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Therapy

Enhanced cytotoxicity of an anti-transferrin receptor IgG3-avidin fusion protein in combination with gambogic acid against human malignant hematopoietic cells: functional relevance of iron, the receptor, and reactive oxygen species

Leukemia volume 23, pages 59–70 (2009)Cite this article

Abstract

The human transferrin receptor (hTfR) is a target for cancer immunotherapy due to its overexpression on the surface of cancer cells. We previously developed an antibody-avidin fusion protein that targets hTfR (anti-hTfR IgG3-Av) and exhibits intrinsic cytotoxicity against certain malignant cells. Gambogic acid (GA), a drug that also binds hTfR, induces cytotoxicity in several malignant cell lines. We now report that anti-hTfR IgG3-Av and GA induce cytotoxicity in a new broader panel of hematopoietic malignant cell lines. Our results show that the effect of anti-hTfR IgG3-Av is iron-dependent whereas that of GA is iron-independent in all cells tested. In addition, we observed that GA exerts a TfR-independent cytotoxicity. We also found that GA increases the generation of reactive oxygen species that may play a role in the cytotoxicity induced by this drug. Additive cytotoxicity was observed by simultaneous combination treatment with these drugs and synergy by using anti-hTfR IgG3-Av as a chemosensitizing agent. In addition, we found a concentration of GA that is toxic to malignant hematopoietic cells but not to human hematopoietic progenitor cells. Our results suggest that these two compounds may be effective, alone or in combination, for the treatment of human hematopoietic malignancies.

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Acknowledgements

We would like to thank Dr Sara Huerta-Yapez (Hospital Infantil de México ‘Federico Gomez’, Mexico City), Dr Mario I Vega (Hospital de Infectología ‘Dr Daniel Mendez Hernández’ Centro Médico ‘La Raza’ del Instituto Mexicano del Seguro Social, Mexico City) and José A. Rodríguez (University of California, Los Angeles) for assistance with isobolographic analysis. We also would like to thank Dr H Phillip Koeffler (Cedars Sinai Medical Center, Los Angeles, CA) for providing us with the CHO-TRVb cells. Our study was supported in part by the NIH/NCI Grants CA86915, CA107023 and SPORE in Lymphoma P50CA096888; and also by the NIH/NCI research supplements CA107023-02S1, CA057152-13S1 and Fogarty AITRP AIDS Malignancies Program D43-TW000013-S1.

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Authors and Affiliations

  1. Division of Surgical Oncology, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    E Ortiz-Sánchez, T R Daniels, G Helguera & M L Penichet

  2. Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    O Martinez-Maza

  3. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    O Martinez-Maza, B Bonavida, & M L Penichet

  4. Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    O Martinez-Maza, B Bonavida, & M L Penichet

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  1. E Ortiz-Sánchez
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  2. T R Daniels
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  3. G Helguera
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  4. O Martinez-Maza
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Correspondence to M L Penichet.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Ortiz-Sánchez, E., Daniels, T., Helguera, G. et al. Enhanced cytotoxicity of an anti-transferrin receptor IgG3-avidin fusion protein in combination with gambogic acid against human malignant hematopoietic cells: functional relevance of iron, the receptor, and reactive oxygen species. Leukemia 23, 59–70 (2009). https://doi.org/10.1038/leu.2008.270

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