Publications by authors named "Peihua Luo"

57 Publications

Cutaneous toxicity of FDA-approved small-molecule kinase inhibitors.

Expert Opin Drug Metab Toxicol 2021 Nov 26;17(11):1311-1325. Epub 2021 Nov 26.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

Introduction: By 1 January 2021, the FDA has approved a total of 62 small-molecule kinase inhibitors (SMKIs). The increasing clinical use of small-molecule kinase inhibitors has led to some side effects, the most common of which is cutaneous toxicity, as reflected by approximately 90% (57 of 62) of the FDA-approved SMKIs have reported treatment-related cutaneous toxicities. Since these cutaneous toxicities may have a crucial influence on the emotional, physical and psychosocial health of the patients, it is of great importance for doctors, patients, oncologists and interrelated researchers to be aware of the cutaneous side effects of these drugs in order to make the diagnosis accurate and the treatment appropriate.

Areas Covered: This review aims to summarize the potential cutaneous toxicities and the frequency of occurrence of FDA-approved 62 SMKIs, and provide a succinct overview of the potential mechanisms of certain cutaneous toxicities. The literature review was performed based on PubMed database and FDA official website.

Expert Opinion: It is significant to determine the risk factors for SMKI-induced cutaneous toxicity. The mechanisms underlying SMKI-induced cutaneous toxicities remain unclear at present. Future research should focus on the mechanisms of SMKI-induced cutaneous toxicities to find out mechanistically driven therapies.
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http://dx.doi.org/10.1080/17425255.2021.2004116DOI Listing
November 2021

Bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation.

Biomed Pharmacother 2021 Dec 12;144:112297. Epub 2021 Oct 12.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, PR China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China. Electronic address:

High incidence of cutaneous toxicity ranging from 29.2% to 71.2% has been reported during clinical use of vandetanib, which is a multi-target kinase inhibitor indicated for the treatment of unresectable medullary thyroid carcinoma. The cutaneous toxicity of vandetanib has limited its clinical benefits, but the underlying mechanisms and protective strategies are not well studied. Hence, we firstly established an in vivo model by continuously administrating vandetanib at 55 mg/kg/day to C57BL/6 for 21 days and verified that vandetanib could induce skin rash in vivo, which was consistent with the clinical study. We further cultured HaCaT and NHEK cells, the immortalized or primary human keratinocyte line, and investigated vandetanib (0-10 μM, 0-24 h)-caused alteration in cellular survival and death processes. The western blot showed that the expression level of apoptotic-related protein, c-PARP, c-Caspase 3 and Bax were increased, while the anti-apoptotic protein Bcl2 and MCL1 level were decreased. Meanwhile, vandetanib downregulated mitochondrial membrane potential which in turn caused the release of Cytochrome C, excessive production of reactive oxygen species and DNA damage. Furthermore, we found that 5 μM bisdemethoxycurcumin partially rescued vandetanib-induced mitochondria pathway-dependent keratinocyte apoptosis via activation of autophagy in vivo and in vitro, thereby ameliorated cutaneous toxicity. Conclusively, our study revealed the mechanisms of vandetanib-induced apoptosis in keratinocytes during the occurrence of cutaneous toxicity, and suggested bisdemethoxycurcumin as a potential protective drug. This work provided a potentially promising therapeutic strategy for the treatment of vandetanib-induced cutaneous toxicity.
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http://dx.doi.org/10.1016/j.biopha.2021.112297DOI Listing
December 2021

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

Biomed Pharmacother 2021 Nov 3;143:112115. Epub 2021 Sep 3.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.biopha.2021.112115DOI Listing
November 2021

Autophagic degradation of CCN2 (cellular communication network factor 2) causes cardiotoxicity of sunitinib.

Autophagy 2021 Aug 25:1-22. Epub 2021 Aug 25.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R.China.

Excessive macroautophagy/autophagy is one of the causes of cardiomyocyte death induced by cardiovascular diseases or cancer therapy, yet the underlying mechanism remains unknown. We and other groups previously reported that autophagy might contribute to cardiomyocyte death caused by sunitinib, a tumor angiogenesis inhibitor that is widely used in clinic, which may help to understand the mechanism of autophagy-induced cardiomyocyte death. Here, we found that sunitinib-induced autophagy leads to apoptosis of cardiomyocyte and cardiac dysfunction as the cardiomyocyte-specific heterozygous mice are resistant to sunitinib. Sunitinib-induced maladaptive autophagy selectively degrades the cardiomyocyte survival mediator CCN2 (cellular communication network factor 2) through the TOLLIP (toll interacting protein)-mediated endosome-related pathway and cardiomyocyte-specific knockdown of through adeno-associated virus serotype 9 (AAV9) mimics sunitinib-induced cardiac dysfunction , suggesting that the autophagic degradation of CCN2 is one of the causes of sunitinib-induced cardiotoxicity and death of cardiomyocytes. Remarkably, deletion of (high mobility group box 1) inhibited sunitinib-induced cardiomyocyte autophagy and apoptosis, and the HMGB1-specific inhibitor glycyrrhizic acid (GA) significantly mitigated sunitinib-induced autophagy, cardiomyocyte death and cardiotoxicity. Our study reveals a novel target protein of autophagic degradation in the regulation of cardiomyocyte death and highlights the pharmacological inhibitor of HMGB1 as an attractive approach for improving the safety of sunitinib-based cancer therapy.
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http://dx.doi.org/10.1080/15548627.2021.1965712DOI Listing
August 2021

Discovery of -((3,4)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1-pyrazol-5-yl)benzamide (Hu7691), a Potent and Selective Akt Inhibitor That Enables Decrease of Cutaneous Toxicity.

