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antitumor effects of a novel photosensitizer-mediated photodynamic therapy and its influence on the cell transcriptome

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Oncology Research 2024年第5期32卷 911-923页

作者： JINGJING CHEN DAN WANG ZEQUN WANG MENGYUAN HAN HOUQING YIN WENTING ZHOU RIBAI YAN YAN PAN Department of pharmacology School of PharmacyChangzhi Medical CollegeChangzhiChina2 Department of PharmacologySchool of Basic Medical SciencesHealth Science CenterPeking UniversityBeijingChina3 Beijing Key Laboratory of Tumor Systems BiologyPeking UniversityBeijingChina4 Department of PharmacologyXinjiang Medical UniversityUrumqiChina5 School of Pharmaceutical SciencesPeking UniversityBeijingChina

Photodynamic therapy(PDT)is a promising cancer *** study investigated the antitumor effects and mechanisms of a novel photosensitizer meso-5-[ρ-diethylene triamine pentaacetic acid-aminophenyl]−10,15,20-triphenyl-porphyrin(DTP)mediated PDT(DTP-PDT).Cell viability,reactive oxygen species(ROS),and apoptosis were measured with a Cell Counting Kit-8 assay,DCFH-DA fluorescent probe,and Hoechst staining,*** apoptosis-and autophagy-related proteins were examined using western *** sequencing was used to screen differentially expressed mRNAs(DERs),and bioinformatic analysis was performed to identify the major biological events after *** results show that DTP-PDT inhibited cell growth and induced ROS generation in MCF-7 and SGC7901 *** ROS scavenger N-acetyl-L-cysteine(NAC)and the P38 MAPK inhibitor SB203580 alleviated DTP-PDT-induced ***-PDT induced cell apoptosis together with upregulated Bax and downregulated Bcl-2,which could also be inhibited by NAC or *** level of LC3B-Ⅱ,a marker of autophagy,was increased by DTP-PDT.A total of 3496 DERs were obtained after *** Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that DERs included those involved in cytosolic ribosomes,the nuclear lumen,protein binding,cell cycle,protein targeting to the endoplasmic reticulum,and ribosomal DNA *** Ontology and Reactome enrichment analyses indicated that DERs were associated with a variety of cancers and cell cycle ***-protein interaction results demonstrated that cdk1 and rps27a ranked in the top 10 interacting ***,DTP-PDT could inhibit cell growth and induce cell apoptosis and autophagy,partly through ROS and the P38 MAPK signaling *** associated with the cell cycle,ribosomes,DNA replication,and protein binding may be the key changes in DTP-PDT-mediated cytotoxicity.

关键词： Photodynamic therapy ROS Apoptosis Autophagy Bioinformatic analysis

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Development of PROTACS degrading KRAS and SOS1

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Oncology Research 2024年第8期32卷 1257-1264页

作者： GERHARD HAMILTON MARIE-THERESE EGGERSTORFER SANDRA STICKLER Institute of pharmacology Medical University of ViennaVienna1090Austria

The Kirsten rat sarcoma virus—son of sevenless 1(KRAS-SOS1)axis drives tumor growth preferentially in pancreatic,colon,and lung ***,KRAS G12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of ***,the range of other KRAS mutations is not amenable to treatment and the G12C-directed agents Sotorasib and Adragrasib show a response rate of only approximately 40%,lasting for a mean period of 8 *** approach to increase the efficacy of inhibitors is their inclusion into proteolysis-targeting chimeras(PROTACs),which degrade the proteins of interest and exhibit much higher antitumor activity through multiple cycles of ***,PROTACs have been developed based on KRAS-or SOS1-directed inhibitors coupled to either von Hippel-Lindau(VHL)or Cereblon(CRBN)ligands that invoke the proteasomal *** of these PROTACs show increased activity in vitro and in vivo compared to their cognate inhibitors but their toxicity in normal tissues is not *** CRBN PROTACs containing thalidomide derivatives cannot be tested in experimental *** to such PROTACS arises through downregulation or inactivation of CRBN or factors of the functional VHL E3 ubiquitin *** highly active KRAS and SOS1 PROTACs have been formulated their clinical application remains difficult.

