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Natural products triptolide, celastrol, and withaferin A inhibit the chaperone activity of peroxiredoxin I.

ABSTRACT: Peroxiredoxin I (Prx I) plays an important role in cancer development and inflammation. It is a dual-functional protein which acts as both an antioxidant enzyme and a molecular chaperone. While there have been intensive studies on its peroxidase activity, Prx I's chaperone activity remains elusive, likely due to the lack of chaperone inhibitors. Here we report that natural product triptolide selectively inhibits the chaperone activity of Prx I, but not its peroxidase activity. Through direct interaction with corresponding cysteines, triptolide triggers dissociation of high-molecular-weight oligomers of Prx I, and thereby inhibits its chaperone activity in a dose-dependent manner. We have also identified celastrol and withaferin A as novel Prx I chaperone inhibitors that are even more potent than triptolide in the chaperone activity assay. By revealing the exact molecular mechanisms of interaction and inhibition, the current study provides the first Prx I chaperone inhibitors as promising pharmacological tools for modulating and dissecting the chaperone function of Prx I.

SUBMITTER: Zhao Q

PROVIDER: S-EPMC5497274 | biostudies-other | 2015 Jul

REPOSITORIES: biostudies-other

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Natural products triptolide, celastrol, and withaferin A inhibit the chaperone activity of peroxiredoxin I.

Zhao Qian Q Ding Yu Y Deng Zhangshuang Z Lee On-Yi OY Gao Peng P Chen Pin P Rose Rebecca J RJ Zhao Hong H Zhang Zhehao Z Tao Xin-Pei XP Heck Albert J R AJR Kao Richard R Yang Dan D

Chemical science 20150519 7

Peroxiredoxin I (Prx I) plays an important role in cancer development and inflammation. It is a dual-functional protein which acts as both an antioxidant enzyme and a molecular chaperone. While there have been intensive studies on its peroxidase activity, Prx I's chaperone activity remains elusive, likely due to the lack of chaperone inhibitors. Here we report that natural product triptolide selectively inhibits the chaperone activity of Prx I, but not its peroxidase activity. Through direct int ...[more]

PMID: 28717468

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Project description:Pancreatic cancer is a lethal disease with a dreadful 5-year survival rate of only 5%. In spite of several treatment options, the prognosis still remains extremely poor. Therefore, novel therapy strategies with combinations of drugs are urgently required to combat this fatal disease. Triptolide (TPL) and celastrol (CL), two main compounds in traditional Chinese medicine isolated from Thunder God Vine, have a broad range of bioactivities including anticancer activity. Silk fibroin (SF), a naturally occurring protein with several unique properties, is an ideal carrier material. In this study, we prepared TPL and CL loaded silk fibroin nanoparticles (TPL-SFNPs and CL-SFNPs) by a modified desolvation method and evaluated their synergistic effects against human pancreatic cancer cells. Both SFNPs were characterized for particle size and zeta potential. The entrapment efficiency, drug loading, and drug release profiles were evaluated by HPLC. The cytotoxicity and synergistic effect of SFNPs were investigated in MIA PaCa-2 and PANC-1 human pancreatic cells. The results showed that the particle sizes of TPL-SFNPs and CL-SFNPs were 166.4 ± 4.6 nm and 170.4 ± 2.3 nm, with a mean zeta potential -27.2 ± 2.0 mV and -25.5 ± 2.57 mV, respectively. TPL-SFNPs and CL-SFNPs have a drug loading of 57.0 ± 4.7 μg mg-1 and 63.5 ± 3.8 μg mg-1 along with an encapsulation efficiency of 81.8 ± 2.8% and 87.0 ± 5.1%, respectively. Drug release studies revealed that a rapid release of the drugs from SFNPs was observed at pH 4.5 (lysosomal pH) and a delayed release was observed at pH 7.4 (plasma pH). TPL-SFNPs (IC50 3.80 and 4.75 nM) and CL-SFNPs (IC50 0.38 and 0.64 μM) were 2-3 fold more potent against MIA PaCa-2 and PANC-1 cells than free TPL (IC50 11.25 and 11.58 nM) and CL (IC50 0.84 and 1.23 μM). Furthermore, co-treatment with TPL-SFNPs and CL-SFNPs increased the growth inhibition of the same cells significantly in comparison with TPL-SFNPs or CL-SFNPs alone. Almost all combination index (CI) values, calculated using the CompuSyn software, were <1, suggesting that the growth inhibition effect of TPL-SFNPs in combination with CL-SFNPs was synergistic rather than additive, further suggesting that this novel combination may offer a potential treatment for pancreatic cancer.

Dataset Information

Natural products triptolide, celastrol, and withaferin A inhibit the chaperone activity of peroxiredoxin I.

Publications

Natural products triptolide, celastrol, and withaferin A inhibit the chaperone activity of peroxiredoxin I.

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