Hepatotoxicity of Small Molecule Protein Kinase Inhibitors for Cancer

Viganò, Mauro; Milia, Marta La; Grassini, Maria Vittoria; Pugliese, Nicola Riccardo; Giorgio, Massimo De; Fagiuoli, S.

doi:10.3390/cancers15061766

Cited by 9 publications

(9 citation statements)

References 242 publications

(250 reference statements)

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“…Liver injury is one of the significant safety concerns for protein kinase inhibitors that cause the discontinuation of the development or label warnings for hepatotoxicity (Vigano et al, 2023). In the current investigation, of those 8 monitored BA-associated metabolizing enzymes and transporters, CYP7A1 was the only highly modulated enzyme.…”

Section: Discussionmentioning

confidence: 78%

CYP7A1 Gene Induction via SHP-Dependent or Independent Mechanisms can Increase the Risk of Drug-Induced Liver Injury Independently or in Synergy with BSEP Inhibition

Niu,

Xie,

Liu

et al. 2024

Drug Metab Dispos

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Drug-induced liver injury (DILI) is a frequent cause of clinical trial failures during drug development. While inhibiting BSEP is a well-documented DILI mechanism, interference with genes related to bile acid (BA) metabolism and transport can further complicate DILI development. Here, the effects of twenty-eight compounds on genes associated with BA metabolism and transport were evaluated, including those with discontinued development or use, boxed warnings, and clean labels for DILI. The study also included rifampicin and omeprazole, PXR and AhR ligands, and four mitogen-activated protein kinase kinase (MEK1/2) inhibitors. BSEP inhibitors with more severe DILI, notably pazopanib and CP-724714, significantly upregulated the expression of 7 alpha-hydroxylase (CYP7A1), independent of small heterodimer partner (SHP) expression. CYP7A1 expression was marginally induced by omeprazole. In contrast, its expression was suppressed by mometasone (10-fold), vinblastine (18-fold), hexachlorophene (2-fold), bosentan (2.1-fold), and rifampin (2-fold). All four MEK1/2 inhibitors that show clinical DILI were not potent BSEP inhibitors but significantly induced CYP7A1 expression, accompanied by a significant SHP gene suppression. SULT2A1 and BSEP were marginally upregulated, but no other genes were altered by the drugs tested. Protein levels of CYP7A1 were increased with the treatment of CYP7A1 inducers and decreased with obeticholic acid, an FXR ligand. CYP7A1 inducers significantly increased BA production in hepatocytes, indicating the overall regulatory effects of BA metabolism. This study demonstrates that CYP7A1 induction via various mechanisms can pose a risk for DILI, independently or in synergy with BSEP inhibition, and it should be evaluated early in drug discovery.

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Section: Discussionmentioning

confidence: 78%

CYP7A1 Gene Induction via SHP-Dependent or Independent Mechanisms can Increase the Risk of Drug-Induced Liver Injury Independently or in Synergy with BSEP Inhibition

Niu,

Xie,

Liu

et al. 2024

Drug Metab Dispos

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“…1 A). In additional to targeting tumor tissues, hepatotoxicity poses a significant challenge in the development and utilization of therapy drug for liver cancer (Mahmoudi et al 2023 ; Vigano et al 2023 ), particularly those derived from herbal products (Lee et al 2015 ; He et al 2019 ). Accordingly, the potential impact of flavokawain C on liver function was assessed through quantification of serum levels of alanine transaminase (ALT) and aspartate transaminase (AST) (Juan et al 2023 ).…”

Section: Resultsmentioning

confidence: 99%

Flavokawain C inhibits proliferation and migration of liver cancer cells through FAK/PI3K/AKT signaling pathway

