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The proteasome inhibitor MLN-273 blocks exoerythrocytic and erythrocytic development of Plasmodium parasites

Published online by Cambridge University Press:  09 March 2005

C. LINDENTHAL ,
N. WEICH ,
Y.-S. CHIA ,
V. HEUSSLER  and
M.-Q. KLINKERT
C. LINDENTHAL
Affiliation:
Pharmaceutical Biotech Production, Roche Diagnostics GmbH, Penzberg, Germany
N. WEICH
Affiliation:
Millenium Pharmaceuticals Inc., Cambridge, MA 02139, USA
Y.-S. CHIA
Affiliation:
Department of Molecular Medicine, Bernhard-Nocht Institute for Tropical Medicine, Hamburg, Germany
V. HEUSSLER
Affiliation:
Department of Molecular Medicine, Bernhard-Nocht Institute for Tropical Medicine, Hamburg, Germany
M.-Q. KLINKERT
Affiliation:
Department of Molecular Medicine, Bernhard-Nocht Institute for Tropical Medicine, Hamburg, Germany
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Abstract

Protein degradation is regulated during the cell cycle of all eukaryotic cells and is mediated by the ubiquitin-proteasome pathway. Potent and specific peptide-derived inhibitors of the 20S proteasome have been developed recently as anti-cancer agents, based on their ability to induce apoptosis in rapidly dividing cells. Here, we tested a novel small molecule dipeptidyl boronic acid proteasome inhibitor, named MLN-273 on blood and liver stages of Plasmodium species, both of which undergo active replication, probably requiring extensive proteasome activity. The inhibitor blocked Plasmodium falciparum erythrocytic development at an early ring stage as well as P. berghei exoerythrocytic progression to schizonts. Importantly, neither uninfected erythrocytes nor hepatocytes were affected by the drug. MLN-273 caused an overall reduction in protein degradation in P. falciparum, as demonstrated by immunoblots using anti-ubiquitin antibodies to label ubiquitin-tagged protein conjugates. This led us to conclude that the target of the drug was the parasite proteasome. The fact that proteasome inhibitors are presently used as anti-cancer drugs in humans forms a solid basis for further development and makes them potentially attractive drugs also for malaria chemotherapy.

Keywords

proteasome inhibitor MLN-273Plasmodiumdevelopment inhibition
Type
Research Article
Information
Parasitology , Volume 131 , Issue 1 , July 2005 , pp. 37 - 44
Copyright
© 2005 Cambridge University Press