J Med Chem 2021 08 10;64(16):12163-12180. Epub 2021 Aug 10.

Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China.

Rash is one of the primary dose-limiting toxicities of Akt (protein kinase B) inhibitors in clinical trials. Here, we demonstrate the inhibition of Akt2 isozyme may be a driver for keratinocyte apoptosis, which promotes us to search for new selective Akt inhibitors with an improved cutaneous safety property. According to our previous research, compound is selected for further optimization for overcoming the disadvantages of compound , including high Akt2 inhibition and high toxicity against HaCaT keratinocytes. The dihedral angle-based design and molecular dynamics simulation lead to the identification of () that achieves a 24-fold selectivity between Akt1 and Akt2. exhibits low activity in inducing HaCaT apoptosis, promising kinase selectivity, and excellent anticancer cell proliferation potencies. Based on the superior results of safety property, pharmacokinetic profile, and efficacy, the National Medical Products Administration (NMPA) approved the investigational new drug (IND) application of .
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http://dx.doi.org/10.1021/acs.jmedchem.1c00815DOI Listing
August 2021

Adverse events associated with nilotinib in chronic myeloid leukemia: mechanisms and management strategies.

Expert Rev Clin Pharmacol 2021 Apr 28;14(4):445-456. Epub 2021 Feb 28.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

: Nilotinib is a second-generation tyrosine kinase inhibitor (TKI) targeting BCR/ABL, which is used for the first-line treatment of newly diagnosed chronic myeloid leukemia (CML) patients and the second-line treatment of most CML patients who are resistant or intolerant to prior therapy that includes imatinib. In addition to common adverse reactions, long-term use of nilotinib shows some toxicities that are different from those of occurring during other BCR/ABL TKI treatments, such as cardiovascular toxicity. It is life-threatening, which would affect not only the choice of initial treatment of CML patients but also the safety of long-term medication.: Through searching literature and reports from PubMed and clinical trials, here we review a profile of the adverse effects induced by nilotinib. We also discuss the potential molecular toxicological mechanisms and clinical management, which may provide strategies to prevent or intervene the toxicity associated with nilotinib.: Severe adverse effects associated with nilotinib limit its long-term clinical application. However, the exact mechanisms underlying these toxicities remain unclear. Future research should focus on the developing strategies to reduce the toxicities of nilotinib as well as to avoid similar toxicity in the development of new drugs.
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http://dx.doi.org/10.1080/17512433.2021.1894129DOI Listing
April 2021

Regulation of p53 stability as a therapeutic strategy for cancer.

Biochem Pharmacol 2021 03 7;185:114407. Epub 2021 Jan 7.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address:

The tumor suppressor protein p53 participates in the control of key biological functions such as cell death, metabolic homeostasis and immune function, which are closely related to various diseases such as tumors, metabolic disorders, infection and neurodegeneration. The p53 gene is also mutated in approximately 50% of human cancer cells. Mutant p53 proteins escape from the ubiquitination-dependent degradation, gain oncogenic function and promote the carcinogenesis, malignant progression, metastasis and chemoresistance. Therefore, the stability of both wild type and mutant p53 needs to be precisely regulated to maintain normal functions and targeting the p53 stability is one of the therapeutic strategies against cancer. Here, we focus on compound-induced degradation of p53 by both the ubiquitination-dependent proteasome and autophagy-lysosome degradation pathways. We also review other posttranslational modifications which control the stability of p53 and the biological functions involved in these processes. This review provides the current theoretical basis for the regulation of p53 abundance and its possible applications in different diseases.
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http://dx.doi.org/10.1016/j.bcp.2021.114407DOI Listing
March 2021

Hepatotoxicity of FDA-approved small molecule kinase inhibitors.

Expert Opin Drug Saf 2021 Mar 27;20(3):335-348. Epub 2020 Dec 27.

Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou China.

: Given their importance in cellular processes and association with numerous diseases, protein kinases have emerged as promising targets for drugs. The FDA has approved greater than fifty small molecule kinase inhibitors (SMKIs) since 2001. Nevertheless, severe hepatotoxicity and related fatal cases have grown as a potential challenge in the advancement of these drugs, and the identification and diagnosis of drug-induced liver injury (DILI) are thorny problems for clinicians.: This article summarizes the progression and analyzes the significant features in the study of SMKI hepatotoxicity, including clinical observations and investigations of the underlying mechanisms.: The understanding of SMKI-associated hepatotoxicity relies on the development of preclinical models and improvement of clinical assessment. With a full understanding of the role of inflammation in DILI and the mediating role of cytokines in inflammation, cytokines are promising candidates as sensitive and specific biomarkers for DILI. The emergence of three-dimensional spheroid models demonstrates potential use in providing clinically relevant data and predicting hepatotoxicity of SMKIs.
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http://dx.doi.org/10.1080/14740338.2021.1867104DOI Listing
March 2021

PLK1 (polo like kinase 1)-dependent autophagy facilitates gefitinib-induced hepatotoxicity by degrading COX6A1 (cytochrome c oxidase subunit 6A1).

Autophagy 2021 10 14;17(10):3221-3237. Epub 2020 Dec 14.

Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

Liver dysfunction is an outstanding dose-limiting toxicity of gefitinib, an EGFR (epidermal growth factor receptor)-tyrosine kinase inhibitor (TKI), in the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to elucidate the mechanisms underlying gefitinib-induced hepatotoxicity, and provide potentially effective intervention strategy. We discovered that gefitinib could sequentially activate macroautophagy/autophagy and apoptosis in hepatocytes. The inhibition of autophagy alleviated gefitinib-induced apoptosis, whereas the suppression of apoptosis failed to lessen gefitinib-induced autophagy. Moreover, liver-specific heterozygous mice showed less severe liver injury than vehicle, suggesting that autophagy is involved in the gefitinib-promoted hepatotoxicity. Mechanistically, gefitinib selectively degrades the important anti-apoptosis factor COX6A1 (cytochrome c oxidase subunit 6A1) in the autophagy-lysosome pathway. The gefitinib-induced COX6A1 reduction impairs mitochondrial respiratory chain complex IV (RCC IV) function, which in turn activates apoptosis, hence causing liver injury. Notably, this autophagy-promoted apoptosis is dependent on PLK1 (polo like kinase 1). Both AAV8-mediated knockdown and PLK1 inhibitor BI-2536 could mitigate the gefitinib-induced hepatotoxicity by abrogating the autophagic degradation of the COX6A1 protein. In addition, PLK1 inhibition could not compromise the anti-cancer activity of gefitinib. In conclusion, our findings reveal the gefitinib-hepatotoxicity pathway, wherein autophagy promotes apoptosis through COX6A1 degradation, and highlight pharmacological inhibition of PLK1 as an attractive therapeutic approach toward improving the safety of gefitinib-based cancer therapy. 3-MA: 3-methyladenine; AAV8: adeno-associated virus serotype 8; ATG5: autophagy related 5; ATG7: autophagy related 7; B2M: beta-2-microglobulin; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CHX: cycloheximide; COX6A1: cytochrome c oxidase subunit 6A1; c-PARP: cleaved poly(ADP-ribose) polymerase; CQ: chloroquine; GOT1/AST: glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT: glutamic pyruvic transaminase, soluble; HBSS: Hanks´ balanced salt solution; H&E: hematoxylin and eosin; MAP1LC3/LC3: microtubule associated proteins 1 light chain 3; PLK1: polo like kinase 1; RCC IV: respiratory chain complex IV; ROS: reactive oxygen species; TUBB8: tubulin beta 8 class VIII.
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http://dx.doi.org/10.1080/15548627.2020.1851492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8526032PMC
October 2021

Crosstalk between alveolar macrophages and alveolar epithelial cells/fibroblasts contributes to the pulmonary toxicity of gefitinib.

Toxicol Lett 2021 Mar 25;338:1-9. Epub 2020 Nov 25.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address:

Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the first-line treatment of patients with metastatic or advanced non-small cell lung cancer (NSCLC) whose tumors have specific EGFR mutations. Pulmonary toxicity is one of the fatal adverse effects of gefitinib and the underlying mechanism remains unclear. Here we demonstrated that alveolar macrophages contributed to gefitinib-induced pulmonary toxicity through promoting alveolar epithelial cells to undergo epithelial to mesenchymal transition (EMT) and inducing activation and antiapoptotic effect in fibroblasts. Further, we found that alveolar macrophage-secreted MCP-1 worked as a key factor in the pathologic changes of these two cell types. Gefitinib increased Mcp-1 transcription level via the nuclear import of the transcription factor STAT3. In conclusion, our data uncovered the underlying mechanisms of macrophage-promoted pulmonary toxicity in the presence of gefitinib. MCP-1 antibody or inhibition of STAT3 activation may represent novel therapeutic strategies for preventing gefitinib-induced pulmonary toxicity.
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http://dx.doi.org/10.1016/j.toxlet.2020.11.011DOI Listing
March 2021

Research Status and Outlook of PD-1/PD-L1 Inhibitors for Cancer Therapy.

Drug Des Devel Ther 2020 8;14:3625-3649. Epub 2020 Sep 8.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China.

PD-1/PD-L1 inhibitors are a group of immune checkpoint inhibitors as front-line treatment of multiple types of cancer. However, the serious immune-related adverse reactions limited the clinical application of PD-1/PD-L1 monoclonal antibodies, despite the promising curative effects. Therefore, it is urgent to develop novel inhibitors, such as small molecules, peptides or macrocycles, targeting the PD-1/PD-L1 axis to meet the increasing clinical demands. Our review discussed the mechanism of action of PD-1/PD-L1 inhibitors and presented clinical trials of currently approved PD-1/PD-L1 targeted drugs and the incidence of related adverse reactions, helping clinicians pay more attention to them, better formulate their intervention and resolution strategies. At last, some new inhibitors whose patent have been published are listed, which provide development ideas and judgment basis for the efficacy and safety of novel PD-1/PD-L1 inhibitors.
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http://dx.doi.org/10.2147/DDDT.S267433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490077PMC
July 2021

COVID-19 epidemic: a special focus on diagnosis, complications, and management.

Expert Rev Clin Pharmacol 2020 Oct 18;13(10):1085-1093. Epub 2020 Sep 18.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, China.

Introduction: The outbreak of COVID-19 caused by SARS-CoV-2 infection has become a serious hazard to global health. Apart from attacking respiratory system, it can induce multiorgan dysfunction, including cardiovascular system, liver, kidney, gastrointestinal, nervous system, and immune system. However, there are few reviews focusing on summary and comparison of diagnostic methods and complications induced by SARS-CoV-2 infection, which places a significant limit on the effective management.

Areas Covered: This review is a blend of evidence obtained by literature retrieval from PubMed, clinical experience, and the authors' opinions. We searched PubMed using the terms 'COVID-19 & diagnosis' and 'COVID-19 & complications' and selected the most relevant articles. Here we summarize the diagnostic methods that are available in clinic and discuss their different characters. Furthermore, the review offers an insight into the symptoms, incidence, and clinical strategies of complications associated with SARS-CoV-2 infection.

