^{12}) for two subresultant-based methods: this notation ignores polylogarithmic factors, where $N$ bounds the degree and the bitsize of the polynomials. The previous record bound was \sOB(N^{14}). Our main tool is signed subresultant sequences. We exploit recent advances on the complexity of univariate root isolation, and extend them to sign evaluation of bivariate polynomials over two algebraic numbers, and real root counting for polynomials over an extension field. Our algorithms apply to the problem of simultaneous inequalities; they also compute the topology of real plane algebraic curves in \sOB(N^{12}), whereas the previous bound was \sOB(N^{14}). All algorithms have been implemented in MAPLE, in conjunction with numeric filtering. We compare them against FGB/RS, system solvers from SYNAPS, and MAPLE libraries INSULATE and TOP, which compute curve topology. Our software is among the most robust, and its runtimes are comparable, or within a small constant factor, with respect to the C/C++ libraries. Key words: real solving, polynomial systems, complexity, MAPLE softwareComment: 17 pages, 4 algorithms, 1 table, and 1 figure with 2 sub-figure

The HK2 Dependent "Warburg Effect" and Mitochondrial Oxidative Phosphorylation in Cancer:Targets for Effective Therapy with 3-Bromopyruvate

This review summarizes the current state of knowledge about the metabolism of cancer cells, especially with respect to the “Warburg” and “Crabtree” effects. This work also summarizes two key discoveries, one of which relates to hexokinase-2 (HK2), a major player in both the “Warburg effect” and cancer cell immortalization. The second discovery relates to the finding that cancer cells, unlike normal cells, derive as much as 60% of their ATP from glycolysis via the “Warburg effect”, and the remaining 40% is derived from mitochondrial oxidative phosphorylation. Also described are selected anticancer agents which generally act as strong energy blockers inside cancer cells. Among them, much attention has focused on 3-bromopyruvate (3BP). This small alkylating compound targets both the “Warburg effect”, i.e., elevated glycolysis even in the presence oxygen, as well as mitochondrial oxidative phosphorylation in cancer cells. Normal cells remain unharmed. 3BP rapidly kills cancer cells growing in tissue culture, eradicates tumors in animals, and prevents metastasis. In addition, properly formulated 3BP shows promise also as an effective anti-liver cancer agent in humans and is effective also toward cancers known as “multiple myeloma”. Finally, 3BP has been shown to significantly extend the life of a human patient for which no other options were available. Thus, it can be stated that 3BP is a very promising new anti-cancer agent in the process of undergoing clinical development

The cytotoxicity of 3-bromopyruvate in breast cancer cells depends on extracellular pH

Although the anti-cancer properties of 3BP have been described previously, its selectivity for cancer cells still needs to be explained. In the work reported here we characterized the kinetic parameters of radiolabelled [14C]-3BP uptake in three breast cancer cell lines that display different levels of resistance to 3BP: ZR-75-1 < MCF-7 < SK-BR-3. At pH 6.0 the affinity of cancer cells for 3BP transport, correlates with their sensitivity, a pattern that does not occur at pH 7.4. In the three cell lines, the uptake of 3BP is dependent on the proton motive force and is decreased by MCTs inhibitors. In the SK-BR-3 cell line, a sodium-dependent transport also occurs. Butyrate promotes the localization of MCT-1 at the plasma membrane and increases the level of MCT-4 expression, leading to a higher sensitivity for 3BP. Here, we demonstrate that this phenotype is accompanied by an increase in affinity for 3BP uptake. Our results confirm the role of MCTs, especially MCT-1 in 3BP uptake and the importance of CD147 glycosylation in this process. We find that the affinity for 3BP transport is higher when the extracellular milieu is acid. This is a typical phenotype of tumor microenvironment and explains the lack of secondary effects of 3BP already described in in vivo studies.FEDER (Fundo Europeu deDesenvolvimento Regional), through POFC (Programa Operacional Factores de Competitividade) – COMPETE, and by Portuguese National Funds from FCT (Fundac¸˜ao para a Ciˆencia e Tecnologia) in the scope of the project PEst-OE/BIA/U14050/2014. JAS [grant number SFRH/BD/76038/2011] received a fellowship from the Portuguese government from the FCT through FSE (Fundo Social Europeu) and POPH (Programa Operacional Potencial Humano)

Assessment of the Type D Personality Construct in the Korean Population: A Validation Study of the Korean DS14

This study aimed to develop a Korean version of the Type D Personality Scale-14 (DS14) and evaluate the psychiatric symptomatology of Korean cardiac patients with Type D personality. Healthy control (n = 954), patients with a coronary heart disease (n = 111) and patients with hypertension and no heart disease (n = 292) were recruited. All three groups completed DS14, the Eysenck Personality Questionnaire (EPQ), the state subscale of Spielberger State and Trait Anxiety Inventory (STAI-S), the Center for Epidemiologic Studies Short Depression Scale (CESD), and the General Health Questionnaire (GHQ). The Korean DS14 was internally consistent and stable over time. 27% of the subjects were classified as Type D. Type D individuals had significantly higher mean scores on the STAI-S, CESD, and GHQ compared to non-Type D subjects in each group. The Korean DS14 was a valid and reliable tool for identifying Type D personality. The general population and cardiovascular patients with Type D personality showed higher rate of depression, anxiety and psychological distress regarding their health. Therefore, identifying Type D personality is important in clinical research and practice in chronic medical disorders, especially cardiovascular disease, in Korea

Novel Designs for Application Specific MEMS Pressure Sensors

In the framework of developing innovative microfabricated pressure sensors, we present here three designs based on different readout principles, each one tailored for a specific application. A touch mode capacitive pressure sensor with high sensitivity (14 pF/bar), low temperature dependence and high capacitive output signal (more than 100 pF) is depicted. An optical pressure sensor intrinsically immune to electromagnetic interference, with large pressure range (0–350 bar) and a sensitivity of 1 pm/bar is presented. Finally, a resonating wireless pressure sensor power source free with a sensitivity of 650 KHz/mmHg is described. These sensors will be related with their applications in  harsh environment, distributed systems and medical environment, respectively. For many aspects, commercially available sensors, which in vast majority are piezoresistive, are not suited for the applications proposed