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Small-molecule agents for cancer immunotherapy

Acta Pharmaceutica Sinica B 2024年第3期14卷 905-952页

作者： Fang Wang Kai Fu Yujue Wang Can Pan Xueping Wang Zeyu Liu Chuan Yang Ying Zheng Xiaopeng Li Yu Lu kenneth kin wah To Chenglai Xia Jianye Zhang Zhi Shi Zeping Hu Min Huang Liwu Fu State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhou 510060China School of Pharmaceutical Sciences Tsinghua-Peking Center for Life SciencesBeijing Frontier Research Center for Biological StructureTsinghua UniversityBeijing 100084China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Department of Cell Biology&Institute of Biomedicine National Engineering Research Center of Genetic MedicineMOE Key Laboratory of Tumor Molecular BiologyGuangdong Provincial Key Laboratory of Bioengineering MedicineCollege of Life Science and TechnologyJinan UniversityGuangzhou 510632China Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target&Clinical Pharmacology NMPA and State Key Laboratory of Respiratory DiseaseSchool of Pharmaceutical Sciences and the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436China School of Pharmacy The Chinese University of Hong KongHong Kong 999077China Affiliated Foshan Maternity and Child Healthcare Hospital Southern Medical UniversityFoshan 528000China

Cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer *** induce long-term tumor regression and overall survival benefit in many types of *** the advances in our knowledge about the tumor immune microenvironment,remarkable progress has been made in the development of small-molecule drugs for *** molecules targeting PRR-associated pathways,immune checkpoints,oncogenic signaling,metabolic pathways,cytokine/chemokine signaling,and immune-related kinases have been extensively *** of smallmolecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor ***,we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.

关键词： Cancer immunotherapy Small-molecule agents Immune checkpoints Oncogenic signaling Metabolic pathways Cytokine/chemokine signaling Antitumor immunity Tumor immune microenvironment

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A20 promotes colorectal cancer immune evasion by upregulating STC1 expression to block “eat-me” signal

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Signal Transduction and Targeted Therapy 2023年第9期8卷 4403-4415页

作者： Min Luo Xueping Wang Shaocong Wu Chuan Yang Qiao Su Lamei Huang Kai Fu Sainan An Fachao Xie kenneth kin wah To Fang Wang Liwu Fu State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteSun Yat-sen University Cancer CenterGuangzhou 510060P.R.China Laboratory Animal Centre The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510080P.R.China School of Pharmacy The Chinese University of Hong KongHong KongChina

Immune checkpoint inhibitors(ICIs)have induced durable clinical responses in a subset of patients with colorectal cancer(CRC).However,the dis-satisfactory response rate and the lack of appropriate biomarkers for selecting suitable patients to be treated with ICIs pose a major challenge to current ***-related molecule A20 is closely related to cancer immune response,but the effect of A20 on“eat-me”signal and immunotherapy efficacy remains *** found that A20 downregulation prominently improved the antitumor immune response and the efficacy of PD-1 inhibitor in CRC in vitro and in *** A20 expression was associated with less infiltration of immune cells including CD3(+),CD8(+)T cells and macrophages in CRC tissues and also poorer ***-and loss-A20 functional studies proved that A20 could decrease the“eat-me”signal calreticulin(CRT)protein on cell membrane translocation via upregulating stanniocalcin 1(STC1),binding to CRT and detaining in ***,A20 inhibited GSK3βphosphorylating STC1 at Thr86 to slow down the degradation of STC1 *** findings reveal a new crosstalk between inflammatory molecule A20 and“eat-me”signal in CRC,which may represent a novel predictive biomarker for selecting CRC patients most likely to benefit from ICI therapy.