Expert Opinion: COVID-19 has been a global pandemic, which requires rapid response. The comparison between different characters of the diagnostic methods and the summary of the symptoms, incidence, and clinical strategies of complications given in this review are not only significant for the optimal use of diagnostic methods, but also beneficial for the prevention and management of complications.
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http://dx.doi.org/10.1080/17512433.2020.1821651DOI Listing
October 2020

Cardiovascular toxicity induced by anti-VEGF/VEGFR agents: a special focus on definitions, diagnoses, mechanisms and management.

Expert Opin Drug Metab Toxicol 2020 Sep 9;16(9):823-835. Epub 2020 Jul 9.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang,China.

Introduction: Vascular endothelial growth factor (VEGF) is a key target in cancer therapy. However, cardiovascular safety has been one of the most challenging aspects of anti-VEGF/VEGF receptor (VEGFR) agent development and therapy. While accurate diagnostic modalities for assessment of cardiac function have been developed over the past few decades, a lack of an optimal definition and precise mechanism still places a significant limit on the effective management of cardiovascular toxicity.

Areas Covered: Here, we report the cardiovascular toxicity profile associated with anti-VEGF/VEGFR agents and summarize the clinical diagnoses as well as management that are already performed in clinical practice or are currently being investigated. Furthermore, the review discusses the potential molecular toxicological mechanisms, which may provide strategies to prevent toxicity and drive drug discovery.

Expert Opinion: Cardiovascular toxicity associated with anti-VEGF/VEGFR agents has been a substantial risk for cancer treatment. To improve its management, the development of guidelines for prevention, monitoring and treatment of cardiovascular toxicity has become a hot topic. The summary of cardiovascular toxicity profile, mechanisms and management given in this review is not only significant for the optimal use of existing anti-VEGF/VEGFR agents to protect patients predisposed to cardiovascular toxicity but is also beneficial for drug development.
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http://dx.doi.org/10.1080/17425255.2020.1787986DOI Listing
September 2020

A Comprehensive Review of Clinical Cardiotoxicity Incidence of FDA-Approved Small-Molecule Kinase Inhibitors.

Front Pharmacol 2020 12;11:891. Epub 2020 Jun 12.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

Numerous protein kinases encoded in the genome have become attractive targets for the treatment of different types of cancer. As of January 2020, a total of 52 small-molecule kinase inhibitors (SMKIs) have been approved by the FDA. With the numerous clinical trials and a heavy focus on drug safety, SMKI-induced cardiotoxicity, which is a life-threatening risk, has greatly attracted the attention of researchers. In this review, the SMKIs with cardiotoxicity incidence were described exhaustively. The data were collected from 42 clinical trials, 25 FDA-published documents, seven meta-analysis/systematic reviews, three case reports and more than 50 other types of articles. To date, 73% (38 of 52) of SMKIs have reported treatment-related cardiotoxicity. Among the 38 SMKIs with known cardiotoxicity, the rates of incidence of cardiac adverse events were QT prolongation: 47% (18 of 38), hypertension: 40% (15 of 38), left ventricular dysfunction: 34% (13 of 38), arrhythmia: 34% (13 of 38), heart failure: 26% (10 of 38) and ischemia or myocardial infarction: 29% (11 of 38). In the development process of novel SMKIs, more attention should be paid to balancing the treatment efficacy and the risk of cardiotoxicity. In preclinical drug studies, producing an accurate and reliable cardiotoxicity evaluation model is of key importance. To avoid the clinical potential cardiotoxicity risk and discontinuation of a highly effective drug, patients treated with SMKIs should be proactively monitored on the basis of a global standard. Moreover, the underlying mechanisms of SMKI-induced cardiotoxicity need to be further studied to develop new therapies for SMKI-induced cardiotoxicity.
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http://dx.doi.org/10.3389/fphar.2020.00891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303342PMC
June 2020

s-HBEGF/SIRT1 circuit-dictated crosstalk between vascular endothelial cells and keratinocytes mediates sorafenib-induced hand-foot skin reaction that can be reversed by nicotinamide.

Cell Res 2020 09 15;30(9):779-793. Epub 2020 Apr 15.

Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.

Hand-foot skin reaction (HFSR), among the most significant adverse effects of sorafenib, has been limiting the clinical benefits of this frontline drug in treating various malignant tumors. The mechanism underlying such toxicity remains poorly understood, hence the absence of effective intervention strategies. In the present study, we show that vascular endothelial cells are the primary cellular target of sorafenib-induced HFSR wherein soluble heparin-binding epidermal growth factor (s-HBEGF) mediates the crosstalk between vascular endothelial cells and keratinocytes. Mechanistically, s-HBEGF released from vascular endothelial cells activates the epidermal growth factor receptor (EGFR) on keratinocytes and promotes the phosphorylation of c-Jun N-terminal kinase 2 (JNK2), which stabilizes sirtuin 1 (SIRT1), an essential keratinization inducer, and ultimately gives rise to HFSR. The administration of s-HBEGF in vivo could sufficiently induce hyper-keratinization without sorafenib treatment. Furthermore, we report that HBEGF neutralization antibody, Sirt1 knockdown, and a classic SIRT1 inhibitor nicotinamide could all significantly reduce the sorafenib-induced HFSR in the mouse model. It is noteworthy that nicotinic acid, a prodrug of nicotinamide, could substantially reverse the sorafenib-induced HFSR in ten patients in a preliminary clinical study. Collectively, our findings reveal the mechanism of vascular endothelial cell-promoted keratinization in keratinocytes and provide a potentially promising therapeutic strategy for the treatment of sorafenib-induced HFSR.
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http://dx.doi.org/10.1038/s41422-020-0309-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608389PMC
September 2020

Bisdemethoxycurcumin attenuates cisplatin-induced renal injury through anti-apoptosis, anti-oxidant and anti-inflammatory.

