Abstract 1862: Natural compound E targets both lung cancer stem and non-cancer stem cells by disrupting HSP70 function
Authors: Seung Yeob Hyun, Huong Thuy Le, HongLan Pei, Simin Chun, Hye-Young Min, Suckchang Hong, Ho-Young Lee
Journal: Cancer Research (2019)

Abstract Solid malignant tumors are composed of heterogeneous populations of cancer cell, including cancer stem-like cells (CSCs), a specialized cell population characterized by the functional properties of self-renewal and have a potential to differentiate into various cancer subtypes. CSCs contribute to tumor recurrence, metastasis, and drug resistance, affecting efficacy of anticancer therapies. However, treatment strategies specifically targeting CSCs are limited, because current chemotherapeutic drugs mainly kill the bulk of sensitive cancer cells, leaving behind CSCs. These remaining CSCs are the main cause of cancer relapse and drug resistance. Hence, development of novel compounds eradicating CSCs are crucial for effective anticancer therapies. To identify novel CSC-targeting anticancer drugs, we have set-up a reporter system based on promoter activities of CSC markers that allows a standardized identification of CSCs. By using the reporter system, we screened a large natural products chemical library consisting 452 compounds with diverse chemical entity. And we selected 4 compounds. To further assess the inhibitory effect of these 4 compounds, we used sphere-forming assay with NSCLC cell lines. Through these processes, we finally chose Compound E. We found that treatment with Compound E significantly reduced the subpopulation of NSCLC CSC. We confirmed the inhibitory effects of Compound E on NSCLC CSCs by performing sphere formation analysis and flow cytometry-based ALDH detection assay. Treatment with Compound E also suppressed the viability and colony-forming abilities of NSCLC cells (non-CSCs) and their sublines carrying acquired chemoresistance by inducing apoptosis. In line with these in vitro results, orally administered Compound E significantly suppressed the growth of xenograft tumors derived from both NSCLC cell lines and patient-derived tumor tissues. To determine the tumor forming capacity of tumor cells derived from the vehicle or Compound E-treated mice, we carried out a limiting dilution tumor-propagating assay. NOD/SCID mice were transplanted with tumor cells over a range from doses unable to initiate tumor growth to dose that initiated tumor formation. Tumor cells derived from Compound E-treated mice displayed reduced tumor forming capacity compared to vehicle treated mice. Mechanistically, Compound E disrupted Hsp70 function by binding to the ATP-binding pockets of Hsp70. These data collectively unveil the potential of Compound E as a natural Hsp70 inhibitor targeting both CSC and non-CSC populations of NSCLC. Citation Format: Seung Yeob Hyun, Huong Thuy Le, HongLan Pei, Simin Chun, Hye-Young Min, Suckchang Hong, Ho-Young Lee. Natural compound E targets both lung cancer stem and non-cancer stem cells by disrupting HSP70 function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1862.