Antibiotic ivermectin preferentially targets renal cancer through inducing mitochondrial dysfunction and oxidative damage (original) (raw)

Highlights

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Ivermectin is preferentially against RCC while sparing normal kidney cells.
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Ivermectin delays RCC tumor growth in vivo.
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Ivermectin induces mitochondrial dysfunction and oxidative stress.
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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.

Section snippets

Cells and drugs

Human renal cell carcinoma (RCC) cell lines, SW-839, Caki-2, 786-O, A-498 and ACHN were purchased from American Type Culture Collection and cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (Hyclone, UK) and 2 mM l-glutamine (Invitrogen). Human normal renal cells including HRPT (human renal proximal tubule), HRE (human renal epithelial), HRCE (human renal cortical epithelial) were purchased from Lona, Inc. and were cultured in Human Kidney Primary Cell Culture Media with

Ivermectin selectively targets RCC while sparing normal kidney cells

To analyze and confirm the effect of ivermectin in RCC, we performed proliferation and apoptosis assays after drug treatment in a panel of RCC cell lines, such as SW-839, Caki-2, 786-O, A498 and ACHN. These cell lines represent the most subtypes: clear cell and papillary RCC, and different disease stage: primary and metastatic. In addition, these lines are genetically different and have various mutation status of cancer including VLH, cMET, TP53 and other mutations [16]. We also analysed the

Discussion

Novel therapeutic strategy is needed for the better clinical management of RCC. Drug repurposing has become an attractive approach due to its rapid translational potential. To identify known drugs with anti-RCC activity, we compiled a library of drugs and screened this library on multiple RCC cell lines using proliferation and apoptosis assays. From this screen, we found that ivermectin is the most potent FDA-approved drug and preferentially toxic to RCC cells while sparing normal kidney cells.

Conflict of interest

All authors declare no conflict of interest.

Acknowledgement

This work was supported by a research grant provided by Jingzhou Central Hospital (Grant No. 201306066).

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