Eur J Pharmacol 2020 May 20;874:173026. Epub 2020 Feb 20.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. Electronic address:

Cisplatin is a widely used chemotherapy drug that is first-line therapy for a variety of tumors. Unfortunately, its adverse effects on various normal tissues and organs, especially nephrotoxicity, threaten the life of patients. Although the mechanism of cisplatin nephrotoxicity has been confirmed to be related to oxidative stress, apoptosis of renal tubular epithelial cells and inflammatory response, there is no effective prevention strategy in the clinic. Here, we found that bisdemethoxycurcumin (BDMC), a natural compound, can significantly attenuates cisplatin-induced apoptosis of renal tubular epithelial cells in vitro at the concentration of 5-20 μM and has a significant protective effect on cisplatin-induced kidney injury in mice at the dose of 50 mg/kg. Mechanistically, BDMC attenuates cisplatin-induced apoptosis of renal tubular epithelial cells by inhibiting cisplatin-induced up-regulation of p53. Meanwhile, BDMC counteracts oxidative stress by inhibiting cisplatin-induced down-regulation of nuclear factor erythroid-2-related factor 2 (Nrf2). BDMC also significantly reduced the expression of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) proteins, as well as the expression and translocation of the p65 subunit of nuclear factor-κB (NF-κB p65) into the nucleus, all of which were increased in the kidney by cisplatin treatment. Collectively, BDMC might be an effective prevention strategy which could against cisplatin-induced nephrotoxicity, and our research may shed a new light on treatment of drug toxicity.
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http://dx.doi.org/10.1016/j.ejphar.2020.173026DOI Listing
May 2020

Enhanced proliferation inhibition and apoptosis in glioma cells elicited by combination of irinotecan and imatinib.

Eur J Pharmacol 2020 May 19;874:173022. Epub 2020 Feb 19.

Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. Electronic address:

Glioma is a kind of lethal malignant tumor, and lacks efficient therapies. Combination therapy has been claimed to be a promising approach to combat cancer, due to its increased anti-cancer effects and reduced side effects. This study aimed to investigate the anti-cancer effect and mechanism of combining imatinib with irinotecan or its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). First, we found that this drug combination exerted synergistic antitumor effects against glioma in vitro and in vivo. In addition, flow cytometry results proved that the SN-38-induced apoptosis was further enhanced by imatinib, and similar results were observed by determining the protein expression levels of apoptosis biomarkers. Interestingly, p53 expression was elevated by the SN-38 mono-treatment, and was not further increased after the co-treatment; besides, knockdown of p53 could only reduce the expression of cleaved-PARP partially, and weaken the enhanced proliferation inhibition induced by SN-38 plus imatinib, indicating that there might be other factors involved in the synergistic effects besides p53. Meanwhile, the markedly elevated p21 expression was observed only in the combination group, instead of the mono-treated groups. According to the results of p21 knockdown, we found that p21 was also required for the synergistic inhibitory effects. Moreover, we explored and ruled out the possibility of imatinib enhancing the sensitivity of irinotecan by inhibiting drug efflux pumps. Thus, our findings collectively suggest that combining irinotecan with imatinib could be a promising new strategy to fight against glioma.
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http://dx.doi.org/10.1016/j.ejphar.2020.173022DOI Listing
May 2020

Corrigendum to "HMGB1 contributes to adriamycin-induced cardiotoxicity via up-regulating autophagy" [Toxicol. Lett. 292 (2018) 115-121].

Toxicol Lett 2020 03 23;321:155. Epub 2019 Dec 23.

Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. Electronic address:

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http://dx.doi.org/10.1016/j.toxlet.2019.12.018DOI Listing
March 2020

Keratinocytes apoptosis contributes to crizotinib induced-erythroderma.

Toxicol Lett 2020 Feb 7;319:102-110. Epub 2019 Nov 7.

Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address:

Crizotinib is a multi-target receptor tyrosine kinase inhibitor which is of great importance for the management of ALK-rearranged non-small cell lung cancer (NSCLC) patients. Serious erythroderma and toxic epidermal necrolysis have been reported associated with crizotinib treatment. The underlying mechanisms have not been examined. In this study, we tested the toxicity of crizotinib on immortal human keratinocytes (HaCaT) and human primary keratinocytes. We found that crizotinib directly cause cytotoxic on these two cells, which could be the explanation of the clinical characteristic of pathology. Apoptosis was observed and Z-VAD-FMK, a pan-caspase inhibitor can almost totally reverse the apoptosis induction effect of crizotinib. However, mitochondrial dysfunction and DNA damage were not involved in crizotinib-induced apoptosis, indicating the intrinsic apoptosis pathway have no connection with this cutaneous toxicity. Further studies showed that crizotinib significantly increased cleaved-caspase-8, a signaling protein of extrinsic apoptosis pathway, in a concentration and time-dependent manner. Moreover, we found the targets of crizotinib were not involved in HaCaT cells apoptosis. Collectively, our findings first report keratinocytes apoptosis is the key cause of crizotinib-induced cutaneous toxicity. We also reveal crizotinib induce apoptosis through the extrinsic apoptosis pathway due to detected up-regulated cleaved-caspase-8. Meanwhile, the apoptosis is independent of mitochondrial dysfunction, DNA damage and related drug targets inhibition.
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http://dx.doi.org/10.1016/j.toxlet.2019.11.007DOI Listing
February 2020

Sorafenib-associated hand-foot skin reaction: practical advice on diagnosis, mechanism, prevention, and management.

Expert Rev Clin Pharmacol 2019 Dec 8;12(12):1121-1127. Epub 2019 Nov 8.

Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

: Sorafenib is a multitargeted tyrosine kinase inhibitor, which has been mainly used in the treatment of advanced hepatocellular carcinoma and renal cancer. However, hand-foot skin reaction (HFSR), as one of the most common adverse reactions, have hindered its long-term clinical application. At present, the mechanism of its occurrence has not been clearly studied and it leads to the lack of effective means of intervention. This article reviews known mechanism and management methods of HFSR caused by sorafenib.: The author reviews HFSR caused by the treatment of sorafenib including the mechanism and management. English language reports located through PubMed are reviewed.: There are some conjectures about the mechanism of HFSR. However, the mechanism of HFSR induced by sorafenib is still unclear at present. In the absence of understanding the mechanism of HFSR, the most common method for clinical treatment of sorafenib-induced HFSR is dose down-regulation or discontinuation of treatment, which affects efficacy and even survival. Future research should focus on the mechanism of HFSR to find out new ways for prevention. Precautionary measures before the occurrence of HFSR can also be studied in the future.
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http://dx.doi.org/10.1080/17512433.2019.1689122DOI Listing
December 2019

ROS-dependent DNA damage contributes to crizotinib-induced hepatotoxicity via the apoptotic pathway.

Toxicol Appl Pharmacol 2019 11 19;383:114768. Epub 2019 Oct 19.

Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.. Electronic address:

Crizotinib is an oral small-molecule tyrosine kinase inhibitor targeting anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) and MET proto-oncogene, receptor tyrosine kinase (MET). Unfortunately, hepatotoxicity is a serious limitation in its clinical application, and the reason remains largely unknown. In this study, we tested the effect of crizotinib in human hepatocyte cell line HL-7702 and human primary hepatocytes, and the results showed that crizotinib treatment caused hepatocyte damage, suggesting that crizotinib induced liver injury by causing hepatocyte death, consistent with the clinical cases. Mechanistically, crizotinib induced hepatocyte death via the apoptotic pathway, and cleaved PARP (c-PARP) was observed as a signaling protein. Moreover, mitochondrial membrane potential (MMP) decrease contributed to crizotinib-induced hepatocyte apoptosis accompanied by hepatocyte DNA damage and reactive oxygen species (ROS) generation. Importantly, crizotinib induced hepatocyte apoptosis independent of its targets, ALK, ROS1 and MET. In conclusion, our data showed that crizotinib induced liver injury through hepatocyte death via the apoptotic pathway which was independent of ALK, ROS1 and MET. And we also found that MMP decrease, DNA damage and ROS generation were involved in the process.
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http://dx.doi.org/10.1016/j.taap.2019.114768DOI Listing
November 2019

Molecular basis for class side effects associated with PI3K/AKT/mTOR pathway inhibitors.

Expert Opin Drug Metab Toxicol 2019 Sep 3;15(9):767-774. Epub 2019 Sep 3.

Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou , China.

: The phosphatidylinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway has emerged as an important target in cancer therapy. Numerous PI3K/AKT/mTOR pathway inhibitors are extensively studied; some are used clinically, but most of these drugs are undergoing clinical trials. Potential adverse effects, such as severe hepatotoxicity and pneumonitis, have largely restricted the application and clinical significance of these inhibitors. A summary of mechanisms underlying the adverse effects is not only significant for the development of novel PI3K/AKT/mTOR inhibitors but also beneficial for the optimal use of existing drugs. : We report a profile of the adverse effects, which we consider the class effects of PI3K/AKT/mTOR inhibitors. This review also discusses potential molecular toxicological mechanisms of these agents, which might drive future drug discovery. : Severe toxicities associated with PI3K/AKT/mTOR inhibitors hinder their approval and limit long-term clinical application of these drugs. A better understanding regarding PI3K/AKT/mTOR inhibitor-induced toxicities is needed. However, the mechanisms underlying these toxicities remain unclear. Future research should focus on developing strategies to reduce toxicities of approved inhibitors as well as accelerating new drug development. This review will be useful to clinical, pharmaceutical, and toxicological researchers.
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http://dx.doi.org/10.1080/17425255.2019.1663169DOI Listing
September 2019

Discrimintion and Mapping of the Primary and Processed Transcripts in Maize Mitochondrion Using a Circular RT-PCR-based Strategy.

J Vis Exp 2019 07 29(149). Epub 2019 Jul 29.

State Key Laboratory of Conservation and Utilization of Subtropical Agro-Bioresources, South China Agricultural University; Guangdong Provincial Key Laboratory of Plant Molecular Breeding, College of Agriculture, South China Agricultural University;

In plant mitochondria, some steady-state transcripts have 5' triphosphate derived from transcription initiation (primary transcripts), while the others contain 5' monophosphate generated post-transcriptionally (processed transcripts). To discriminate between the two types of transcripts, several strategies have been developed, and most of them depend on presence/absence of 5' triphosphate. However, the triphosphate at primary 5' termini is unstable, and it hinders a clear discrimination of the two types of transcripts. To systematically differentiate and map the primary and processed transcripts stably accumulated in maize mitochondrion, we have developed a circular RT-PCR (cRT-PCR)-based strategy by combining cRT-PCR, RNA 5' polyphoshpatase treatment, quantitative RT-PCR (RT-qPCR), and Northern blot. As an improvement, this strategy includes an RNA normalization step to minimize the influence of unstable 5' triphosphate. In this protocol, the enriched mitochondrial RNA is pre-treated by RNA 5' polyphosphatase, which converts 5' triphsophate to monophosphate. After circularization and reverse transcription, the two cDNAs derived from 5' polyphosphatase-treated and non-treated RNAs are normalized by maize 26S mature rRNA, which has a processed 5' end and is insensitive to 5' polyphosphatase. After normalization, the primary and processed transcripts are discriminated by comparing cRT-PCR and RT-qPCR products obtained from the treated and non-treated RNAs. The transcript termini are determined by cloning and sequencing of the cRT-PCR products, and then verified by Northern blot. By using this strategy, most steady-state transcripts in maize mitochondrion have been determined. Due to the complicated transcript pattern of some mitochondrial genes, a few steady-state transcripts were not differentiated and/or mapped, though they were detected in a Northern blot. We are not sure whether this strategy is suitable to discriminate and map the steady-state transcripts in other plant mitochondria or in plastids.
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http://dx.doi.org/10.3791/60019DOI Listing
July 2019

Bisdemethoxycurcumin protects against renal fibrosis via activation of fibroblast apoptosis.

