Page 107 - TD-4-1

Tumor Discovery

ORIGINAL RESEARCH ARTICLE
Homoharringtonine inhibits pancreatic

cancer progression via mitochondrial energy
metabolism suppression and macrophages

reduction

Xiaoxia Wang , Tao Wang , Xuelu Peng , Ke Zhu , Ming Ye , Jie Meng* ,
and Haiyan Xu*

Department of Biomedical Engineering, Institute of Basic Medical Sciences, Chinese Academy of
Medical Sciences and Peking Union Medical College, Beijing, China

Abstract

Homoharringtonine (HHT) has been used in leukemia therapy since the 1970s.
Its inhibitory effects on solid tumors have attracted increasing interest and have
been actively explored in recent years. This study investigates the therapeutic
effects and pharmacological mechanisms of HHT on pancreatic cancer, focusing
on mitochondrial energy metabolism and macrophage sensitivity to HHT. HHT
*Corresponding authors: significantly inhibited the proliferation and colony formation of pancreatic cancer
Haiyan Xu cell lines PANC-1 and Pan02 in vitro and suppressed tumorigenic potential in vivo.
(xuhy@pumc.edu.cn) The mechanistic study revealed that HHT induced a significant elevation of reactive
Jie Meng
(mengjie@ibms.pumc.edu.cn) oxygen species (ROS) levels in pancreatic cancer cells over time, as evidenced by
the enhanced dichlorodihydrofluorescein diacetate fluorescence and an elevated
Citation: Wang X, Wang T, Peng X, +
et al. Homoharringtonine inhibits NAD /NADH ratio. This resulted in mitochondrial respiratory dysfunction, including
pancreatic cancer progression via reductions in basal respiration, maximal respiration, and adenosine triphosphate
mitochondrial energy metabolism production. In addition, HHT caused cell cycle arrest and disrupted the cytoskeleton,
suppression and macrophages
reduction. Tumor Discov. thereby inhibiting cell division and proliferation. The anti-tumor effects of HHT were
2025;4(1):99-112. further evaluated using a subcutaneous pancreatic tumor-bearing mouse model,
doi: 10.36922/td.7825 showing that HHT inhibited the proliferation of pancreatic tumor cells in vivo, which
Received: December 17, 2024 led to reduced tumor mass. Moreover, HHT significantly reduced the viability of
macrophages both in vitro and in vivo, leading to the depletion of tumor-associated
Revised: January 20, 2025
macrophages in the tumor microenvironment (TME), thereby alleviating immune
Accepted: January 24, 2025 suppression. In conclusion, HHT effectively inhibits pancreatic cancer progression
Published online: February 24, through upregulating cellular ROS levels over time, thereby disrupting mitochondrial
2025 respiratory capacity in tumor cells and reducing macrophage populations,
Copyright: © 2025 Author(s). contributing to TME reprogramming and immune restoration.
This is an Open-Access article
distributed under the terms of the
Creative Commons Attribution Keywords: Pancreatic cancer; Reactive oxygen species; Mitochondrial energy
License, permitting distribution, metabolism; Cell cycle; Tumor microenvironment
and reproduction in any medium,
provided the original work is
properly cited.
Publisher’s Note: AccScience
Publishing remains neutral with 1. Introduction
regard to jurisdictional claims in
published maps and institutional Pancreatic cancer is a malignant tumor of the digestive system with high lethality
1
affiliations. and low cure rates. It is the sixth leading cause of cancer-related deaths in China and

Volume 4 Issue 1 (2025) 99 doi: 10.36922/td.7825