关键词： STC1 GSK3β A20

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Rociletinib(CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo

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Acta Pharmaceutica Sinica B 2020年第5期10卷 799-811页

作者： Fanpu Zeng Fang Wang Zongheng Zheng Zhen Chen kenneth kin wah To Hong Zhang Qian Han Liwu Fu The Third Affiliated Hospital of Sun Yat-sen University Guangzhou 510000China State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteSun Yat-sen University Cancer CenterGuangzhou 510060China School of Pharmacy Faculty of Medicinethe Chinese University of Hong KongHong KongSARChina Guangzhou Handy Biotechnological Co. Ltd.Guangzhou 511400China

Overexpression of adenosine triphosphate(ATP)-binding cassette subfamily G member 2(ABCG2)in cancer cells is known to cause multidrug resistance(MDR),which severely limits the clinical efficacy of ***,there is no FDA-approved MDR modulator for clinical *** this study,rociletinib(CO-1686),a mutant-selective epidermal growth factor receptor(EGFR)tyrosine kinase inhibitor(TKI),was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice,without incurring additional *** studies revealed that in ABCG2-overexpressing cancer cells,rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe ***,rociletinib,inhibited the ATPase activity,and competed with[125I]iodoarylazidoprazosin(IAAP)photolabeling of ***,ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with *** addition,rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B(AKT)and extracellular signal-regulated kinase(ERK).Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function,thus increasing the cellular accumulation of the transporter substrate anticancer *** findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.

关键词： Rociletinib Tyrosine kinase inhibitor Multidrug resistance ABCG2 ATPase

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Surgical cystogastrostomy: Is it still worthwhile?

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World Journal of Gastroenterology 2024年第17期30卷 2298-2301页

作者： kin Pan Au kenneth Siu Ho Chok Department of Surgery Queen Mary HospitalThe University of Hong KongHong Kong 999077China Department of Surgery The Chinese University of Hong KongHong Kong 999077China

The article by Ker et al explores the treatment of peripancreatic fluid collection(PFC).The use of percutaneous drainage,endoscopy,and surgery for managing PFC are *** drainage is noted for its low risk profile,while endoscopic cystogastrostomy is more effective due to the wider orifice of the metallic *** cystogastrostomy is a definitive treatment with a reduced need for reintervention,especially for cases with extensive collections and significant *** choice of treatment modality should be tailored to individual patient characteristics and disease factors,considering the expertise available.

关键词： Endoscopic cystgastrostomy Surgical cystgastrostomy Pancreatitis Pancreatic necrosis Peripancreatic collection

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Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo

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Acta Pharmaceutica Sinica B 2021年第7期11卷 1885-1902页

作者： Xu Wu Chun Yin Jiang Ma Stella Chai Chunyuan Zhang Sheng Yao Onat Kadioglu Thomas Efferth Yang Ye kenneth kin-wah to Ge Lin School of Biomedical Sciences Faculty of Medicinethe Chinese University of Hong KongHong Kong 999077China Joint Research Laboratory of Promoting Globalization of Traditional Chinese Medicines between the Chinese University of Hong Kong and Shanghai Institute of Materia Medica Chinese Academy of SciencesHong Kong 999077China State Key Laboratory of Drug Research and Natural Products Chemistry Department Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Department of Pharmaceutical Biology Johannes Gutenberg UniversityMainz 55099Germany School of Pharmacy Faculty of Medicinethe Chinese University of Hong KongHong Kong 999077China Laboratory of Molecular Pharmacology Department of PharmacologySchool of PharmacySouthwest Medical UniversityLuzhou 646000China

Multidrug resistance(MDR)mediated by ATP binding cassette subfamily B member 1(ABCB1)is significantly hindering effective cancer ***,currently,no ABCB1-inhibitory drugs have been approved to treat MDR cancer clinically,mainly due to the inhibitor specificity,toxicity,and drug ***,we reported that three polyoxypregnanes(POPs)as the most abundant constituents of Marsdenia tenacissima(***)were novel ABCB1-modulatory pro-drugs,which underwent intestinal microbiota-mediated biotransformation in vivo to generate active *** metabolites at non-toxic concentrations restored chemosensitivity in ABCB1-overexpressing cancer cells via inhibiting ABCB1 efflux activity without changing ABCB1 protein expression,which were further identified as specific non-competitive inhibitors of ABCB1 showing multiple binding sites within ABCB1 drug *** POPs did not exhibit ABCB1/drug metabolizing enzymes interplay,and their repeated administration generated predictable pharmacokinetic interaction with paclitaxel without obvious toxicity in *** further showed that these POPs enhanced the accumulation of paclitaxel in tumors and overcame ABCB1-mediated *** results suggested that these POPs had the potential to be developed as safe,potent,and specific pro-drugs to reverse ABCB1-mediated *** work also provided scientific evidence for the use of *** in combinational chemotherapy.

