Synergistic antitumor effect of 5-fluorouracil with the novel LSD1 inhibitor ZY0511 in colorectal cancer.

Abstract

BACKGROUND:

Lysine-specific histone demethylase 1 (LSD1) is a potential target of cancer therapy. In the present study, we aimed to investigate the combined antitumor activity of a novel LSD1 inhibitor (ZY0511) with 5-fluorouracil (5-FU) and elucidate the underlying mechanism in colorectal cancer (CRC).

METHODS:

We evaluated LSD1 expression in CRC tissues from patients who received 5-FU treatment. The synergistic antitumor effect of 5-FU with ZY0511 against human CRC cells was detected both in vitro and in vivo. The underlying mechanism was explored based on mRNA sequencing (mRNA-seq) technology.

RESULTS:

Overexpression of LSD1 was observed in human CRC tissues, and correlated with CRC development and 5-FU resistance. ZY0511, a novel LSD1 inhibitor, effectively inhibited CRC cells proliferation, both in vitro and in vivo. Notably, the combination of ZY0511 and 5-FU synergistically reduced CRC cells viability and migration in vitro. It also suppressed Wnt/β-catenin signaling and DNA synthesis pathways, which finally induced apoptosis of CRC cells. In addition, the combination of ZY0511 with 5-FU significantly reduced CRC xenograft tumor growth, along with lung and liver metastases in vivo.

CONCLUSIONS:

Our findings identify LSD1 as a potential marker for 5-FU resistance in CRC. ZY0511 is a promising candidate for CRC therapy as it potentiates 5-FU anticancer effects, thereby providing a new combinatorial strategy for treating CRC.

• Authors: Wen Peng, Huaqing Zhang, Shisheng Tan, Yan Li, Yang Zhou, Liang Wang, Chunqi Liu, Qiu Li, Xiaobo Cen, Shengyong Yang, Yinglan Zhao
• Journal: Therapeutic advances in medical oncology (Ther Adv Med Oncol) Vol. 12 Pg. 1758835920937428 ( 2020) ISSN: 1758-8340 [Print] England
• PMID: 32754230 (Publication Type: Journal Article)
• Copyright: © The Author(s), 2020.