Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo

Guang Biao Zhou, Hui Kang, Lan Wang, Li Gao, Ping Liu, Jun Xie, Feng Xiang Zhang, Xiang Qin Weng, Zhi Xiang Shen, Jue Chen, Long Jun Gu, Ming Yan, Dong Er Zhang, Sai Juan Chen, Zhen Yi Wang, Chen Zhu

Research output: Contribution to journalArticle

155 Citations (Scopus)

Abstract

Studies have documented the potential antitumor activities of oridonin, a compound extracted from medicinal herbs. However, whether oridonin can be used in the selected setting of hematology/oncology remains obscure. Here, we reported that oridonin induced apoptosis of t(8;21) acute myeloid leukemic (AML) cells. Intriguingly, the t(8;21) product AML1-ETO (AE) fusion protein, which plays a critical role in leukemogenesis, was degraded with generation of a catabolic fragment, while the expression pattern of AE target genes investigated could be reprogrammed. The ectopic expression of AE enhanced the apoptotic effect of oridonin in U937 cells. Preincubation with caspase inhibitors blocked oridonin-triggered cleavage of AE, while substitution of Ala for Asp at residues 188 in ETO moiety of the fusion abrogated AE degradation. Furthermore, oridonin prolonged lifespan of C57 mice bearing truncated AE-expressing leukemic cells without suppression of bone marrow or reduction of body weight of animals, and exerted synergic effects while combined with cytosine arabinoside. Oridonin also inhibited tumor growth in nude mice inoculated with t(8;21)-harboring Kasumi-1 cells. These results suggest that oridonin may be a potential antileukemia agent that targets AE oncoprotein at residue D188 with low adverse effect, and may be helpful for the treatment of patients with t(8;21) AML.

Original languageEnglish (US)
Pages (from-to)3441-3450
Number of pages10
JournalBlood
Volume109
Issue number8
DOIs
StatePublished - Apr 15 2007
Externally publishedYes

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Diterpenes
Medicinal Plants
Leukemia
Fusion reactions
Proteins
Bearings (structural)
U937 Cells
Caspase Inhibitors
Oncology
oridonin
In Vitro Techniques
Oncogene Proteins
Cytarabine
Hematology
Myeloid Cells
Nude Mice
Tumors
Bone
Animals
Substitution reactions

ASJC Scopus subject areas

  • Hematology

Cite this

Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo. / Zhou, Guang Biao; Kang, Hui; Wang, Lan; Gao, Li; Liu, Ping; Xie, Jun; Zhang, Feng Xiang; Weng, Xiang Qin; Shen, Zhi Xiang; Chen, Jue; Gu, Long Jun; Yan, Ming; Zhang, Dong Er; Chen, Sai Juan; Wang, Zhen Yi; Zhu, Chen.

In: Blood, Vol. 109, No. 8, 15.04.2007, p. 3441-3450.

Research output: Contribution to journalArticle

Zhou, GB, Kang, H, Wang, L, Gao, L, Liu, P, Xie, J, Zhang, FX, Weng, XQ, Shen, ZX, Chen, J, Gu, LJ, Yan, M, Zhang, DE, Chen, SJ, Wang, ZY & Zhu, C 2007, 'Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo', Blood, vol. 109, no. 8, pp. 3441-3450. https://doi.org/10.1182/blood-2006-06-032250
Zhou, Guang Biao ; Kang, Hui ; Wang, Lan ; Gao, Li ; Liu, Ping ; Xie, Jun ; Zhang, Feng Xiang ; Weng, Xiang Qin ; Shen, Zhi Xiang ; Chen, Jue ; Gu, Long Jun ; Yan, Ming ; Zhang, Dong Er ; Chen, Sai Juan ; Wang, Zhen Yi ; Zhu, Chen. / Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo. In: Blood. 2007 ; Vol. 109, No. 8. pp. 3441-3450.
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abstract = "Studies have documented the potential antitumor activities of oridonin, a compound extracted from medicinal herbs. However, whether oridonin can be used in the selected setting of hematology/oncology remains obscure. Here, we reported that oridonin induced apoptosis of t(8;21) acute myeloid leukemic (AML) cells. Intriguingly, the t(8;21) product AML1-ETO (AE) fusion protein, which plays a critical role in leukemogenesis, was degraded with generation of a catabolic fragment, while the expression pattern of AE target genes investigated could be reprogrammed. The ectopic expression of AE enhanced the apoptotic effect of oridonin in U937 cells. Preincubation with caspase inhibitors blocked oridonin-triggered cleavage of AE, while substitution of Ala for Asp at residues 188 in ETO moiety of the fusion abrogated AE degradation. Furthermore, oridonin prolonged lifespan of C57 mice bearing truncated AE-expressing leukemic cells without suppression of bone marrow or reduction of body weight of animals, and exerted synergic effects while combined with cytosine arabinoside. Oridonin also inhibited tumor growth in nude mice inoculated with t(8;21)-harboring Kasumi-1 cells. These results suggest that oridonin may be a potential antileukemia agent that targets AE oncoprotein at residue D188 with low adverse effect, and may be helpful for the treatment of patients with t(8;21) AML.",
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T1 - Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo

AU - Zhou, Guang Biao

AU - Kang, Hui

AU - Wang, Lan

AU - Gao, Li

AU - Liu, Ping

AU - Xie, Jun

AU - Zhang, Feng Xiang

AU - Weng, Xiang Qin

AU - Shen, Zhi Xiang

AU - Chen, Jue

AU - Gu, Long Jun

AU - Yan, Ming

AU - Zhang, Dong Er

AU - Chen, Sai Juan

AU - Wang, Zhen Yi

AU - Zhu, Chen

PY - 2007/4/15

Y1 - 2007/4/15

N2 - Studies have documented the potential antitumor activities of oridonin, a compound extracted from medicinal herbs. However, whether oridonin can be used in the selected setting of hematology/oncology remains obscure. Here, we reported that oridonin induced apoptosis of t(8;21) acute myeloid leukemic (AML) cells. Intriguingly, the t(8;21) product AML1-ETO (AE) fusion protein, which plays a critical role in leukemogenesis, was degraded with generation of a catabolic fragment, while the expression pattern of AE target genes investigated could be reprogrammed. The ectopic expression of AE enhanced the apoptotic effect of oridonin in U937 cells. Preincubation with caspase inhibitors blocked oridonin-triggered cleavage of AE, while substitution of Ala for Asp at residues 188 in ETO moiety of the fusion abrogated AE degradation. Furthermore, oridonin prolonged lifespan of C57 mice bearing truncated AE-expressing leukemic cells without suppression of bone marrow or reduction of body weight of animals, and exerted synergic effects while combined with cytosine arabinoside. Oridonin also inhibited tumor growth in nude mice inoculated with t(8;21)-harboring Kasumi-1 cells. These results suggest that oridonin may be a potential antileukemia agent that targets AE oncoprotein at residue D188 with low adverse effect, and may be helpful for the treatment of patients with t(8;21) AML.

AB - Studies have documented the potential antitumor activities of oridonin, a compound extracted from medicinal herbs. However, whether oridonin can be used in the selected setting of hematology/oncology remains obscure. Here, we reported that oridonin induced apoptosis of t(8;21) acute myeloid leukemic (AML) cells. Intriguingly, the t(8;21) product AML1-ETO (AE) fusion protein, which plays a critical role in leukemogenesis, was degraded with generation of a catabolic fragment, while the expression pattern of AE target genes investigated could be reprogrammed. The ectopic expression of AE enhanced the apoptotic effect of oridonin in U937 cells. Preincubation with caspase inhibitors blocked oridonin-triggered cleavage of AE, while substitution of Ala for Asp at residues 188 in ETO moiety of the fusion abrogated AE degradation. Furthermore, oridonin prolonged lifespan of C57 mice bearing truncated AE-expressing leukemic cells without suppression of bone marrow or reduction of body weight of animals, and exerted synergic effects while combined with cytosine arabinoside. Oridonin also inhibited tumor growth in nude mice inoculated with t(8;21)-harboring Kasumi-1 cells. These results suggest that oridonin may be a potential antileukemia agent that targets AE oncoprotein at residue D188 with low adverse effect, and may be helpful for the treatment of patients with t(8;21) AML.

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