Small-molecule STAT3 Signaling Pathway Modulators from Polygonum cuspidatum

Jiawei Liu; Qing Zhang; Kaotang Chen; Jingli Liu; Shan Kuang; Weiwen Chen; Qiang Yu

doi:10.1055/s-0032-1315121

Planta Medica, Table of Contents

Planta Med 2012; 78(14): 1568-1570
DOI: 10.1055/s-0032-1315121

Biological and Pharmacological Activity

Letters

Georg Thieme Verlag KG Stuttgart · New York

Small-molecule STAT3 Signaling Pathway Modulators from Polygonum cuspidatum

Jiawei Liu^*

¹Ministry of Education Key Laboratory of Chinese Medicinal Plants Resource from Lingnan, Research Center of Medicinal Plants Resource Science and Engineering, Guangzhou University of Chinese Medicine, Guangzhou, Peopleʼs Republic of China

,

Qing Zhang^*

²Departments of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Peopleʼs Republic of China

,

Kaotang Chen

¹Ministry of Education Key Laboratory of Chinese Medicinal Plants Resource from Lingnan, Research Center of Medicinal Plants Resource Science and Engineering, Guangzhou University of Chinese Medicine, Guangzhou, Peopleʼs Republic of China

,

Jingli Liu

²Departments of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Peopleʼs Republic of China

,

Shan Kuang

²Departments of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Peopleʼs Republic of China

,

Weiwen Chen

¹Ministry of Education Key Laboratory of Chinese Medicinal Plants Resource from Lingnan, Research Center of Medicinal Plants Resource Science and Engineering, Guangzhou University of Chinese Medicine, Guangzhou, Peopleʼs Republic of China

,

Qiang Yu

²Departments of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Peopleʼs Republic of China

› Author Affiliations

Abstract

Constitutively activated STAT3 plays a pivotal role in oncogenesis and metastasis in many human cancers, and STAT3 has been validated as a novel anticancer drug target. Thus, the identification of small molecules that modulate STAT3 activity could be of great therapeutic importance. The aim of this study was to isolate novel modulators of the STAT3 signaling pathway from the roots of Polygonum cuspidatum by bioassay-guided fractionation using a STAT3 reporter gene assay. 2-Methoxystypandrone (1), as well as three anthraquinones (2–4), were identified as major active components of P. cuspidatum. Compound 1 demonstrated a potent inhibitory effect on STAT3 activation and significantly inhibited cell proliferation of human breast cancer cells, especially those with constitutively activated STAT3 (IC₅₀ = 2.7–3.1 µM). The SAR analysis of quinone analogues suggested that the phenolic and carbonyl groups are the key structures contributing to their inhibitory activities against the STAT3 signaling.

Key words

Polygonum cuspidatum - Polygonaceae - STAT3 signaling - modulators - 2-methoxystypandrone

Full Text

References

References
1 Bromberg JF, Darnell JE. The role of STATs in transcriptional control and their impact on cellular function. Oncogene 2000; 19: 2468-2473
2 Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE. STAT3 as an oncogene. Cell 1999; 98: 295-303
3 Devarajan E, Huang S. STAT3 as a central regulator of tumor metastases. Curr Mol Med 2009; 9: 626-633
4 Lin Q, Lai R, Chirieac LR, Li C, Thomazy VA, Grammatikakis I, Rassidakis GZ, Zhang W, Fujio Y, Kunisada K, Hamilton SR, Amin HM. Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines: inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells. Am J Pathol 2005; 167: 969-980
5 Turkson J. STAT proteins as novel targets for cancer drug discovery. Exp Opin Ther Targets 2004; 8: 409-422
6 Pharmacopoeia of China, Part 1. Beijing: Peopleʼs Health Press; 2010: 194-195
7 Pan M, Wang X. Chemical constituents and pharmacological action of Polygonum cuspidatum Sieb. et Zucc. J Chin Med Mater 2000; 23: 56-58
8 Hughes AB, Sargent MV. Synthesis of 2-methoxystypandrone: comments on the structure of ventilaginone. J Chem Soc [Perkin I] 1989; 1: 449-452
9 Buchalter L. Isolation and identification of emodin (1,3,8-tri-hydroxy-6-methyl anthraquinone) from Rumex hymenosepalus, family Polygonaceae. J Pharm Sci 1969; 58: 904
10 Demuth G, Hinz H, Seligmann O, Wagner H. Investigations on anthrachinonglycosides of Rhamnus species. V. Emodin-8-O-beta-gentiobioside,a new O-glycoside from Rhamnus frangula . Planta Med 1978; 33: 53-56
11 King NM. Isolation of physcion from Ditremexa occidentalis . J Am Pharm Assoc 1957; 46: 271-272
12 Muto A, Hori M, Sasaki Y, Saitoh A, Yasuda I, Maekawa T, Uchida T, Asakura K, Nakazato T, Kaneda T, Kizaki M, Ikeda Y, Yoshida T. Emodin has a cytotoxic activity against human multiple myeloma as a Janus-activated kinase 2 inhibitor. Mol Cancer Ther 2007; 6: 987-994
13 Diaz N, Minton S, Cox C, Bowman T, Gritsko T, Garcia R, Eweis I, Wloch M, Livingston S, Seijo E, Cantor A, Lee JH, Beam CA, Sullivan D, Jove R, Muro-Cacho CA. Activation of STAT3 in primary tumors from high-risk breast cancer patients is associated with elevated levels of activated SRC and survivin expression. Clin Cancer Res 2006; 12: 20-28
14 Garcia R, Bowman TL, Niu G, Yu H, Minton S, Muro-Cacho CA, Cox CE, Falcone R, Fairclough R, Parsons S, Laudano A, Gazit A, Levitzki A, Kraker A, Jove R. Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 2001; 20: 2499-2513
15 Chiou WF, Liao JF, Huang CY, Chen CC. 2-Methoxystypandrone represses RANKL-mediated osteoclastogenesis by down-regulating formation of TRAF6-TAK1 signalling complexes. Br J Pharmacol 2010; 161: 321-335

Supplementary Material

Supporting Information