A novel acridine derivative, LS-1-10 inhibits autophagic degradation and triggers apoptosis in colon cancer cells

Wan Fu,Yue Wang,Shan Liu,Xue Li,Xin Yang,Ying Zhao,Ran Li,Wei-Guo Zhu,Luyao Zhang,Xiangbao Meng,Xiaopeng Lu,Nan Zhang

doi:10.1038/cddis.2017.498

Abstract

Autophagy promotes cancer cell survival and drug resistance by degrading harmful cellular components and maintaining cellular energy levels. Disruption of autophagy may be a promising approach to sensitize cancer cells to anticancer drugs. The combination of autophagic inhibitors, such as chloroquine (CQ) and lucanthone with conventional cancer therapeutics has been investigated in clinical trials, but adverse drug–drug interactions are a high possibility. Here we designed and synthesized a novel, small-molecule library based on an acridine skeleton and the CQ structure with various modifications and substitutions and screened the compounds for effective autophagy inhibition. We found that 9-chloro-2-(3-(dimethylamino)propyl)pyrrolo[2,3,4-kl]acridin-1(2H)-one (LS-1-10) was the most effective from our library at inhibiting autophagic-mediated degradation and could decrease the viability of multiple colon cancer cells. In addition, LS-1-10 induced DNA damage and caspase 8-mediated apoptosis. Overall, this small molecule was more efficient at reducing the viability of cancer cells than other conventional chemotherapeutic agents, such as CQ and amsacrine. The anticancer and autophagy-inhibiting activities of LS-1-10 were confirmed in vivo in a xenograft mouse model. Collectively, this study has identified a new and efficient single compound with both autophagy-inhibiting and anticancer activity, which may provide a novel approach for cancer therapy.

Highlights

Autophagy is an important catabolic process that is highly conserved across all eukaryotes.[1,2,3,4] It is a protein degradation pathway by which cytoplasmic constituents are delivered to lysosome for digestion.[5]
Autophagy can be monitored by the accumulation of the autophagy marker LC3 and the degradation of p62.32 Inhibition of autophagic degradation usually causes accumulations and puncta formations of both LC3-I/II and p62.32 we analyzed the abundance and distribution of these two biological markers after treating DLD1 and LoVo human colon cancer cell lines with eight in-house generated molecules (Figures 1b and c, S1A)
We found that the active forms of both cathepsin B (CTSB) and cathepsin D (CTSD) decreased upon LS-1-10 treatment (Figure 3c)

Summary

Introduction

Autophagy is an important catabolic process that is highly conserved across all eukaryotes.[1,2,3,4] It is a protein degradation pathway by which cytoplasmic constituents are delivered to lysosome for digestion.[5]. Adverse drug–drug interactions may arise from these complex drug combinations, the development of a small, single molecule that possesses both potent anticancer and anti-autophagy activity is required. Acridine derivatives, such as amsacrine (m-AMSA) and DACA,[22,23,24] exhibit DNA-intercalating and topoisomeraseinhibiting activity and are prime candidates as anticancer agents.[25] m-AMSA has been used to treat acute leukemia and malignant lymphoma, but is ineffective against solid tumors.[22,26,27,28,29] Acridine provides an ideal scaffold as an antitumor drug for two reasons. Tel: Received 23.4.17; revised 15.7.17; accepted 31.7.17; Edited by Y Shi

Methods

Results

Conclusion