Theranostics 2021; 11(6):2932-2952. doi:10.7150/thno.49876

Research Paper

Evodiamine inhibits both stem cell and non-stem-cell populations in human cancer cells by targeting heat shock protein 70

Seung Yeob Hyun1, Huong Thuy Le1, Hye-Young Min1,2, Honglan Pei1, Yijae Lim2, Injae Song2, Yen T. K. Nguyen2, Suckchang Hong2, Byung Woo Han2, Ho-Young Lee1,2,✉

1. Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
2. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea

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Citation:
Hyun SY, Le HT, Min HY, Pei H, Lim Y, Song I, Nguyen YTK, Hong S, Han BW, Lee HY. Evodiamine inhibits both stem cell and non-stem-cell populations in human cancer cells by targeting heat shock protein 70. Theranostics 2021; 11(6):2932-2952. doi:10.7150/thno.49876. Available from https://www.thno.org/v11p2932.htm

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Abstract

Rationale: Cancer stem cells (CSCs) are known to cause tumor recurrence and drug resistance. The heat shock protein (HSP) system plays a major role in preserving expression and function of numerous oncoproteins, including those involved in the CSC activities. We explored novel anticancer drugs, especially those targeting HSP components required for the functional role of CSCs.

Methods: Investigation of the role of the HSP system in CSCs and screening of a natural product chemical library were performed by utilizing cancer cell lines, primary cultures of patient-derived xenografts (PDXs), and their putative CSC subpopulations (i.e., those grown under sphere-forming conditions, stably transfected with reporter vectors carrying NANOG or POUSF1 promoters, or carrying high ALDH activity) in vitro and PDX and KrasG12D/+-driven tumor models in vivo. Regulation of the HSP system was investigated by immunoprecipitation, drug affinity responsive target stability assay, binding experiments using ATP-agarose beads and biotinylated drug, and docking analysis.

Results: The HSP system was activated in CSCs via transcriptional upregulation of the HSP system components, especially HSP70. Evodiamine (Evo) was identified to induce apoptosis in both CSC and bulk non-CSC populations in human lung, colon, and breast cancer cells and their sublines with chemoresistance. Evo administration decreased the multiplicity, volume, and load of lung tumors in KrasG12D/+ transgenic mice and the growth of cancer cell line- and PDX-derived tumors without detectable toxicity. Mechanistically, Evo disrupted the HSP system by binding the N-terminal ATP-binding pocket of HSP70 and causing its ubiquitin-mediated degradation.

Conclusions: Our findings illustrate HSP70 as a potential target for eliminating CSCs and Evo as an effective HSP70-targeting anticancer drug eradicating both CSCs and non-CSCs with a minimal toxicity.

Keywords: heat shock protein 70, evodiamine, cancer stem cells, antitumor, alkaloid