关键词： Proteolysis-targeting chimeras(PROTACs) Kirsten rat sarcoma virus(KRAS) Son of sevenless 1(SOS1) Von Hippel-Lindau Cereblon

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Biological factors driving colorectal cancer metastasis

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World Journal of Gastrointestinal Oncology 2024年第2期16卷 259-272页

作者： Shuai-Xing An Zhao-Jin Yu Chen Fu Min-Jie Wei Long-Hai Shen Department of pharmacology School of PharmacyChina Medical UniversityShenyang 110122Liaoning ProvinceChina Liaoning Key Laboratory of Molecular Targeted antitumor Drug Development and Evaluation Liaoning Cancer Immune Peptide Drug Engineering Technology Research CenterKey Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors(China Medical University)Ministry of EducationShenyang 110122Liaoning ProvinceChina BD Department Greenpine Pharma Group Co.LtdTianjin 300020China Center of Oncology Genertec Liaoyou Gem Flower HospitalPanJin 124010Liaoning ProvinceChina

Approximately 20%of colorectal cancer(CRC)patients present with metastasis at *** Stage I-III CRC patients who undergo surgical resection,18%typically suffer from distal metastasis within the first three years following initial *** median survival duration after the diagnosis of metastatic CRC(mCRC)is only 9 *** is traditionally considered to be an advanced stage malignancy or is thought to be caused by incomplete resection of tumor tissue,allowing cancer cells to spread from primary to distant organs;however,increa-sing evidence suggests that the mCRC process can begin early in tumor *** patients present with high heterogeneity and diverse cancer phenotypes that are classified on the basis of molecular and morphological *** genomic and nongenomic events can induce subclone diversity,which leads to cancer and *** the course of mCRC,metastatic cascades are associated with invasive cancer cell migration through the circulatory system,extravasation,distal seeding,dormancy,and reactivation,with each step requiring specific molecular ***,cancer cells presenting neoantigens can be recognized and eliminated by the immune *** this review,we explain the biological factors that drive CRC metastasis,namely,genomic instability,epigenetic instability,the metastatic cascade,the cancer-immunity cycle,and external lifestyle *** remarkable progress in CRC research,the role of molecular classification in therapeutic intervention remains *** review shows the driving factors of mCRC which may help in identifying potential candidate biomarkers that can improve the diagnosis and early detection of mCRC cases.

关键词： cancer Metastasis cascade Cancer immunity Genomic variation Epigenetic instability Lifestyle factor

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Network pharmacology to decipher the mechanism of Danggui Longhui Wan against chronic myeloid leukemia

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Asian Journal of Traditional Medicines 2024年第4期19卷 177-191页

作者： Xuehan Ma Qiulin Yan Shaojiang Song Guodong Yao Key Laboratory of Computational Chemistry Based Natural antitumor Drug Research&Development Liaoning ProvinceSchool of Traditional Chinese Materia MedicaShenyang Pharmaceutical UniversityShenyang 110016China

Chronic myeloid leukemia(CML)is a hematopoietic myeloproliferative *** Chinese prescription Danggui Longhui Wan(DGLHW)has been utilized in CML treatment,but its underlying mechanisms remain *** this study,we gathered 794 constituents,1249 drug targets,1654 disease genes and 129 intersection *** and KEGG were used to analyze the function of these *** of prescription study showed that monarch drug,minister drug,assistant and guide drug played a synergistic role in the treatment of *** addition,we obtained 20 hub genes and 12 key *** docking indicated that the main compounds and core proteins had good binding *** results of this study also showed that DGLHW might play a role in the treatment of CML by affecting MAPK,PI3K/AKT,FoxO and p53 signaling pathways.

