Journal of Ethnopharmacology 127 (2010) 760–767
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Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jethpharm
Aqueous extract of Carica papaya leaves exhibits anti-tumor activity and
immunomodulatory effects
Noriko Otsukia,1, Nam H. Dangb,1, Emi Kumagaia, Akira Kondoc, Satoshi Iwataa, Chikao Morimotoa,d,∗
a Division of Clinical Immunology, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Japan
b Division of Hematology/Oncology, The University of Florida, Gainesville, FL, USA
c Kondo Hospital, 1-6-25, Nishishinhama, Tokushima, Tokushima 770-8008, Japan
d Department of Rheumatology and Allergy, Research Hospital, The Institute of Medical Science, The University of Tokyo, Japan
a b s t r a c t
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 IL-
12p40, IL-12p70, IFN-_ and TNF-_ was 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
immunoadjuvant for vaccine therapy.
© 2009 Elsevier Ireland Ltd. All rights reserved.
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