Echinacoside induces apoptotic cancer cell death by inhibiting the nucleotide pool sanitizing enzyme MTH1

نویسندگان

  • Liwei Dong
  • Hongge Wang
  • Jiajing Niu
  • Mingwei Zou
  • Nuoting Wu
  • Debin Yu
  • Ye Wang
  • Zhihua Zou
چکیده

Inhibition of the nucleotide pool sanitizing enzyme MTH1 causes extensive oxidative DNA damages and apoptosis in cancer cells and hence may be used as an anticancer strategy. As natural products have been a rich source of medicinal chemicals, in the present study, we used the MTH1-catalyzed enzymatic reaction as a high-throughput in vitro screening assay to search for natural compounds capable of inhibiting MTH1. Echinacoside, a compound derived from the medicinal plants Cistanche and Echinacea, effectively inhibited the catalytic activity of MTH1 in an in vitro assay. Treatment of various human cancer cell lines with Echinacoside resulted in a significant increase in the cellular level of oxidized guanine (8-oxoguanine), while cellular reactive oxygen species level remained unchanged, indicating that Echinacoside also inhibited the activity of cellular MTH1. Consequently, Echinacoside treatment induced an immediate and dramatic increase in DNA damage markers and upregulation of the G1/S-CDK inhibitor p21, which were followed by marked apoptotic cell death and cell cycle arrest in cancer but not in noncancer cells. Taken together, these studies identified a natural compound as an MTH1 inhibitor and suggest that natural products can be an important source of anticancer agents.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2

Deregulated redox metabolism in cancer leads to oxidative damage to cellular components including deoxyribonucleoside triphosphates (dNTPs). Targeting dNTP pool sanitizing enzymes, such as MTH1, is a highly promising anticancer strategy. The MTH2 protein, known as NUDT15, is described as the second human homologue of bacterial MutT with 8-oxo-dGTPase activity. We present the first NUDT15 crysta...

متن کامل

Induction of apoptosis by novel inosine monophosphate dehydrogenase, 3-hydrogenkwadaphnin

Today’s medical word is highly dependent on severel natural products (e.g. taxol) in fighting different kinds of cancer and in constantly working to found new compounds. In this respect, 3-hydrogenkwadaphnin is a new diterpene ester isolated from Dendrostellera lessertii (Thymelaceae). It has been previously shown that this new compound has high anti-tumor activity and the capability of arresti...

متن کامل

Induction of apoptosis by novel inosine monophosphate dehydrogenase, 3-hydrogenkwadaphnin

Today’s medical word is highly dependent on severel natural products (e.g. taxol) in fighting different kinds of cancer and in constantly working to found new compounds. In this respect, 3-hydrogenkwadaphnin is a new diterpene ester isolated from Dendrostellera lessertii (Thymelaceae). It has been previously shown that this new compound has high anti-tumor activity and the capability of arresti...

متن کامل

Cellular Levels of 8-Oxoguanine in either DNA or the Nucleotide Pool Play Pivotal Roles in Carcinogenesis and Survival of Cancer Cells

8-Oxoguanine, a major oxidized base lesion formed by reactive oxygen species, causes G to T transversion mutations or leads to cell death in mammals if it accumulates in DNA. 8-Oxoguanine can originate as 8-oxo-dGTP, formed in the nucleotide pool, or by direct oxidation of the DNA guanine base. MTH1, also known as NUDT1, with 8-oxo-dGTP hydrolyzing activity, 8-oxoguanine DNA glycosylase (OGG1) ...

متن کامل

Anticancer Activity a of Caspian Cobra (Naja naja oxiana) snake Venom in Human Cancer Cell Lines Via Induction of Apoptosis

Abstract Cancer is the leading cause of death worldwide. Current anticancer drugs involve various toxic side effects; efforts are ongoing to develop new anticancer agents especially from the screening of natural compounds. Present study investigated cytotoxic effects and mode of cell death induced by the Caspian cobra venom in some human cancer cell lines. Cytotoxic effects of snake venom toxin...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:

دوره 8  شماره 

صفحات  -

تاریخ انتشار 2015