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References

REFERENCES

ADAMS, J., PALOMBELLA, V. J., SAUSVILLE, E. A., JOHNSON, J., DESTREE, A., LAZARUS, D. D., MAAS, J., PIEN, C. S., PRAKASH, S. & ELLIOTT, P. J. ( 1999). Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Research 59, 2615–2622.Google Scholar
AGHAJANIAN, C., SOIGNET, S., DIZON, D. S., PIEN, C. S., ADAMS, J., ELLIOTT, P. J., SABBATINI, P., MILLER, V., HENSLEY, M. L., PEZZULLI, S., CANALES, C., DAUD, A. & SPRIGGS, D. R. ( 2002). A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clinical Cancer Research 8, 2505–2511.Google Scholar
BRATOSIN, D., ESTAQUIER, J., PETIT, F., ARNOULT, D., QUATANNENS, B., TISSIER, J. P., SLOMIANNY, C., SARTIAUX, C., ALONSO, C., HUART, J. J., MONTREUIL, J. & AMEISEN, J. C. ( 2001). Programmed cell death in mature erythrocytes: a model for investigating death effector pathways operating in the absence of mitochondria. Cell Death and Differentiation 8, 1143–1156.CrossRefGoogle Scholar
DARWIN, K. H., EHRT, S., GUTIERREZ-RAMOS, J. C., WEICH, N. & NATHAN, C. F. ( 2003). The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide. Science 302, 1963–1966.CrossRefGoogle Scholar
DESAKORN, V., SILAMUT, K., ANGUS, B., SAHASSANANDA, D., CHOTIVANICH, K., SUNTHARASAMAI, P., SIMPSON, J. & WHITE, N. J. ( 1997). Semi-quantitative measurement of Plasmodium falciparum antigen PfHRP2 in blood and plasma. Transactions of the Royal Society for Tropical Medicine and Hygiene 91, 479–483.CrossRefGoogle Scholar
ETLINGEN, J. D. & GOLDBERG, A. L. ( 1977). A soluble ATP-dependent proteolytic system responsible for the degradation of abnormal proteins in reticulocytes. Proceedings of the National Academy of Sciences, USA 74, 54–58.CrossRefGoogle Scholar
GANTT, S. M., MYUNG, J. M., BRIONES, M. R., LI, W. D., COREY, E. J., OMURA, S., NUSSENZWEIG, V. & SINNIS, P. ( 1998). Proteasome inhibitors block development of Plasmodium spp. Antimicrobial Agents and Chemotherapy 42, 2731–2738.Google Scholar
GONZALEZ, J., BAI, G., FREVERT, U., COREY, E. J. & EICHINGER, D. ( 1999). Proteasome-dependent cyst formation and stage-specific ubiquitin mRNA accumulation in Entamoeba invadens. European Journal of Biochemistry 264, 897–904.CrossRefGoogle Scholar
GONZALEZ, J., RAMALHO-PINTO, F. J., FREVERT, U., GHISO, J., TOMLINSON, S., SCHARFSTEIN, J., COREY, E. J. & NUSSENZWEIG, V. ( 1996). Proteasome activity is required for the stage-specific transformation of a protozoan parasite. Journal of Experimental Medicine 184, 1909–1918.CrossRefGoogle Scholar
GRASSILLI, E., BENATTI, F., DANSI, P., GIAMMARIOLI, A. M., MALORNI, W., FRANCESCHI, C. & DESIDERIO, M. A. ( 1998). Inhibition of proteasome function prevents thymocyte apoptosis: involvement of ornithine decarboxylase. Biochemical and Biophysical Research Communications 250, 293–297.CrossRefGoogle Scholar
GRIMM, L. M., GOLDBERG, A. L., POIRIER, G. G., SCHWARTZ, L. M. & OSBORNE, B. A. ( 1996). Proteasomes play an essential role in thymocyte apoptosis. EMBO Journal 1, 3835–3844.Google Scholar
KISSELEV, A. F. & GOLDBERG, A. L. ( 2001). Proteasome inhibitors: from research tools to drug candidates. Chemistry and Biology 8, 739–758.CrossRefGoogle Scholar
KOTHAKOTA, S., AZUMA, T., REINHARD, C., KLIPPEL, A., TANG, J., CHU, K., MCGARRY, T. J., KIRSCHNER, M. W., KOTHS, K., KWIATKOWSKI, D. J. & WILLIAMS, L. T. ( 1997). Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis. Science 278, 294–298.CrossRefGoogle Scholar
KOZLOWSKI, L., STOKLOSA, T., OMURA, S., WOJCIK, C., WOJTUKIEWICZ, M. Z., WOROWSKI, K. & OSTROWSKA, H. ( 2001). Lactacystin inhibits cathepsin A activity in melanoma cell lines. Tumour Biology 22, 211–215.Google Scholar
KRNAJSKI, Z., WALTER, R. D. & MULLER, S. ( 2001). Isolation and functional analysis of two thioredoxin peroxidases (peroxiredoxins) from Plasmodium falciparum. Molecular and Biochemical Parasitology 113, 303–308.CrossRefGoogle Scholar
LANG, K. S., DURANTON, C., POEHLMANN, H., MYSSINA, S., BAUER, C., LANG, F., WIEDER, T. & HUBER, S. M. ( 2003). Cation channels trigger apoptotic death of erythrocytes. Cell Death and Differentiation 10, 249–256.CrossRefGoogle Scholar
LJUNGSTRÖM, I., PERLMANN, H., SCHLICHTERLE, M., SCHERF, A. & WAHLGREN, M. ( 2004). Methods in Malaria Research, 4th Edn. MR4/ATCC, Manassas, Virginia.
MUTOMBA, M. C., TO, W. Y., HYUN, W. C. & WANG, C. C. ( 1997). Inhibition of proteasome activity blocks cell cycle progression at specific phase boundaries in African trypanosomes. Molecular and Biochemical Parasitology 90, 491–504.CrossRefGoogle Scholar
NOEDL, H., WERNSDORFER, W. H., MILLER, R. S. & WONGSRICHANALAI, C. ( 2002). Histidine-rich protein II: a novel approach to malaria drug sensitivity testing. Antimicrobial Agents and Chemotherapy 46, 1658–1664.CrossRefGoogle Scholar
NOEDL, H., WONGSRICHANALAI, C. & WERNSDORFER, W. H. ( 2003). Malaria drug-sensitivity testing: new assays, new perspectives. Trends in Parasitology 19, 175–181.CrossRefGoogle Scholar
ORLOWSKI, R. Z., STINCHCOMBE, T. E., MITCHELL, B. S., SHEA, T. C., BALDWIN, A. S., STAHL, S., ADAMS, J., ESSELTINE, D. L., ELLIOTT, P. J., PIEN, C. S., GUERCIOLINI, R., ANDERSON, J. K., DEPCIK-SMITH, N. D., BHAGAT, R., LEHMAN, M. J., NOVICK, S. C., O'CONNOR, O. A. & SOIGNET, S.-L. ( 2002). Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. Journal of Clinical Oncology 20, 4420–4427.CrossRefGoogle Scholar
STEFANELLI, C., BONAVITA, F., STANIC, I., PIGNATTI, C., FARRUGGIA, G., MASOTTI, L., GUARNIERI, C. & CALDARERA, C. M. ( 1998). Inhibition of etoposide-induced apoptosis with peptide aldehyde inhibitors of proteasome. The Biochemical Journal 332, 661–665.CrossRefGoogle Scholar
TRAGER, W. ( 1971). A new method for intraerythrocytic cultivation of malaria parasites (Plasmodium coatneyi and P. falciparum). Journal of Protozoology 18, 239–242.CrossRefGoogle Scholar
VOORHEES, P. M., DEES, E. C., O'NEIL, B. & ORLOWSKI, R. Z. ( 2003). The proteasome as a target for cancer therapy. Clinical Cancer Res. 9, 6316–6325.Google Scholar
WORLD HEALTH ORGANIZATION ( 2001). Drug Resistance in Malaria. CSR Resources WHO, Geneva.