The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration

Objective The sodium-glucose transporter 2 (SGLT2) inhibitors Canagliflozin and Dapagliflozin are recently approved medications for type 2 diabetes. Recent studies indicate that SGLT2 inhibitors may inhibit the growth of some cancer cells but the mechanism(s) remain unclear. Methods Cellular proliferation and clonogenic survival were used to assess the sensitivity of prostate and lung cancer cell growth to the SGLT2 inhibitors. Oxygen consumption, extracellular acidification rate, cellular ATP, glucose uptake, lipogenesis, and phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase, and the p70S6 kinase were assessed. Overexpression of a protein that maintains complex-I supported mitochondrial respiration (NDI1) was used to establish the importance of this pathway for mediating the anti-proliferative effects of Canagliflozin. Results Clinically achievable concentrations of Canagliflozin, but not Dapagliflozin, inhibit cellular proliferation and clonogenic survival of prostate and lung cancer cells alone and in combination with ionizing radiation and the chemotherapy Docetaxel. Canagliflozin reduced glucose uptake, mitochondrial complex-I supported respiration, ATP, and lipogenesis while increasing the activating phosphorylation of AMPK. The overexpression of NDI1 blocked the anti-proliferative effects of Canagliflozin indicating reductions in mitochondrial respiration are critical for anti-proliferative actions. Conclusion These data indicate that like the biguanide metformin, Canagliflozin not only lowers blood glucose but also inhibits complex-I supported respiration and cellular proliferation in prostate and lung cancer cells. These observations support the initiation of studies evaluating the clinical efficacy of Canagliflozin on limiting tumorigenesis in pre-clinical animal models as well epidemiological studies on cancer incidence relative to other glucose lowering therapies in clinical populations

Particle density fluctuations

Event-by-event fluctuations in the multiplicities of charged particles and photons at SPS energies are discussed. Fluctuations are studied by controlling the centrality of the reaction and rapidity acceptance of the detectors. Results are also presented on the event-by-event study of correlations between the multiplicity of charged particles and photons to search for DCC-like signals.Comment: Talk presented at Quark Matter 2002, Nantes, Franc

Suppression of High-p_T Neutral Pion Production in Central Pb+Pb Collisions at sqrt{s_NN} = 17.3 GeV Relative to p+C and p+Pb Collisions

Neutral pion transverse momentum spectra were measured in p+C and p+Pb collisions at sqrt{s_NN} = 17.4 GeV at mid-rapidity 2.3 < eta_lab < 3.0 over the range 0.7< p_T < 3.5 GeV/c. The spectra are compared to pi0 spectra measured in Pb+Pb collisions at sqrt{s_NN} = 17.3 GeV in the same experiment. For a wide range of Pb+Pb centralities (N_part < 300) the yield of pi0's with p_T > 2 GeV/c is larger than or consistent with the p+C or p+Pb yields scaled with the number of nucleon-nucleon collisions (N_coll), while for central Pb+Pb collisions with N_part > 350 the pi0 yield is suppressed.Comment: 5 pages, 4 figure

Search for DCC in 158A GeV Pb+Pb Collisions

A detailed analysis of the phase space distributions of charged particles and photons have been carried out using two independent methods. The results indicate the presence of nonstatistical fluctuations in localized regions of phase space.Comment: Talk at the PANIC99 Conference, June 9-16, 199

Pion Freeze-Out Time in Pb+Pb Collisions at 158 A GeV/c Studied via pi-/pi+ and K-/K+ Ratios

The effect of the final state Coulomb interaction on particles produced in Pb+Pb collisions at 158 A GeV/c has been investigated in the WA98 experiment through the study of the pi-/pi+ and K-/K+ ratios measured as a function of transverse mass. While the ratio for kaons shows no significant transverse mass dependence, the pi-/pi+ ratio is enhanced at small transverse mass values with an enhancement that increases with centrality. A silicon pad detector located near the target is used to estimate the contribution of hyperon decays to the pi-/pi+ ratio. The comparison of results with predictions of the RQMD model in which the Coulomb interaction has been incorporated allows to place constraints on the time of the pion freeze-out.Comment: 9 pages, 12 figure