Wang,

Li,

Yang

et al. 2024

J Cancer Res Clin Oncol

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Purpose This study investigated the potential applicability and the underlying mechanisms of flavokawain C, a natural compound derived from kava extracts, in liver cancer treatment. Methods Drug distribution experiment used to demonstrate the preferential tissues enrichment of flavokawain C. Cell proliferation, apoptosis and migration effect of flavokawain C were determined by MTT, colony formation, EdU staining, cell adhesion, transwell, flow cytometry and western blot assay. The mechanism was explored by comet assay, immunofluorescence assay, RNA-seq-based Kyoto encyclopedia of genes and genomes analysis, molecular dynamics, bioinformatics analysis and western blot assay. The anticancer effect of flavokawain C was further confirmed by xenograft tumor model. Results The studies first demonstrated the preferential enrichment of flavokawain C within liver tissues in vivo. The findings demonstrated that flavokawain C significantly inhibited proliferation and migration of liver cancer cells, induced cellular apoptosis, and triggered intense DNA damage along with strong DNA damage response. The findings from RNA-seq-based KEGG analysis, molecular dynamics, bioinformatics analysis, and western blot assay mechanistically indicated that treatment with flavokawain C notably suppressed the FAK/PI3K/AKT signaling pathway in liver cancer cells. This effect was attributed to the induction of gene changes and the binding of flavokawain C to the ATP sites of FAK and PI3K, resulting in the inhibition of their phosphorylation. Additionally, flavokawain C also displayed the strong capacity to inhibit Huh-7-derived xenograft tumor growth in mice with minimal adverse effects. Conclusions These findings identified that flavokawain C is a promising anticancer agent for liver cancer treatment.

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“…It will also be important to determine the extent to which these pathways hinder the effect of recently clinically explored VX-661/VX-445 additive corrector combination and whether the YES1/MAPK-mediated PM removal mechanism can be attenuated by any of the many new CFTR modulators in clinical trials. Moreover, while several drugs are currently available to inhibit both the MAPK pathway and the activity of Src family kinases, such as YES1, [ 25 , 47 ] the continuous inhibition of these pathways may have deleterious side effects [ 48 ]. Therefore, translation of our findings into a CF therapeutic context will require additional research in order to develop ways to safely target these pathways to enhance CFTR modulator therapy.…”

Section: Discussionmentioning

confidence: 99%

YES1 Kinase Mediates the Membrane Removal of Rescued F508del-CFTR in Airway Cells by Promoting MAPK Pathway Activation via SHC1

Barros

Matos

et al. 2023

Biomolecules

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Recent developments in CFTR modulator drugs have had a significant transformational effect on the treatment of individuals with Cystic Fibrosis (CF) who carry the most frequent F508del-CFTR mutation in at least one allele. However, the clinical effects of these revolutionary drugs remain limited by their inability to fully restore the plasma membrane (PM) stability of the rescued mutant channels. Here, we shed new light on the molecular mechanisms behind the reduced half-life of rescued F508del-CFTR at the PM of airway cells. We describe that YES1 protein kinase is enriched in F508del-CFTR protein PM complexes, and that its interaction with rescued channels is mediated and dependent on the adaptor protein YAP1. Moreover, we show that interference with this complex, either by depletion of one of these components or inhibiting YES1 activity, is sufficient to significantly improve the abundance and stability of modulator-rescued F508del-CFTR at the surface of airway cells. In addition, we found that this effect was mediated by a decreased phosphorylation of the scaffold protein SHC1, a key regulator of MAPK pathway activity. In fact, we showed that depletion of SHC1 or inhibition of MAPK pathway signaling was sufficient to improve rescued F508del-CFTR surface levels, whereas an ectopic increase in pathway activation downstream of SHC1, through the use of a constitutively active H-RAS protein, abrogated the stabilizing effect of YES1 inhibition on rescued F508del-CFTR. Taken together, our findings not only provide new mechanistic insights into the regulation of modulator-rescued F508del-CFTR membrane stability, but also open exciting new avenues to be further explored in CF research and treatment.

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Hepatotoxicity of Small Molecule Protein Kinase Inhibitors for Cancer

Cited by 9 publications

References 242 publications

CYP7A1 Gene Induction via SHP-Dependent or Independent Mechanisms can Increase the Risk of Drug-Induced Liver Injury Independently or in Synergy with BSEP Inhibition

CYP7A1 Gene Induction via SHP-Dependent or Independent Mechanisms can Increase the Risk of Drug-Induced Liver Injury Independently or in Synergy with BSEP Inhibition

Flavokawain C inhibits proliferation and migration of liver cancer cells through FAK/PI3K/AKT signaling pathway

YES1 Kinase Mediates the Membrane Removal of Rescued F508del-CFTR in Airway Cells by Promoting MAPK Pathway Activation via SHC1

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