Page 14 - I. Chemical biology and drug discovery

[I. Chemical biology and drug discovery-7]

The natural alkaloid natural compound e 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, Honglan Pei¹, Yijae Lim¹, Injae Song¹, Yen T. Nguyen¹,

Suckchang Hong¹, Byung Woo Han¹, Ho Young Lee¹˙*

¹College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea

Cancer stem cells (CSCs) play critical roles in tumor recurrence and drug resistance. However, anticancer drugs

targeting CSCs are limited due to the poor understanding of the underlying biology in CSCs. Here, we applied
reporter vectors carrying NANOG or POUSF1 promoters and selected ALDH high and sphere-forming

subpopulations from non-small-cell lung cancer (NSCLC) and patient-derived xenografts (PDXs) to obtain potential
CSCs. Using these CSCs, we demonstrated that activation of the heat shock protein (Hsp) system in CSCs and

pharmacological or genomic approaches that target the Hsp system eliminate CSCs. From a screen with a large
natural product chemical library, we identified the natural alkaloid compound E as a novel antitumor drug that

targets both the CSC and bulk non-CSC populations in human lung, colon, and breast cancer cells by inducing
apoptosis. Compound E administration decreased the multiplicity, volume, and load of lung tumors in KrasG12D/+

transgenic mice and suppressed the growth of cell line- and PDX-derived tumors by inducing apoptosis.
Mechanistically, Compound E disrupts the Hsp system by binding the N-terminal ATP-binding pocket of Hsp70. The

present study demonstrates that targeting Hsp70 would be an effective anticancer strategy to eradicate CSCs.