queous extract of Carica papaya leaves exhibits anti-tumor activity and mmunomodulatory effects

Aim of the study: Various parts of Carica papaya Linn. (CP) have been traditionally used as ethnomedicine for a number of disorders, including cancer. There have been anecdotes of patients with advanced cancers achieving remission following consumption of tea extract made from CP leaves. However, the precise cellular mechanism of action of CP tea extracts remains unclear. The aim of the present study is to examine the effect of aqueous-extracted CP leaf fraction on the growth of various tumor cell lines and on the anti-tumor effect of human lymphocytes. In addition, we attempted to identify the functional molecular weight fraction in the CP leaf extract. Materials and methods: The effect of CP extract on the proliferative responses of tumor cell lines and human peripheral blood mononuclear cells (PBMC), and cytotoxic activities of PBMC were assessed by [3H]-thymidine incorporation. Flow cytometric analysis and measurement of caspase-3/7 activities were performed to confirm the induction of apoptosis on tumor cells. Cytokine productions by PBMC were measured by ELISA. Gene profiling of the effect of CP extract treatment was performed by microarray analysis and real-time RT-PCR. Results: We observed significant growth inhibitory activity of the CP extract on tumor cell lines. In PBMC, the production of IL-2 and IL-4 was reduced following the addition of CP extract, whereas that of IL12p40, IL-12p70, IFNand TNFwas enhanced without growth inhibition. In addition, cytotoxicity of activated PBMC against K562 was enhanced by the addition of CP extract. Moreover, microarray analyses showed that the expression of 23 immunomodulatory genes, classified by gene ontology analysis, was enhanced by the addition of CP extract. In this regard, CCL2, CCL7, CCL8 and SERPINB2 were representative of these upregulated genes, and thus may serve as index markers of the immunomodulatory effects of CP extract. Finally, we identified the active components of CP extract, which inhibits tumor cell growth and stimulates anti-tumor effects, to be the fraction with M.W. less than 1000. Conclusion: Since Carica papaya leaf extract can mediate a Th1 type shift in human immune system, our results suggest that the CP leaf extract may potentially provide the means for the treatment and prevention of selected human diseases such as cancer, various allergic disorders, and may also serve as ine t immunoadjuvant for vacc Abbreviations: CP, Carica papaya; PBMC, peripheral blood mononuclear cells; PC, antigen-presenting cell; DC, dendritic cell; NK cell, natural killer cell; 7-AAD, -amino-actinomycin D; E:T ratio, effector–target ratio; GO, gene ontology. ∗ Corresponding author at: Division of Clinical Immunology, The Institute of edical Science, The University of Tokyo, 4-6-1, Shirokanedai Minato-ku, Tokyo 08-8639, Japan. Tel. : +81 3 5449 5548; fax: +81 3 6409 2098. E-mail address: morimoto@ims.u-tokyo.ac. jp (C. Morimoto). 1 These two authors contributed equally to this report. 378-8741/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. oi:10.1016/j.jep. 2009.11. 024 herapy. © 2009 Elsevier Ireland Ltd. All rights reserved.