ABSTRACT
Title
Maesopsin 4-O-β-D-glucoside (TAT-2), a natural compound isolated from the leaves of Artocarpus tonkinensis, inhibits proliferation of acute myeloid leukemia.
Authors
N. Pozzesi, S. Pierangeli, C. Riccardi, D. V. Delfino.
Section of Pharmacology, Toxicology and Chemotherapy - Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
Section of Pharmacology, Toxicology and Chemotherapy - Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
Abstract
The leaves of Artocarpus tonkinensis (A. tonkinensis)are used in Vietnamese traditional medicine (TM) for treatment of arthritis, and the compound maesopsin 4-O-β-D-glucoside (TAT-2), isolated from them, inhibits the proliferation of activated T cells. Our goal was to test the anti-proliferative activity of TAT-2 on the T-cell leukemia cell line, Jurkat, and on the acute myeloid leukemia (AML) cell line, OCI AML3. TAT-2 inhibited the growth of OCI AML3 but not Jurkat cells. Growth inhibition was shown to be due to inhibition of proliferation rather than increase in cell death. Analysis of cytokine release showed that TAT-2 stimulates the release of TGF-β, yet TGF-β neutralization did not reverse the TAT-2-dependent effect. Gene expression profiling determined that TAT-2 modulates 19 genes. Transcription factor CP2 was the most significantly modulated gene. Real-time PCR validates the up-regulation of sulphiredoxin 1 homolog (SRXN-1), hemeoxiganse 1 (HMOX-1), and Breast carcinoma amplified sequence 3 (BCAS-3) were consistently modulated.
The tree A. tonkinensis is distributed over the tropical regions of Asia and Africa. The bark and the leaves of A. tonkinensis have been used in Vietnamese traditional medicine for the treatment of backache and joint diseases1,2. Constituents in the leaves and the bark of A. tonkinensis are known to contain several potentially bioactive molecules such as lectins3, oxyresveratrol, catechin and triterpenoid, kaempferol, and ampelopsin3,4. A crude extract from A. tonkinensis leaves has been used successfully in Vietnam as an immunosuppressive agent for skin transplantation in mice4,5. Four different flavonoids have been isolated and their structure determined. The flavonoids purified from A. tonkinensis were shown to have potent anti-proliferative and anti-inflammatory effects both in vitro and in vivo. The anti-inflammatory effects demonstrated in a rat model of arthritis correlated well with the inhibition of mitogen-induced T-cell proliferation1.
Patients diagnosed with AML undergo two initial phases of chemotherapy, induction and consolidation6. Induction aims at achieving complete remission (CR), whereas consolidation aims at preventing relapse of leukemia by eradicating residual leukemic cells7. The combination of anthracycline and cytarabine typically used in induction chemotherapy induces CR in the majority of AML patients. The ensuing consolidation phase usually comprises repeated cycles of high dose cytarabine or similar compounds. In addition, younger patients with intermediate or unfavorable prognosis may undergo allogeneic bone marrow transplantation (allo-BMT), depending on the availability of suitable donors.
A relapse of AML is thought to be a result of expansion of leukemic cells that have escaped chemotherapy. The residual leukemic clone comprises a low number of cells that should represent an attractive target for therapeutic intervention. However, with the exception of allo-BMT, no therapy beyond the consolidation phase is known to reduce the risk of relapse, and the current standard of care for non-transplanted patients is no treatment. The high rate of relapse, along with the poor prospect of survival after a relapse, points towards the need for additional therapy.
In this study, we tested the effect of TAT-2, a natural compound isolated from the leaves of A. tonkinensis, and found it had anti-proliferative activity on AML cells. Moreover, gene expression profiling identified 19 genes modulated by TAT-2 and, among them, validation indicated HMOX-1 and SRXN-1 as consistently and highly upregulated.
References
1. Shanmugham LN et al. (2006) Riv Biol. 99:227-247
2. Dang DTN et al. (2009) 69:110-118
3. Uyama H. (2007) Macromol Biosci10:410-422
4. Thuy TT et al. (2004) Pharmazie 59:297-300
5. Ngoc DD et al. (2005) Scand J Immunol 61:234-241
6. Tallman MS et al. (2005) Blood 106 :1154-1163
7. Redaelli A et al. (2003) Expert Rev Anticancer Ther 3:695-710
The tree A. tonkinensis is distributed over the tropical regions of Asia and Africa. The bark and the leaves of A. tonkinensis have been used in Vietnamese traditional medicine for the treatment of backache and joint diseases1,2. Constituents in the leaves and the bark of A. tonkinensis are known to contain several potentially bioactive molecules such as lectins3, oxyresveratrol, catechin and triterpenoid, kaempferol, and ampelopsin3,4. A crude extract from A. tonkinensis leaves has been used successfully in Vietnam as an immunosuppressive agent for skin transplantation in mice4,5. Four different flavonoids have been isolated and their structure determined. The flavonoids purified from A. tonkinensis were shown to have potent anti-proliferative and anti-inflammatory effects both in vitro and in vivo. The anti-inflammatory effects demonstrated in a rat model of arthritis correlated well with the inhibition of mitogen-induced T-cell proliferation1.
Patients diagnosed with AML undergo two initial phases of chemotherapy, induction and consolidation6. Induction aims at achieving complete remission (CR), whereas consolidation aims at preventing relapse of leukemia by eradicating residual leukemic cells7. The combination of anthracycline and cytarabine typically used in induction chemotherapy induces CR in the majority of AML patients. The ensuing consolidation phase usually comprises repeated cycles of high dose cytarabine or similar compounds. In addition, younger patients with intermediate or unfavorable prognosis may undergo allogeneic bone marrow transplantation (allo-BMT), depending on the availability of suitable donors.
A relapse of AML is thought to be a result of expansion of leukemic cells that have escaped chemotherapy. The residual leukemic clone comprises a low number of cells that should represent an attractive target for therapeutic intervention. However, with the exception of allo-BMT, no therapy beyond the consolidation phase is known to reduce the risk of relapse, and the current standard of care for non-transplanted patients is no treatment. The high rate of relapse, along with the poor prospect of survival after a relapse, points towards the need for additional therapy.
In this study, we tested the effect of TAT-2, a natural compound isolated from the leaves of A. tonkinensis, and found it had anti-proliferative activity on AML cells. Moreover, gene expression profiling identified 19 genes modulated by TAT-2 and, among them, validation indicated HMOX-1 and SRXN-1 as consistently and highly upregulated.
References
1. Shanmugham LN et al. (2006) Riv Biol. 99:227-247
2. Dang DTN et al. (2009) 69:110-118
3. Uyama H. (2007) Macromol Biosci10:410-422
4. Thuy TT et al. (2004) Pharmazie 59:297-300
5. Ngoc DD et al. (2005) Scand J Immunol 61:234-241
6. Tallman MS et al. (2005) Blood 106 :1154-1163
7. Redaelli A et al. (2003) Expert Rev Anticancer Ther 3:695-710