Abstract
The use of chemoprotective agents to minimize the side effects of the chemotherapy, primarily via activation of the Nrf2 pathway, is an emerging research field, which has attracted broad attention from both academia and pharmaceutical industry. Through high-throughput chemical screens we have disclosed that pterisolic acid B (J19), a naturally occuring diterpenoid, is an effective Nrf2 activator. We have also identified a more potent natural product analogue J19-1 by semisynthesis and the subsequent biochemical evaluations revealed that J19-1 activates the Nrf2 pathway by covalently modifying Cys171 of keap1, which inhibits Nrf2 degradation mediated by Keap1-Cul3 complexes. Ultimately, we have demonstrated that J19-1 shows significant cytoprotective effect against cisplatin-induced cytotoxicity in HKC cells.
Highlights
The landscape of cancer treatment is changing dramatically
We demonstrate that pterisolic acid B has significant cytoprotective effect for normal tissue cells in cancer chemotherapy in a Nrf[2] dependent manner
We found that the probe interacted with the recombinant Keap[1] in good dose dependent manner (Fig. 4c), and this interaction could be completed off with 2 folds of J19-1 (Fig. 4d)
Summary
The landscape of cancer treatment is changing dramatically. Traditional chemotherapeutics, which have dominated treatment for over half a century, are typically DNA-damaging or microtubule-targeting agents designed to inhibit or kill rapidly dividing cells[1,2,3,4]. Current studies suggest that chemoprotective drugs accelerate the metabolism and excretion of toxic chemotherapy agents within specific tissues by the induction of phase II detoxification enzymes. The cytoplasmic level of Nrf[2] is regulated by Keap[1] (Kelch-like ECH-associated protein 1) and the BTB domain within Keap[1] serves as an adaptor that bridges Nrf[2] to a Cul3-Based E3 Ligase, leading to Nrf[2] degradation[15,16] In view of their pivotal role in cell protection from environmental insults, several Nrf[2] activators are currently undergoing clinical trials as cytoprotective agents[17,18,19]. We demonstrate that pterisolic acid B has significant cytoprotective effect for normal tissue cells in cancer chemotherapy in a Nrf[2] dependent manner
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