DF/HCC Program Affiliation

Translational Pharmacology and Early Therapeutic Trials

Research Abstract

My cancer research originated with the discovery of the anticancer effect of the anti-fungal drug clotrimazole (CLT). I found that CLT has a dual effect on intracellular calcium: it releases clacium from internal stores and closes restorative calcium influx. The resulting partial depletion of internal calcium activates the enzyme PKR, which phosphorylates and thereby inhibits eukaryotic initiation factor 2, the first step in mRNA translation initiation. In this manner, CLT inhibits translation initiation and synthesis of a subset of proteins that includes cyclin D1 and E, and stops cell cycle progression in the G1. My identification of the pharmacophore responsible for this anti-cancer effect of CLT has led to the rational design of analogs that are more potent and less toxic inhibitors of translation initiation.

My laboratory's most recent finding is that the n-3 unsaturated fatty acid EPA as well as thiazoinianones (TZDs) have anti-cancer effects that are mediated by inhibition of translation initiation in a manner almost identical to the effect of CLT. This is potentially important because epidemiological studies have shown that populations eating fish diets rich in EPA exhibit a very low incidence of cnacer, and the TZDs have already been tested in clinical trials for human cancers.

In summary, my cancer research has led to the uncovering of translation initiation as a valid target for anticancer drugs and to the discovery of new inhibitors of translation initiation soon to be tested in humans.