关键词： chronic myeloid leukemia Danggui Longhui Wan network pharmacology compatibility analysis

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A novel strategy for treating oncogene-mutated tumors by targeting tumor microenvironment and synergistically enhancing anti-PD-1 immunotherapy

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Cancer Communications 2024年第3期44卷 438-442页

作者： Yingqiang Liu Linjiang Tong Mengge Zhang Qi Zhang Qiupei Liu Fang Feng Yan Li Mengzhen Lai Haotian Tang Yi Chen Meiyu Geng Wenhu Duan Jian Ding Hua Xie division of antitumor pharmacology&State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiP.R.China University of Chinese Academy of Sciences BeijingP.R.China Department of Chemical and Environmental Engineering University of Nottingham Ningbo ChinaNingboZhejiangP.R.China Zhongshan Institute for Drug Discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshanGuangdongP.R.China Shandong Laboratory of Yantai Drug Discovery Bohai Rim Advanced Research Institute for Drug DiscoveryYantaiShandongP.R.China Small-Molecule Drug Research Center Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiP.R.China

Oncogenes are critical factors in tumorigenesis of diverse cancer types and play essential roles in tumor immune *** in Kirsten rat sarcoma viral oncogene homolog(KRAS)and epidermal growth factor receptor(EGFR)are among the most frequent gain-of-function alterations[1].After many years of in-depth research,inhibitors targeting EGFR or KRAS mutations have been successfully developed,however,their clinical benefit is relatively limited,and they will inevitably encounter the challenge of drug *** emergence of resistance is attributed to secondary mutations in driver genes and other complicated factors.

关键词： alterations KRAS sarcoma

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Targeting ERK,an Achilles' Heel of the MAPK pathway,in cancer therapy

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Acta Pharmaceutica Sinica B 2018年第4期8卷 552-562页

作者： Feifei Liu Xiaotong Yang Meiyu Geng Min Huang division of antitumor pharmacology State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of Sciences

The mitogen-activated protein kinases(MAPK) pathway, often known as the RAS-RAFMEK-ERK signal cascade, functions to transmit upstream signals to its downstream effectors to regulate physiological process such as cell proliferation, differentiation, survival and death. As the most frequently mutated signaling pathway in human cancer, targeting the MAPK pathway has long been considered a promising strategy for cancer therapy. Substantial efforts in the past decades have led to the clinical success of BRAF and MEK inhibitors. However, the clinical benefits of these inhibitors are compromised by the frequently occurring acquired resistance due to cancer heterogeneity and genomic instability. This review briefly introduces the key protein kinases involved in this pathway as well as their activation mechanisms. We also generalize the correlations between mutations of MAPK members and human cancers, followed by a summarization of progress made on the development of small molecule MAPK kinases inhibitors. In particular, this review highlights the potential advantages of ERK inhibitors in overcoming resistance to upstream targets and proposes that targeting ERK kinase may hold a promising prospect for cancer therapy.

关键词： Mitogen-activated protein kinases Extracellular signal-regu lated kinase ERK inhibitor ERK kinase Cancer therapy Drug resistance

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Salvicine,a novel topoisomerase Ⅱ inhibitor,exerts its potent anticancer activity by ROS generation

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Acta Pharmacologica Sinica 2007年第9期28卷 1460-1465页

作者： Ling-hua MENG Jian DING division of antitumor pharmacology,State Key laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China division of antitumor pharmacology State Key laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China

Salvicine is a novel diterpenoid quinone compound obtained by structural modi-fication of a natural product lead isolated from a Chinese herb with potent growthinhibitory activity against a wide spectrum of human tumor cells in vitro and inmice bearing human tumor xenografts. Salvicine has also been found to have aprofound cytotoxic effect on multidrug-resisitant (MDR) cells. Moreover, Salvicinesignificantly reduced the lung metastatic foci of MDA-MB-435 orthotopicxenograft. Recent studies demonstrated that salvicine is a novel non-intercalativetopoisomerase II (Topo II) poison by binding to the ATPase domain, promotingDNA-Topo II binding and inhibiting Topo II-mediated DNA relegation and ATPhydrolysis. Further studies have indicated that salcivine-elicited ROS plays acentral role in salvicine-induced cellular response including Topo II inhibition,DNA damage, circumventing MDR and tumor cell adhesion inhibition.