Present Status and Future of DCC Analysis

Disoriented Chiral Condensates (DCC) have been predicted to form in high energy heavy ion collisions where the approximate chiral symmetry of QCD has been restored. This leads to large imbalances in the production of charged to neutral pions. Sophisticated analysis methods are being developed to disentangle DCC events out of the large background of events with conventionally produced particles. We present a short review of current analysis methods and future prospects.Comment: 12 pages, 5 figures. Invited talk presented at the 13th International Conference on Ultrarelativistic Nucleus-Nucleus Collisions (Quark Matter 97), Tsukuba, Japan, 1-5 Dec 199

Central Pb+Pb Collisions at 158 A GeV/c Studied by Pion-Pion Interferometry

Two-particle correlations have been measured for identified negative pions from central 158 AGeV Pb+Pb collisions and fitted radii of about 7 fm in all dimensions have been obtained. A multi-dimensional study of the radii as a function of kT is presented, including a full correction for the resolution effects of the apparatus. The cross term Rout-long of the standard fit in the Longitudinally CoMoving System (LCMS) and the vl parameter of the generalised Yano-Koonin fit are compatible with 0, suggesting that the source undergoes a boost invariant expansion. The shapes of the correlation functions in Qinv and Qspace have been analyzed in detail. They are not Gaussian but better represented by exponentials. As a consequence, fitting Gaussians to these correlation functions may produce different radii depending on the acceptance of the experimental setup used for the measurement.Comment: 13 pages including 10 figure

Search for Disoriented Chiral Condensates in 158 AGeV Pb+Pb Collisions

The restoration of chiral symmetry and its subsequent breaking through a phase transition has been predicted to create regions of Disoriented Chiral Condensates (DCC). This phenomenon has been predicted to cause anomalous fluctuations in the relative production of charged and neutral pions in high-energy hadronic and nuclear collisions. The WA98 experiment has been used to measure charged and photon multiplicities in the central region of 158 AGeV Pb+Pb collisions at the CERN SPS. In a sample of 212646 events, no clear DCC signal can be distinguished. Using a simple DCC model, we have set a 90% C.L. upper limit on the maximum DCC production allowed by the data.Comment: 20 Pages, LaTeX, uses elsart.cls, 8 eps figures included, submitted to Physics Letters

Proximity effect at superconducting Sn-Bi2Se3 interface

We have investigated the conductance spectra of Sn-Bi2Se3 interface junctions down to 250 mK and in different magnetic fields. A number of conductance anomalies were observed below the superconducting transition temperature of Sn, including a small gap different from that of Sn, and a zero-bias conductance peak growing up at lower temperatures. We discussed the possible origins of the smaller gap and the zero-bias conductance peak. These phenomena support that a proximity-effect-induced chiral superconducting phase is formed at the interface between the superconducting Sn and the strong spin-orbit coupling material Bi2Se3.Comment: 7 pages, 8 figure

Centrality Dependence of the High p_T Charged Hadron Suppression in Au+Au collisions at sqrt(s_NN) = 130 GeV

PHENIX has measured the centrality dependence of charged hadron p_T spectra from central Au+Au collisions at sqrt(s_NN)=130 GeV. The truncated mean p_T decreases with centrality for p_T > 2 GeV/c, indicating an apparent reduction of the contribution from hard scattering to high p_T hadron production. For central collisions the yield at high p_T is shown to be suppressed compared to binary nucleon-nucleon collision scaling of p+p data. This suppression is monotonically increasing with centrality, but most of the change occurs below 30% centrality, i.e. for collisions with less than about 140 participating nucleons. The observed p_T and centrality dependence is consistent with the particle production predicted by models including hard scattering and subsequent energy loss of the scattered partons in the dense matter created in the collisions.Comment: 7 pages text, LaTeX, 6 figures, 2 tables, 307 authors, resubmitted to Phys. Lett. B. Revised to address referee concerns. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are publicly available at http://www.phenix.bnl.gov/phenix/WWW/run/phenix/papers.htm