The Combination of Gefitinib and Acetaminophen Exacerbates Hepatotoxicity via ROS-Mediated Apoptosis.

Gefitinib is the well-tolerated first-line treatment of non-small cell lung cancer. As it need for analgesics during oncology treatment, particularly in the context ofthe coronavirus disease, where patients are more susceptible to contract high fever and sore throat. This has increased the likelihood of taking both gefitinib and antipyretic analgesic acetaminophen (APAP). Given that gefitinib and APAP overdose can predispose patients to liver injury or even acute liver failure, there is a risk of severe hepatotoxicity when these two drugs are used concomitantly. However, little is known regarding their safety at therapeutic doses. This study simulated the administration of gefitinib and APAP at clinically relevant doses in an animal model and confirmed that gefitinib in combination with APAP exhibited additional hepatotoxicity. We found that gefitinib plus APAP significantly exacerbated cell death, whereas each drug by itself had little or minor effect on hepatocyte survival. Mechanistically, combination of gefitinib and APAP induces hepatocyte death via the apoptotic pathway obviously. Reactive oxygen species (ROS) generation and DNA damage accumulation are involved in hepatocyte apoptosis. Gefitinib plus APAP also promotes the expression of Kelch-like ECH-associated protein 1 (Keap1) and downregulated the antioxidant factor, Nuclear factor erythroid 2-related factor 2 (Nrf2), by inhibiting p62 expression. Taken together, this study revealed the potential ROS-mediated apoptosis-dependent hepatotoxicity effect of the combination of gefitinib and APAP, in which the p62/Keap1/Nrf2 signaling pathway participates and plays an important regulatory role.

Chloroquine Intervenes Nephrotoxicity of Nilotinib through Deubiquitinase USP13-Mediated Stabilization of Bcl-XL.

Nephrotoxicity has become prominent due to the increase in the clinical use of nilotinib, a second-generation BCR-ABL1 inhibitor in the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia. To date, the mechanism of nilotinib nephrotoxicity is still unknown, leading to a lack of clinical intervention strategies. Here, it is found that nilotinib could induce glomerular atrophy, renal tubular degeneration, and kidney fibrosis in an animal model. Mechanistically, nilotinib induces intrinsic apoptosis by specifically reducing the level of BCL2 like 1 (Bcl-XL) in both vascular endothelial cells and renal tubular epithelial cells, as well as in vivo. It is confirmed that chloroquine (CQ) intervenes with nilotinib-induced apoptosis and improves mitochondrial integrity, reactive oxygen species accumulation, and DNA damage by reversing the decreased Bcl-XL. The intervention effect is dependent on the alleviation of the nilotinib-induced reduction in ubiquitin specific peptidase 13 (USP13) and does not rely on autophagy inhibition. Additionally, it is found that USP13 abrogates cell apoptosis by preventing excessive ubiquitin-proteasome degradation of Bcl-XL. In conclusion, the research reveals the molecular mechanism of nilotinib's nephrotoxicity, highlighting USP13 as an important regulator of Bcl-XL stability in determining cell fate, and provides CQ analogs as a clinical intervention strategy for nilotinib's nephrotoxicity.

An update on Alectinib: a first line treatment for ALK-positive advanced lung cancer.

INTRODUCTION: Alectinib is a second-generation, anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) for the treatment of ALK+ non-small cell lung cancer (NSCLC) and is able to induce significant and durable CNS responses. However, long-term use of alectinib has been clinically reported to cause some serious and even life-threatening adverse events. There are currently no effective interventions for its adverse events, and this undoubtedly leads to delays in patient treatment and limits its long-term clinical use. AREAS COVERED: Based on the clinical trials conducted so far, we summarize the efficacy and adverse events that occurred, especially those related to cardiovascular disorders, gastrointestinal disorders, hepatobiliary disorders, musculoskeletal and connective tissue disorders, skin and subcutaneous tissue disorders, and respiratory disorders. The factors that may influence alectinib selection are also described. Findings are based on a PubMed literature search of clinical and basic science research papers spanning 1998-2023. EXPERT OPINION: The significant prolongation of patient survival compared with first-generation ALK inhibitor suggests its potential as a first-line treatment for the NSCLC, but the severe adverse events of alectinib limit its long-term clinical use. Future research should focus on the exact mechanisms of these toxicities, how to alleviate the adverse events caused by alectinib clinically, and the development of next-generation drugs with reduced toxicities.

Regorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axis.

The hepatotoxicity of regorafenib is one of the most noteworthy concerns for patients, however the mechanism is poorly understood. Hence, there is a lack of effective intervention strategies. Here, by comparing the target with sorafenib, we show that regorafenib-induced liver injury is mainly due to its nontherapeutic target Eph receptor A2 (EphA2). EphA2 deficiency attenuated liver damage and cell apoptosis under regorafenib treatment in male mice. Mechanistically, regorafenib inhibits EphA2 Ser897 phosphorylation and reduces ubiquitination of p53 by altering the intracellular localization of mouse double minute 2 (MDM2) by affecting the extracellular signal-regulated kinase (ERK)/MDM2 axis. Meanwhile, we found that schisandrin C, which can upregulate the phosphorylation of EphA2 at Ser897 also has protective effect against the toxicity in vivo. Collectively, our findings identify the inhibition of EphA2 Ser897 phosphorylation as a key cause of regorafenib-induced hepatotoxicity, and chemical activation of EphA2 Ser897 represents a potential therapeutic strategy to prevent regorafenib-induced hepatotoxicity.

Defining therapeutic targets for renal fibrosis: Exploiting the biology of pathogenesis.

Renal fibrosis is a failed wound-healing process of the kidney tissue after chronic, sustained injury, which is a common pathway and pathological marker of virtually every type of chronic kidney disease (CKD), regardless of cause. However, there is a lack of effective treatment specifically targeting against renal fibrosis per se to date. The main pathological feature of renal fibrosis is the massive activation and proliferation of renal fibroblasts and the excessive synthesis and secretion of extracellular matrix (ECM) deposited in the renal interstitium, leading to structural damage, impairment of renal function, and eventually end-stage renal disease. In this review, we summarize recent advancements regarding the participation and interaction of many types of kidney residents and infiltrated cells during renal fibrosis, attempt to comprehensively discuss the mechanism of renal fibrosis from the cellular level and conclude by highlighting novel therapeutic targets and approaches for development of new treatments for patients with renal fibrosis.

The effect of structural asymmetry on thermal rectification in nanostructures.

Three SWCNT-graphene nanostructure-based models are designed to probe the thermal rectification caused by the structural asymmetry in the boundary thermal contacts, the device, and the whole system, respectively. We find that both the asymmetry of entire system and the asymmetry of the device are not necessary condition for the existence of thermal rectification, and the asymmetry in boundary thermal contacts is more important than the asymmetry in device toward determining both the magnitude and the direction of thermal rectification. Interestingly, notable thermal rectification can exist in the systems with overall structural symmetry when the boundary thermal contacts are structurally asymmetric. Moreover, nanostructures with a structurally symmetric device and structurally asymmetric boundary thermal contacts can still display significant thermal rectification. These findings could offer insight into the future design and performance improvement of nanostructured thermal rectifiers.