AccScience Publishing / TD / Volume 4 / Issue 1 / DOI: 10.36922/td.7825
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ORIGINAL RESEARCH ARTICLE

Homoharringtonine inhibits pancreatic cancer progression via mitochondrial energy metabolism suppression and macrophages reduction

Xiaoxia Wang1 ,  Tao Wang1 ,  Xuelu Peng1 ,  Ke Zhu1 ,  Ming Ye1 ,  Jie Meng1* ,  Haiyan Xu1*
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1 Department of Biomedical Engineering, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Tumor Discovery 2025, 4(1), 99–112; https://doi.org/10.36922/td.7825
Submitted: 17 December 2024 | Revised: 20 January 2025 | Accepted: 24 January 2025 | Published: 24 February 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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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 significantly inhibited the proliferation and colony formation of pancreatic cancer cell lines PANC-1 and Pan02 in vitro and suppressed tumorigenic potential in vivo. The mechanistic study revealed that HHT induced a significant elevation of reactive oxygen species (ROS) levels in pancreatic cancer cells over time, as evidenced by the enhanced dichlorodihydrofluorescein diacetate fluorescence and an elevated NAD+/NADH ratio. This resulted in mitochondrial respiratory dysfunction, including reductions in basal respiration, maximal respiration, and adenosine triphosphate production. In addition, HHT caused cell cycle arrest and disrupted the cytoskeleton, thereby inhibiting cell division and proliferation. The anti-tumor effects of HHT were further evaluated using a subcutaneous pancreatic tumor-bearing mouse model, showing that HHT inhibited the proliferation of pancreatic tumor cells in vivo, which 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 macrophages in the tumor microenvironment (TME), thereby alleviating immune suppression. In conclusion, HHT effectively inhibits pancreatic cancer progression through upregulating cellular ROS levels over time, thereby disrupting mitochondrial respiratory capacity in tumor cells and reducing macrophage populations, contributing to TME reprogramming and immune restoration.

Keywords
Pancreatic cancer
Reactive oxygen species
Mitochondrial energy metabolism
Cell cycle
Tumor microenvironment
Funding
This work was supported by CAMS Innovation Fund for Medical Science (CIFMS 2021-I2M-1- 026), Haihe Laboratory of Cell Ecosystem Innovation Fund (22HHXBSS00040) and Beijing Natural Science Foundation (7244372).
Conflict of interest
The authors declare they have no competing interests.
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Tumor Discovery, Electronic ISSN: 2810-9775 Print ISSN: 3060-8597, Published by AccScience Publishing
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