Inhibition of TNF-α and JNK Signaling Pathway Can Reduce Paclitaxel-Induced Apoptosis of Mouse Cardiomyocytes

Abstract

Paclitaxel (PTX) is a widely used chemotherapeutic drug for treating tumors. However, studies have shown that it can cause cardiac problems such as arrhythmia, myocarditis, chronic cardiomyopathy, and heart failure. Therefore, it is essential to study the mechanism behind the cardiotoxicity of PTX in tumor treatment. In this study, we initially injected PTX into mice to establish a myocardial cell apoptosis model to observe the degree of damage to mouse myocardium caused by PTX. Upon determining the levels of mouse myocardial creatine phosphokinase (CK), myokinase isoenzyme (CK-MB), aspartate transaminase (AST), and lactate dehydrogenase (LDH), we found that all of these levels showed apparent increases in mice treated with PTX. Further analyses of the TNF-α level and the expression of Jun N-terminal kinase (JNK) and Bcl-2 family-related proteins in myocardial tissue were performed. It was found that PTX increased the protein levels of TNF-α, Bax, p-JNK, and JNK in myocardial tissue but decreased the protein level of Bcl-2. After 1 month of PTX treatment in mice, we inhibited the expression of TNF-α and JNK proteins, which reduced the effect of paclitaxel on the apoptosis of mouse cardiomyocytes. The protein levels of Bax, p-JNK, and TNF-α in cardiomyocytes were reduced, while there was a relative increase in the Bcl-2 protein level. The findings suggested that inhibition of the NK signaling pathway and TNF-α can lessen the effect of PTX on mouse cardiomyocytes.

Paclitaxel Protects against Isoproterenol-Induced Damage in Rat Myocardium: Its Heme-Oxygenase Mediated Role in Cardiovascular Research

“…Since TNF-α is a major activator of NF-κB, the decreased expression in our study likely resulted in the suppression of this canonical proinflammatory signaling pathway [31]. In contrast to our findings, paclitaxel administration increased myocardial TNF-α concentration and apoptosis in mice as discussed in [16]. In this study, paclitaxel was administered every three days for three months via intraperitoneal injection, while our protocol included a 10 mg/kg paclitaxel dose for five days in an oral formulation by gavage [19].…”

“…Importantly, paclitaxel dosing of 25 µg vs. 125 µg on a coated stent determined the myocardial concentration of the drug, with an approximately 10-fold increase with the high-dose stent compared to the low-dose used [33]. As opposed to previous research [16,21], in the present work paclitaxel administration alone did not affect any of the measured molecules in the ventricles without isoproterenol-induced damage. Others also demonstrated that paclitaxel did not induce any myocardial damage in isolated rat hearts during normoxia [8].…”

“…In another investigation, paclitaxel induced mitochondrial permeability transition pore (mPTP) opening in cardiac myocytes, which was explained by the elevated ROS levels in the cells [15]. Moreover, long-term paclitaxel administration led to increased TNF-α protein level and apoptosis in mice hearts [16]. The different (1-10 µM) doses and protocols used in these studies might account for the discrepancies, as higher drug exposures seem excessive and may even produce toxic effects.…”

Retracted: Inhibition of TNF-α and JNK Signaling Pathway Can Reduce Paclitaxel-Induced Apoptosis of Mouse Cardiomyocytes

“…This article has been retracted by Hindawi following an investigation undertaken by the publisher [ 1 ]. This investigation has uncovered evidence of one or more of the following indicators of systematic manipulation of the publication process: Discrepancies in scope Discrepancies in the description of the research reported Discrepancies between the availability of data and the research described Inappropriate citations Incoherent, meaningless and/or irrelevant content included in the article Manipulated or compromised peer review …”

“…This article has been retracted by Hindawi following an investigation undertaken by the publisher [1]. This investigation has uncovered evidence of one or more of the following indicators of systematic manipulation of the publication process:…”