Eur J Pharmacol 2019 Mar 17;847:26-31. Epub 2019 Jan 17.

Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address:

Renal fibrosis is the common final outcome of nearly all progressive chronic kidney diseases (CKD) that eventually develop into end-stage renal failure, which threatens the lives of patients. Currently, there are no effective drugs for the treatment of renal fibrosis. However, studies have shown that certain plant natural products have a fibrosis-alleviating effect. Thus, we have screened a large number of natural products for their ability to protect against renal fibrosis and found that bisdemethoxycurcumin has a good therapeutic effect in renal fibrosis according to the data obtained in a mouse model of unilateral ureteral obstruction (UUO). The results indicate that bisdemethoxycurcumin can efficiently attenuate renal fibrosis induced by UUO. Additional studies of the bisdemethoxycurcumin mechanism of action in the treatment of renal fibrosis demonstrated that the therapeutic effect of bisdemethoxycurcumin is mediated by the specific induction of fibroblast apoptosis at a concentration of 20 μM. bisdemethoxycurcumin can efficiently protect against renal fibrosis both in vitro and in vivo. This discovery will provide new ideas for renal fibrosis treatment in clinics and a new direction for the development of effective drug therapy of renal fibrosis.
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http://dx.doi.org/10.1016/j.ejphar.2019.01.012DOI Listing
March 2019

Macrophage-secreted TSLP and MMP9 promote bleomycin-induced pulmonary fibrosis.

Toxicol Appl Pharmacol 2019 03 14;366:10-16. Epub 2019 Jan 14.

Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address:

Idiopathic pulmonary fibrosis is a pathological result of dysfunctional repair response to tissue injury, leading to chronically impaired gas exchange and death. Macrophages are believed to be critical in this disease pathogenesis; However, the exact mechanisms remain enigmatic. Here, we demonstrated that macrophages might contribute to pulmonary fibrosis at the early stage because the aggregation of macrophages appeared earlier than epithelial-mesenchymal transition and fibrosis in mouse and rat experimental models of pulmonary fibrosis. It has been found that macrophages could promote epithelial-mesenchymal transition of alveolar epithelial cells and fibroblast migration in co-culture models between macrophages and alveolar epithelial cells/fibroblasts. Importantly, we used protein micro array to analyze the cytokines that were altered after bleomycin treatment. Only thymic stromal lymphopoietin and matrix metalloproteinase 9 were significantly increased. We further confirmed that TSLP participated in the macrophage-induced epithelial-mesenchymal transition of alveolar epithelial cells using a TSLP recombinant protein. MMP9 was also involved in macrophage-induced fibroblast migration, which can be reversed by an inhibitor of MMP9. Collectively, these findings explained the underlying mechanisms of macrophage-promoted pulmonary fibrosis.
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http://dx.doi.org/10.1016/j.taap.2019.01.011DOI Listing
March 2019

HMGB1 represses the anti-cancer activity of sunitinib by governing TP53 autophagic degradation via its nucleus-to-cytoplasm transport.

Autophagy 2018 11;14(12):2155-2170. Epub 2018 Sep 11.

a Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , China.

Sunitinib, a multikinase inhibitor approved for a number of cancer indications has a low response rate. Identifying mechanisms of resistance could lead to rational combination regimens that could improve clinical outcomes. Here we report that resistance to sunitinib therapy was driven by autophagic degradation of TP53/p53. Deletion of ATG7 or ATG5 suppressed TP53 degradation, as did knockdown of SQSTM1/p62. Mechanistically, the transport of TP53 from the nucleus to the cytoplasm was essential for the sunitinib-induced autophagic degradation of TP53 and did not require TP53 nuclear export signals (NESs). Moreover, TP53 degradation was achieved by the transport of its nuclear binding target, HMGB1, which shifted TP53 from the nucleus to the cytoplasm. The inhibition of HMGB1 sensitized cancer cells to sunitinib. Importantly, sunitinib induced the degradation of all TP53 proteins, except for TP53 proteins with mutations in the interaction domain of TP53 with HMGB1 (amino acids 313 to 352). In conclusion, our data identify an alternative HMGB1-mediated TP53 protein turnover mechanism that participates in the resistance of sunitinib and suggest HMGB1 as a potential therapeutic target for improving clinical outcomes of sunitinib.
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http://dx.doi.org/10.1080/15548627.2018.1501134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984767PMC
October 2019

High-mobility group box 1 protein-mediated necroptosis contributes to dasatinib-induced cardiotoxicity.

Toxicol Lett 2018 Oct 4;296:39-47. Epub 2018 Aug 4.

Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address:

Dasatinib shows remarkable activity against imatinib-refractory chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (PhALL). However, severe cardiovascular toxicity limits the clinical applications of dasatinib. Since the underlying mechanism of dasatinib-induced cardiotoxicity is still elusive, we aim to clarify this. Recent studies have shown that necroptosis and apoptosis participate in multiple toxicity development. Here, we first report that dasatinib could directly induce cardiomyocytes death, as analyzed by the Sulforhodamine B (SRB) assay. This type of cardiomyocytes death was mediated by the necrosis pathway rather than apoptosis, as determined by using flow cytometry to characterize the mode of dasatinib-induced cell death. Inhibition of receptor-interacting protein kinase 1 (RIP1)activity and knockdown of receptor-interacting protein kinase 3 (RIP3)expression can block dasatinib-evoked cardiotoxicity, which further confirmed the involvement of necroptosis. We next found that the classic substrates of RIP3, mixed lineage kinase domain-like protein (MLKL) and Ca-calmodulin-dependent protein kinase II (CaMKII) were not involved in dasatinib-induced cardiomyocytes necroptosis. What's more, unlike the inflammation-associated necroptosis, dasatinib-triggered necroptosis was dependent on intracellular instead of secreted High-mobility group box 1 (HMGB1) protein. Collectively, our study revealed that dasatinib-induced cardiotoxicity acted via leading cardiomyocytes to HMGB1-mediated necroptosis, indicating a viable strategy for prevention of dasatinib-induced cardiotoxicity.
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http://dx.doi.org/10.1016/j.toxlet.2018.08.003DOI Listing
October 2018

HMGB1 contributes to adriamycin-induced cardiotoxicity via up-regulating autophagy.

Toxicol Lett 2018 Aug 30;292:115-122. Epub 2018 Apr 30.

Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address:

Adriamycin (ADR) is one of the most widely used and effective anthracycline antitumor agents in the treatment of certain hematological malignancies and solid tumors. However, the severe cardiotoxicity of ADR limits its clinical application. So far, the mechanism of the cardiotoxicity of ADR has not been completely clarified. In our research, cardiomyocyte autophagy and cardiac damage were observed in accompany ADR treatment, and autophagy appeared earlier than cardiac damage. Inhibition of autophagy by silencing ATG7 improved the survival rate of cardiomyocytes treated with ADR. The release of HMGB1 increased after ADR treatment, and silencing HMGB1 could reverse cardiomyocyte damage by attenuating autophagy. In addition, the expression of YAP was decreased, and overexpressing YAP down-regulated HMGB1 and alleviated cardiomyocyte damage. These results indicated that autophagy was the leading cause of ADR-induced cardiotoxicity, and HMGB1 played a vital role in the process of up-regulating autophagy.
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http://dx.doi.org/10.1016/j.toxlet.2018.04.034DOI Listing
August 2018

Multikinase Inhibitor CT-707 Targets Liver Cancer by Interrupting the Hypoxia-Activated IGF-1R-YAP Axis.

Cancer Res 2018 07 18;78(14):3995-4006. Epub 2018 Apr 18.

Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

Given that Yes-associated protein (YAP) signaling acts as a critical survival input for hypoxic cancer cells in hepatocellular carcinoma (HCC), disruption of YAP function and the maintenance of hypoxia is an attractive way to treat HCC. Utilizing a cell-based YAP-TEAD luciferase reporter assay and functional analyses, we identified CT-707, a China-FDA approved multi-kinase inhibitor under clinical trial with remarkable inhibitory activity against YAP function. CT-707 exhibited prominent cytotoxicity under hypoxia on HCC cells, which was attributable to the inhibition of YAP signaling. CT-707 arrested tumor growth in HepG2, Bel-7402, and HCC patient-derived xenografts. Mechanistically, the inhibitory activity of CT-707 on YAP signaling was due to the interruption of hypoxia-activated IGF1R. Overall, these findings not only identify CT-707 as a promising hypoxia-targeting agent against HCC, but they also unveil IGF1R as a new modulator specifically regulating hypoxia-activated YAP signaling. CT-707 may represent a novel clinical approach for patients with HCC suffering poor drug response due to intratumor hypoxia. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1548DOI Listing
July 2018

Vascular endothelial growth factor (VEGF) antibody significantly increases the risk of hand-foot skin reaction to multikinase inhibitors (MKIs): A systematic literature review and meta-analysis.

Clin Exp Pharmacol Physiol 2018 07 25;45(7):659-667. Epub 2018 Apr 25.

Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

With the use of multikinase inhibitors (MKIs) having emerged in recent years, skin toxicities such as hand-foot skin reaction (HFSR) are primary side effects, and they lack effective prediction methods. Here, we updated a previous systematic review by establishing a meta-analysis of the risk of developing HFSR among patients receiving MKIs and antivascular endothelial growth factor antibody. Publications from PubMed and abstracts presented at the American Society of Clinical Oncology Annual Meeting up to February 5, 2015, were searched to identify relevant studies, and a total of 236 patients with metastatic tumours in nine trials were included for analysis. In the meta-analysis, the pooled incidence rates of all-grade and high-grade HFSR among patients who received the combination therapy were 56.9% [95% confidence interval (CI), 45%-71.1%] and 14.3% (95% CI, 9%-24.2%), respectively, with significant differences observed with MKI monotherapy (P < .05). Further subgroup analysis demonstrated that increasing the dosages of bevacizumab (77.8% vs 51.1%, P = .04) and MKIs (64.3% vs 52.6%, P = .02) significantly increased HFSR incidence. Moreover, combination with chemotherapy exerted a minimal effect on HFSR risk (61% vs 55.3%, P = .5). This updated review and meta-analysis confirm the increased risk of HFSR incidence due to the use of MKIs and antivascular endothelial growth factor antibody. Thus, using these therapies requires safety standards.
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http://dx.doi.org/10.1111/1440-1681.12935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032857PMC
July 2018
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