Minimal systems analysis of mitochondria-dependent apoptosis induced by cisplatin

Abstract

Recently, it was reported that the role of mitochondria-reactive oxygen species (ROS) generating pathway in cisplatin-induced apoptosis is remarkable. Since a variety of molecules are involved in the pathway, a comprehensive approach to delineate the biological interactions of the molecules is required. However, quantitative modeling of the mitochondria-ROS generating pathway based on experiment and systemic analysis using the model have not been attempted so far. Thus, we conducted experiments to measure the concentration changes of critical molecules associated with mitochondrial apoptosis in both human mesothelioma H2052 and their ρ0 cells lacking mitochondrial DNA (mtDNA). Based on the experiments, a novel mathematical model that can represent the essential dynamics of the mitochondrial apoptotic pathway induced by cisplatin was developed. The kinetic parameter values of the mathematical model were estimated from the experimental data. Then, we have investigated the dynamical properties of this model and predicted the apoptosis levels for various concentrations of cisplatin beyond the range of experiments. From parametric perturbation analysis, we further found that apoptosis will reach its saturation level beyond a certain critical cisplatin concentration.

C-phycocyanin from Limnothrix Species KNUA002 Alleviates Cisplatin-Induced Ototoxicity by Blocking the Mitochondrial Apoptotic Pathway in Auditory Cells

“…Individuals with cancers requiring irradiation of the base of the skull or brain are particularly vulnerable to cisplatin-induced ototoxicity [6], although the underlying molecular mechanism of cisplatin-induced ototoxicity is not fully understood. The generation of excessive ROS is considered to be one of the causative pathogenesis of cisplatin-induced ototoxicity [7]. In the antioxidant model, excessive ROS formation within the cochlea leads to a reduction in antioxidant enzymes following exposure to cisplatin chemotherapy [8,9].…”

Evaluating protective and therapeutic effects of alpha-lipoic acid on cisplatin-induced ototoxicity

“…Hearing loss can significantly hinder a patient’s quality of life, especially influencing social development such as language learning and speech in pediatric patients 5 . Although the underlying molecular mechanisms by which cisplatin causes ototoxicity is not fully understood, previous studies have demonstrated that cisplatin activates the death receptor pathway, endoplasmic reticulum-stress pathway, and mitochondrial reactive oxygen species (ROS)-generating pathway in normal cells, eventually leading to cell death 6 – 8 . The generation of excessive ROS is considered to be the major cause of cisplatin-induced ototoxicity, as well as the direct attack of cisplatin against DNA 8 .…”

Combined Cisplatin Treatment and Photobiomodulation at High Fluence Induces Cytochrome c Release and Cytomorphologic Alterations in HEp-2 Cells

“…The antitumor effect of cisplatin is fundamentally exerted through cross-linking mitochondrial DNA, to form non-functional adducts, causing transcription blockage and impaired synthesis of many electron transport chain (ETC) components. Subsequently, reactive oxygen species (ROS) build up to provoke a state of mitochondrial oxidative stress, leading to the release of CYC to the cytosol to activate the caspases accomplishing apoptotic death [4], [26]. The phototoxic effect of PBM was explained by Karu [27], who reported that LLLI brings about an overall shift in the intracellular redox status and tilts the balance toward greater oxidation.…”

“…Cisplatin is a potent and widely used chemotherapeutic agent, being one of the first-line therapies for HNC [2]. Anticancer action of cisplatin is primarily mediated through induction of mitochondrial oxidative stress, leading to p53-dependent upregulation of proapoptotic Bax/Bak proteins, which allow for the exodus of cytochrome c (CYC) to the cytosol to further activate the executioner caspases 3, 6, and 7 of apoptotic death [3], [4]. Photobiomodulation (PBM) is a therapeutic approach that involves the use of LLL light in the visible red (600-700 nm) or near-infrared (NIR) (780-1000 nm) spectrum, to induce biological alterations in the irradiated cells, through induction of a nonthermal photochemical reaction [5].…”