A Glucose-Triptolide Conjugate Selectively Targets Cancer Cells under Hypoxia
Emmanuel Datan,
Il Minn,
Peng Xu,
Qing-Li He,
Hye-Hyun Ahn,
Biao Yu,
Martin G. Pomper,
Jun O. Liu
Affiliations
Emmanuel Datan
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Il Minn
Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Peng Xu
State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and University of Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
Qing-Li He
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Hye-Hyun Ahn
Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Biao Yu
State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and University of Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China; Corresponding author
Martin G. Pomper
Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Corresponding author
Jun O. Liu
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Corresponding author
Summary: A major hurdle in the treatment of cancer is chemoresistance induced under hypoxia that is characteristic of tumor microenvironment. Triptolide, a potent inhibitor of eukaryotic transcription, possesses potent antitumor activity. However, its clinical potential has been limited by toxicity and water solubility. To address those limitations of triptolide, we designed and synthesized glucose-triptolide conjugates (glutriptolides) and demonstrated their antitumor activity in vitro and in vivo. Herein, we identified a lead, glutriptolide-2 with an altered linker structure. Glutriptolide-2 possessed improved stability in human serum, greater selectivity toward cancer over normal cells, and increased potency against cancer cells. Glutriptolide-2 exhibits sustained antitumor activity, prolonging survival in a prostate cancer metastasis animal model. Importantly, we found that glutriptolide-2 was more potent against cancer cells under hypoxia than normoxia. Together, this work provides an attractive glutriptolide drug lead and suggests a viable strategy to overcome chemoresistance through conjugation of cytotoxic agents to glucose.
