Parasitology Seminar

Holly Haberman

A Potential New Drug for Chagas’ Disease

Matsuo AL, Silva LS, Torrecilhas AC, Pascoalino BS, Ramos TC, Rodrigues EG, Schenkman S, Caires ACF, Travassos LR. 2010. In Vitro and In Vivo Trypanocidal Effects of the Cyclopalladated Compound 7a, a Drug Candidate for Treatment of Chagas’ Disease. Antimicrobial Agents and Chemotherapy 2010 Aug; 54(8): 3318-3325.

An estimated 10 million people are currently infected with T. cruzi throughout the world, yet currently there are only two drug treatments, benznidazole and nifurtimox, that are effective only in the acute phase of the disease. Additionally, these drugs cause severe side effects, especially in adults, and require a long time course of treatment, up to sixty days in duration. Recently, there has been limited reported progress in Chagas’ drug development. The current study looks at a potential new drug, synthesized from palladium III, in the treatment of acute Chagas’ disease. Already studied in cancer treatment, cyclopalladated compound 7a was already known to be biologically active and able to induce apoptosis in tumor cells. In order to further explore the potential for compound 7a as a drug for Chagas’ disease, the research team ran a series of in vitro experiments to measure cytoxicity, inhibition of cellular invasion, intracellular growth, mitochondrion disruption, and DNA fragmentation. Also, two in vivo experiments were conducted to measure the effectiveness of compound 7a in the pre-treatment and treatment of T. cruzi infection in female BALB/c mice. The in vitro studies found compound 7a to preferentially kill trypomastigotes, to be faster acting than benznidazole and to inhibit the cell invasion as well as the intracellular growth of T. cruzi. Also, the in vitro studies indicate that compound 7a may effectively kill the trypomastigotes via an apoptosis-like death mechanism, as mitochondrion structural changes and DNA fragmentation due to treatment with compound 7a was demonstrated. As shown in the in vivo studies, compound 7a significantly increased the survival rate of the BALB/c when administered before and after infection. Also, significantly less amastigote nests were found in heart and bladder tissue. Further in vivo studies need to be conducted to further explore the effectiveness and exact mechanism of compound 7a as a drug for Chagas’ disease.

References:

1. “Chagas disease (American Trypanosomiasis).” Neglected Tropical Diseases. World Health Organization, June 2010. Web. 7 Nov 2010.

2. “Cyclopalladated Compounds as Chemotherapeutic Agents: Antitumor Activity Against a Murine Melanoma Cell Line.” 2003. Int. J. Cancer. 107: 498-504.

3. “The Molecular Biology of Apoptosis.” 1996 Proc. Natl. Acad. Sci. 93:2239-2244.