关键词： Salvicine is a novel diterpenoid quinone compound obtained by structural modi-fication of a natural product lead isolated from a Chinese herb with potent growthinhibitory activity against a wide spectrum of human tumor cells in vitro and inmice

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Exploiting histone deacetylases for cancer therapy： from hematological malignancies to solid tumors

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Science China(Life Sciences) 2017年第1期60卷 94-97页

作者： Min Huang Meiyu Geng division of antitumor pharmacology State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China

Perturbations of the epigenomic landscape, as defined by genome-wide localization of histone post-translational mod- ifications, DNA methylations and chromatin regulatory proteins, have been increasingly appreciated as a common feature of cancer. While epigenetic changes were previ- ously argued as merely a consequence of the cancerous state, recent evidence collectively points to a perception that altered epigenetic states may play a causal role in cancer development （Brien et al., 2016）. In fact, cancer genome sequencing studies have shown that genes encoding chro- matin regulatory proteins are among the most commonly mutated gene sets in cancer （Garraway and Lander, 2013）.

关键词：组蛋白去乙酰化酶癌症治疗恶性肿瘤血液系统表观遗传学实体 DNA甲基化基因组测序

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Enantioselective Synthesis of Benzimidazole Atropisomers Featuring a N-N Axis

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Chinese Journal of Chemistry 2024年第7期42卷 711-718页

作者： Fang-Bei Ge Qi-Kun Yin Chuan-Jun Lu Xuan Xuan Jia Feng Ren-Rong Liu College of Chemistry and Chemical Engineering Qingdao UniversityQingdaoShandong 266071China School of Pharmacy Key Laboratory of Molecular Pharmacology and Drug EvaluationMinistry of EducationYantai UniversityYantaiShandong 264005China

Atroposelective synthesis of N-N atropisomers is an emerging area but remains underexplored;in particular,the synthesis of N-N benzimidazole atropisomers is still ***,the first enantioselective synthesis of N-N benzimidazole atropisomers via the palladium-catalyzed de novo construction of benzimidazole skeleton is *** readily available palladium catalyst and biphosphine ligand,a broad range of nonbiaryl benzimidazole and indole-benzimidazole atropisomers were conveniently ac-cessed in high yields and with excellent ***,these N-N benzimidazole atropisomers showed great anti-tumor activity and selectivity to breast cancer MCF-7 *** simple catalytic system,broad substrate scope,high enantioselectivi-ty,and good bioactivity make this approach highly attractive.

关键词： Asymmetric synthesis Atropisomerism Palladium Benzimidazole antitumor

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Targeting sphingosine-1-phosphate signaling for cancer therapy

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Science China(Life Sciences) 2017年第6期60卷 585-600页

作者： Zuoquan Xie Hong Liu Meiyu Geng division of antitumor pharmacology State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China division of Chemistry State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China

Sphingosine-1-phosphate(S1P) is a potent pleotropic bioactive lipid mediator involved in immune cell trafficking, cell survival,cell proliferation, cell migration, angiogenesis and many other cellular processes. S1 P either activates S1 P receptors(S1PR1-5) through "inside-out signaling" or acts directly on intracellular targets to regulate various cellular processes. In the past two decades, much progress has been made in exploring S1 P signaling and its pathogenic roles in diseases as well as in developing modulators of S1 P signaling, including S1 P agonists, S1 P antagonists and sphingosine kinase(SphK) *** and S1 P have been defined as reciprocal regulators of cell fate, and S1 P signaling has been shown to be crucial for the pathogenesis of various diseases, including autoimmune diseases, inflammation and cancer; therefore, targeting S1 P signaling may curtail the process of pathogenesis and serve as a potential therapeutic target for the treatment of these diseases. In this review, we describe recent advances in our understanding of S1 P signaling in cancer development(particularly in inflammationassociated cancer) as well as in innate and adaptive immunity, and we also discuss modulators of S1 P signaling in cancer treatment.

关键词： sphingosine-1-phosphate sphingosine ceramide cancer inflammation immunity

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