Ivermectin Inhibits Bladder Cancer Cell
Growth and Induces Oxidative Stress and
DNA Damage
• By Ning Fan, Lixiu Zhang, Zhiping Wang, Hui Ding and Zhongjin Yue
• Source: Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal
Chemistry - Anti-Cancer Agents), Volume 24, Issue 5, mars 2024, p. 348 - 357
• DOI: https://doi.org/10.2174/0118715206274095231106042833
• Available online: 01 mars 2024
• Previous Article
• Table of Contents
• Next Article
• Abstract
• Metrics
• Related Content
Background: Bladder cancer is the most common malignant tumor of the urinary system.
Nevertheless, current therapies do not provide satisfactory results. It is imperative that novel
strategies should be developed for treating bladder cancer. Objectives: To evaluate the effect of a
broad-spectrum anti-parasitic agent, Ivermectin, on bladder cancer cells in vitro and in vivo.
Methods: CCK-8 and EdU incorporation assays were used to evaluate cell proliferation. Apoptosis
was detected by flow cytometry, TUNEL assay, and western blotting. Flow cytometry and DCFH-
DA assay were used to analyze the reactive oxygen species (ROS) levels. DNA damage was
determined by Neutral COMET assay and γ H2AX expression. Proteins related to apoptosis and
DNA damage pathways were determined by WB assay. Xenograft tumor models in nude mice were
used to investigate the anti-cancer effect of Ivermectin in vivo. Results: Our study showed that in
vitro and in vivo, Ivermectin inhibited the growth of bladder cancer cells. In addition, Ivermectin
could induce apoptosis, ROS production, DNA damage, and activate ATM/P53 pathwayrelated
proteins in bladder cancer cells. Conclusion: According to these findings, Ivermectin may be a
potential therapeutic candidate against bladder cancer due to its significant anti-cancer effect.
© Bentham Science Publishers
https://www.sciencedirect.com/science/article/abs/pii/S0006291X1731656X
Antibiotic ivermectin preferentially targets
renal cancer through inducing mitochondrial
dysfunction and oxidative damage
Author links open overlay panelMin Zhu a, Youkong Li a, Zhifang Zhou b
Show moreAdd to Mendeley
Share
Cite
https://doi.org/10.1016/j.bbrc.2017.08.097
Get rights and content
Highlights
• •
Ivermectin is preferentially against RCC while sparing normal kidney cells.
• •
Ivermectin delays RCC tumor growth in vivo.
• •
Ivermectin induces mitochondrial dysfunction and oxidative stress.
• •
RCC has increased mitochondrial biogenesis than normal kidney cells.
Abstract
Renal cell carcinoma (RCC) is the most aggressive type of genitourinary cancer and highly resistant
to current available therapies. In this work, we investigated the effects and mechanism of anti-
parasitic agent ivermectin in RCC. We show that ivermectin significantly inhibits proliferation and
induces apoptosis in multiple RCC cell lines that represent different histological subtypes and
various mutation status. Importantly, ivermectin is significantly less or ineffective in normal kidney
cells compared with RCC cells, demonstrating the preferential toxicity of ivermectin to RCC.
Ivermectin also significantly inhibits RCC tumor growth in vivo. Mechanistically, ivermectin
induces mitochondrial dysfunction via decreasing mitochondrial membrane potential, mitochondrial
respiration and ATP production. As a consequence of mitochondrial dysfunction, oxidative stress
and damage is detected in ivermectin treated RCC cells and xenograft mouse model. The rescue of
ivermectin's effect by acetyl-l-Carnitine (ALCAR, a mitochondrial fuel) or antioxidant N-acetyl-l-
cysteine (NAC) confirms mitochondria as the target of ivermectin in RCC cells. Compared to
normal kidney cells, RCC cells have higher mitochondrial mass and respiration, and ATP
production, which might explain the preferential toxicity of ivermectin to RCC. Our work suggest
that ivermectin is a promising candidate for RCC treatment and targeting mitochondrial metabolism
is an alternative therapeutic strategy for RCC.
Introduction
Renal cell carcinoma (RCC) is an epithelial tumor derived from the proximal tubules of nephrons
and resistant to chemotherapy and radiotherapy [1], [2]. Although targeted therapy significantly
improved the clinical of outcomes of patients with metastatic RCC, patients still relapse when
disease progresses [3]. Novel and effective therapeutic strategies is therefore needed for patients
who relapse after surgery or who have metastatic RCC. Recent studies demonstrate that many
cancers highly reply on oxidative phosphorylation to meet energy demands for growth and survival
[4], [5]. Compared to differentiated tumor cells, tumor stem cells are more dependent on
mitochondrial metabolism rather than glycolysis [6]. All of which suggest that the unique
dependence of cancer cells on mitochondrial metabolism can be exploited therapeutically.
Ivermectin is an anti-parasitic agent with known pharmacology, safety and toxicity profiling in
humans. It is licensed for the treatment of strongyloidiasis, onchocerciasis and other worm
infestations [7]. Ivermectin kills parasites via binding and activating chloride ion channels in
nematodes [8]. The inhibitory effects of ivermectin in various cancers (eg, ovarian cancer,
leukaemia and glioblastoma) have been recently demonstrated and the mechanisms of its action
include inhibition of WNT-TCF pathway, deactivation of the oncogenic kinase PAK1 and
modulating P2X4 receptors [9], [10], [11], [12]. It also inhibits flavivirus replication via targeting
NS3 helicase activity [13].
In our study, we demonstrated that ivermectin displayed preferential activity against RCC in vitro
using a panel of RCC cell lines and delayed tumor growth in vivo at concentration that is clinically
achievable. Mechanistically, ivermectin induces. mitochondrial dysfunctions, leading to energy
crisis and oxidative stress. In addition, RCC cells have increased mitochondrial biogenesis and ATP
levels than normal kidney cells which might contribute to the preferential toxicity of ivermectin to
RCC.