Publications

• Hu W, Ferris SP, Tweten RK, Wu G, Radaeva S, Gao B, Bronson RT, Halperin JA, Qin X.Rapid conditional targeted ablation of cells expressing human CD59 in transgenic mice by intermedilysin.Nat Med 2008 Jan;14(1):98-103.
  18157141
• Moerke NJ, Aktas H, Chen H, Cantel S, Reibarkh MY, Fahmy A, Gross JD, Degterev A, Yuan J, Chorev M, Halperin JA, Wagner G.Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G.Cell 2007 Jan 26;128(2):257-6
  17254965
• Qin X, Dobarro M, Bedford SJ, Ferris S, Miranda PV, Song W, Bronson RT, Visconti PE, Halperin JA.Further characterization of reproductive abnormalities in mCd59b knockout mice: a potential new function of mCd59 in male reproduction.J Immunol 2005 Nov 15;1
  16272280
• Halperin AC, Rigotti NA.US public universities' compliance with recommended tobacco-control policies.J Am Coll Health 2003 Mar;51(5):181-8.
  12822709
• Palakurthi SS, Aktas H, Grubissich LM, Mortensen RM, Halperin JA.Anticancer effects of thiazolidinediones are independent of peroxisome proliferator-activated receptor gamma and mediated by inhibition of translation initiation.Cancer Res 2001 Aug 15;61(16
  11507074
• Qin X, Miwa T, Aktas H, Gao M, Lee C, Qian YM, Morton CC, Shahsafaei A, Song WC, Halperin JA.Genomic structure, functional comparison, and tissue distribution of mouse Cd59a and Cd59b.Mamm Genome 2001 Aug;12(8):582-9.
  11471050
• Qian YM, Qin X, Miwa T, Sun X, Halperin JA, Song WC.Identification and functional characterization of a new gene encoding the mouse terminal complement inhibitor CD59.J Immunol 2000 Sep 1;165(5):2528-34.
  10946279
• Palakurthi SS, Flückiger R, Aktas H, Changolkar AK, Shahsafaei A, Harneit S, Kilic E, Halperin JA.Inhibition of translation initiation mediates the anticancer effect of the n-3 polyunsaturated fatty acid eicosapentaenoic acid.Cancer Res 2000 Jun 1;60(11):
  10850438
• Acosta J, Hettinga J, Flückiger R, Krumrei N, Goldfine A, Angarita L, Halperin J.Molecular basis for a link between complement and the vascular complications of diabetes.Proc Natl Acad Sci U S A 2000 May 9;97(10):5450-5.
  10805801
• Aktas H, Flückiger R, Acosta JA, Savage JM, Palakurthi SS, Halperin JA.Depletion of intracellular Ca2+ stores, phosphorylation of eIF2alpha, and sustained inhibition of translation initiation mediate the anticancer effects of clotrimazole.Proc Natl Acad S
  9653178
• Shen Y, Halperin JA, Benzaquen L, Lee CM.Characterization of neuronal cell death induced by complement activation.Brain Res Brain Res Protoc 1997 May;1(2):186-94.
  9385083
• Acosta JA, Benzaquen LR, Goldstein DJ, Tosteson MT, Halperin JA.The transient pore formed by homologous terminal complement complexes functions as a bidirectional route for the transport of autocrine and paracrine signals across human cell membranes.Mol M
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• Benzaquen LR, Brugnara C, Byers HR, Gatton-Celli S, Halperin JA.Clotrimazole inhibits cell proliferation in vitro and in vivo.Nat Med 1995 Jun;1(6):534-40.
  7585119
• Shen Y, Halperin JA, Lee CM.Complement-mediated neurotoxicity is regulated by homologous restriction.Brain Res 1995 Feb 13;671(2):282-92.
  7743216
• Benzaquen LR, Nicholson-Weller A, Halperin JA.Terminal complement proteins C5b-9 release basic fibroblast growth factor and platelet-derived growth factor from endothelial cells.J Exp Med 1994 Mar 1;179(3):985-92.
  8113689
• Berger HJ, Taratuska A, Smith TW, Halperin JA.Activated complement directly modifies the performance of isolated heart muscle cells from guinea pig and rat.Am J Physiol 1993 Jul;265(1 Pt 2):H267-72.
  8342642
• Halperin JA, Taratuska A, Nicholson-Weller A.Terminal complement complex C5b-9 stimulates mitogenesis in 3T3 cells.J Clin Invest 1993 May;91(5):1974-8.
  8486768
• Nicholson-Weller A, Halperin JA.Membrane signaling by complement C5b-9, the membrane attack complex.Immunol Res 1993;12(3):244-57.
  8288945
• Halperin JA, Taratuska A, Rynkiewicz M, Nicholson-Weller A.Transient changes in erythrocyte membrane permeability are induced by sublytic amounts of the complement membrane attack complex (C5b-9).Blood 1993 Jan 1;81(1):200-5.
  7678066
• Halperin JA, Cornelius F.A voltage-activated cation transport pathway associated with the sodium pump.Biochim Biophys Acta 1991 Dec 9;1070(2):497-500.
  1662540
• Tosteson MT, Halperin JA, Kishi Y, Tosteson DC.Palytoxin induces an increase in the cation conductance of red cells.J Gen Physiol 1991 Nov;98(5):969-85.
  1684984
• Halperin JA, Brugnara C, Van Ha T, Tosteson DC.Voltage-activated cation permeability in high-potassium but not low-potassium red blood cells.Am J Physiol 1990 Jun;258(6 Pt 1):C1169-72.
  1694398
• Lorenzo AV, Taratuska A, Halperin JA.Suppression of cerebrospinal fluid (CSF) production by a Na+/K+ pump inhibitor extracted from human cerebrospinal fluid.Z Kinderchir 1989 Dec;44 Suppl 1:24-6.
  2560297
• Halperin JA, Brugnara C, Tosteson MT, Van Ha T, Tosteson DC.Voltage-activated cation transport in human erythrocytes.Am J Physiol 1989 Nov;257(5 Pt 1):C986-96.
  2596592
• Halperin JA, Brugnara C, Nicholson-Weller A.Ca2+-activated K+ efflux limits complement-mediated lysis of human erythrocytes.J Clin Invest 1989 May;83(5):1466-71.
  2708520
• Halperin JA.Digitalis-like properties of an inhibitor of the Na+/K+ pump in human cerebrospinal fluid.J Neurol Sci 1989 Apr;90(2):217-30.
  2542468
• Halperin JA, Nicholson-Weller A.Paroxysmal nocturnal hemoglobinuria. A complement-mediated disease.Complement Inflamm 1989;6(1):65-72.
  2650991
• Nicholson-Weller A, Halperin JA.Mechanisms by which the erythrocyte protects itself from complement damage.Prog Clin Biol Res 1989;297:263-70; discussion 270-1.
  2479950
• Halperin JA, Nicholson-Weller A, Brugnara C, Tosteson DC.Complement induces a transient increase in membrane permeability in unlysed erythrocytes.J Clin Invest 1988 Aug;82(2):594-600.
  3403718
• Halperin JA, Riordan JF, Tosteson DC.Characteristics of an inhibitor of the Na+/K+ pump in human cerebrospinal fluid.J Biol Chem 1988 Jan 15;263(2):646-51.
  2826458
• Halperin JA, Brugnara C, Kopin AS, Ingwall J, Tosteson DC.Properties of the Na+-K+ pump in human red cells with increased number of pump sites.J Clin Invest 1987 Jul;80(1):128-37.
  2439543
• Halperin JA, Lobb RR.Effect of heparin-binding growth factors on monovalent cation transport in Balb/C 3T3 cells.Biochem Biophys Res Commun 1987 Apr 14;144(1):115-22.
  2437904
• Halperin JA, Martin AM, Malave S.Increased digitalis-like activity in human cerebrospinal fluid after expansion of the extracellular fluid volume.Life Sci 1985 Aug 12;37(6):561-6.
  2991687
• Halperín J, Schaeffer R, Galvez L, Malavé S.Ouabain-like activity in human cerebrospinal fluid.Proc Natl Acad Sci U S A 1983 Oct;80(19):6101-4.
  6310614
• Goldstein DJ, Marante Perez DJ, Gunst JP, Halperin JA.Prostaglandin E1 inhibits acute cell dehydration thirst.Pharmacol Biochem Behav 1979 Jun;10(6):895-8.
  482310
• Goldstein DJ, Halperin JA.Mast cell histamine and cell dehydration thirst.Nature 1977 May 19;267(5608):250-2.
  405619