Related Experiment Video

Updated: Sep 2, 2025

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

Published on: August 11, 2017

c-kit inhibitor masitinib induces reactive oxygen species-dependent apoptosis in c-kit-negative HepG2 cells

Yuta Semba¹, Shintaro Yamamoto¹, Shunsuke Takahashi¹

¹Division of Life Science and Engineering, College of Science and Engineering, Tokyo Denki University, Hatoyama, Hiki-gun, Saitama, Japan.

European Journal of Pharmacology

|August 8, 2022

Abstract:

Tumor-specific growth signal inhibition is a major anticancer strategy. Receptor tyrosine kinases (RTKs) are the most upstream receptors for growth signaling in cancer. Therefore, inhibition of RTKs has been proposed as an efficient therapeutic target. Masitinib, a c-kit inhibitor of the c-kit RTK, was developed to treat mastocytoma in dogs. In humans, however, the antitumor efficacy of masitinib was found to be attenuated against tumor cells with mutations of the c-kit gene. Here, we report that masitinib induced cell death via the intrinsic apoptotic pathway in HepG2, a c-kit-negative hepatocellular carcinoma cell line. In masitinib-treated HepG2 cells, increases in intracellular reactive oxygen species levels, loss of mitochondrial membrane potential, and cleavage of caspase-9 were observed, activating the intrinsic apoptotic pathway. Moreover, the cytotoxicity of masitinib to HepG2 cells was suppressed by treatment with the antioxidant N-acetyl-_L-cysteine or a c-Jun N-terminal kinase/stress-activated protein kinase (JNKs) inhibitor. Thus, we demonstrated that the anticancer effects of masitinib are not due to its targeting c-kit, but rather to its targeting the redox balance via the JNK pathway in HepG2 cells. These results suggest that masitinib has the potential to provide a robust antitumor effect in tumor lesions and could also be applied to a broad range of other anticancer therapies.

Insights

Masitinib induces cancer cell death by disrupting redox balance and activating the JNK pathway, not by targeting c-kit. This finding broadens its potential anticancer applications beyond c-kit-related therapies.

Area of Science:

Oncology
Molecular Biology
Pharmacology

Background:

Receptor tyrosine kinases (RTKs) are key targets for anticancer therapies.
Masitinib, a c-kit inhibitor, shows limited efficacy in humans with mutated c-kit.
Hepatocellular carcinoma (HCC) presents a significant therapeutic challenge.

Purpose of the Study:

To investigate the anticancer mechanism of masitinib in c-kit-negative hepatocellular carcinoma cells.
To explore alternative pathways mediating masitinib's cytotoxicity.
To evaluate masitinib's potential in broader anticancer strategies.

Main Methods:

Treatment of HepG2 (c-kit-negative HCC cell line) with masitinib.
Assessment of intracellular reactive oxygen species (ROS) levels.
Analysis of mitochondrial membrane potential and caspase-9 cleavage.
Evaluation of masitinib's cytotoxicity with N-acetyl-L-cysteine and JNK inhibitors.

Main Results:

Masitinib induced cell death via the intrinsic apoptotic pathway in HepG2 cells.
Increased intracellular ROS and loss of mitochondrial membrane potential were observed.
Caspase-9 cleavage indicated activation of the apoptotic pathway.
Antioxidant and JNK inhibition suppressed masitinib-induced cytotoxicity.

Conclusions:

Masitinib's anticancer effects in HepG2 cells are mediated by targeting redox balance via the JNK pathway, independent of c-kit inhibition.
Masitinib demonstrates potential for broad anticancer applications by modulating cellular redox state.
These findings suggest masitinib could be a valuable agent in diverse cancer therapies.

Read full analysis

Keywords:

Masitinib Mitochondrial apoptosis Reactive oxygen species (ROS)Receptor tyrosine kinase c-Jun N-Terminal kinases (JNKs)

More Related Videos

A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds

A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds

Published on: April 6, 2016

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

Related Concept Videos

Mitogens and the Cell Cycle

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...

Targeted Cancer Therapies

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...

Inhibition of Cdk Activity

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...

The Intrinsic Apoptotic Pathway

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...

Articles linked to this work by shared authors, journal, and citation graph.

Hemocompatible polymer coating for extracorporeal circulation circuit affects lactate levels during cardiopulmonary bypass surgery.

Asian cardiovascular & thoracic annals·2026

Efficacy of Overtube in Preventing Aspiration Pneumonia During Esophageal Endoscopic Submucosal Dissection.

DEN open·2026

Draft genome sequences of four strains of Ralstonia pseudosolanacearum.

Microbiology resource announcements·2026

Secondary Adrenal Insufficiency Presenting With Severe Hyponatremia in an Elderly Patient With Primary Aldosteronism Suggesting Underlying Autonomous Cortisol Secretion.

Clinical case reports·2026

Multicentre international audit of IMACS malignancy screening guidelines in idiopathic inflammatory myopathies: insights from the myositis audit and research collaborative group.

RMD open·2026

Critical ischemia of multiple organ systems in a patient with systemic lupus erythematosus complicated by catastrophic antiphospholipid syndrome: Potential pathogenetic role of non-inhibitory anti-ADAMTS13 autoantibodies.

Modern rheumatology case reports·2026

See all related articles