关键词： Multidrug resistance ABCB1 Polyoxypregnane Combination chemotherapy Marsdenia tenacissima

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Rociletinib(CO-1686) enhanced efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo

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中国药理学与毒理学杂志 2019年第10期 891-892页

作者： ZENG Fan-pu WANG Fang ZHENG Zong-heng CHEN Zhen kenneth kin wah To ZHANG Hong HAN Qian FU Li-wu State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Esophageal Cancer Institute Sun Yat-Sen University Cancer Center

The abnormal expression and function of ATP-binding cassette subfamily G member 2(ABCG2) is correlated with development of multidrug resistance(MDR), and lead to lower response to ***, there is no FDA-approved commercial MDR modulator for clinical use. Here, We found rociletinib(CO-1686), a mutant-selective epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor(TKI), significantly improved the efficacy of substrate chemotherapeutic agents in ABCG2-overexpressing cancer cells and also in ABCG2-overexpressing S1-MI-80 cell xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux, and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [125 I] iodoarylazidoprazosin(IAAP) photolabeling of ABCG2. The expression of ABCG2 at protein and m RNA levels was not altered when ABCG2-overexpressing cells were treated with rociletinib. In addition, rociletinib did not inhibit Erb B downstream signaling of AKT and ERK and their phosphorylations. The all results showed that rociletinib increased the accumulation of substrates in cells by inhibiting the efflux function of ABCG2, and reversed ABCG2-related MDR. Therefore, rociletinib might be useful in developing combination chemotherapy in the patients with ABCG2-overexpressing MDR tumors.

关键词： rociletinib combination chemotherapy chemotherapeutic agents

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Phytochemical Guttiferone K Triggers Apoptosis Through Inducing Endoplasmic Reticulum Stress Aggravation in Colorectal Cancer Cells

Phytochemical Guttiferone K Triggers Apoptosis Through Induc...

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第十四届全国中药和天然药物学术研讨会

作者： Kai-Kei Miu kenneth kin-wah to Hong-Xi Xu Ge Lin School of Biomedical Sciences The Chinese University of Hong Kong School of Pharmacy The Chinese University of Hong Kong Shanghai University of Traditional Chinese Medicine

＜正＞Guttiferone K（GutK）is a polycyclic polyprenylated acylphloroglucinol（PPAP）isolated from Garcinia *** group had previously confirmed that GutK can trigger apoptosis in colorectal cancer cells,however,the mechanism underlying GutK-induced apoptosis is *** present study demonstrated that GutK elicited endoplasmic reticulum（ER）stress in a variety

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Characterization of a smog chamber for studying formation of gas-phase products and secondary organic aerosol

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Journal of Environmental Sciences 2024年第2期136卷 570-582页

作者： Qi Yuan Zhuozhi Zhang Meng Wang kin Fai Ho Tao Wang Shuncheng Lee Department of Civil and Environmental Engineering The Hong Kong Polytechnic UniversityKowloonHong KongChina School of Public Health and Primary Care The Chinese University of Hong KongShatinHong KongChina

Smog chambers provide a potent approach to explore the secondary organic aerosol formation under varied *** study describes the construction and characterization of a new smog chamber facility for studying the formation mechanisms of gas-phase products and secondary organic aerosol from the photooxidation of volatile organic *** chamber is a 5.4 m^(3) Fluorinated Ethylene Propylene(FEP)Teflon reactor with the potential to perform photooxidation experiments at controlled temperature and relative *** characterizations were conducted for evaluation of stability of environmental parameters,mixing time,background contamination,light intensity,and wall losses of gases and *** photolysis rate of NO_(2)(J_(NO2))ranged from(1.02-3.32)×10^(-3)sec^(-1),comparable to the average J_(NO2)in ambient *** wall loss rates for NO,NO_(2),and O_(3)were 0.47×10^(-4),0.37×10^(-4),and 1.17×10^(-4)min^(-1),while wall loss of toluene was obsoletely found in a 6 hr *** particle number wall loss rates are(0.01-2.46)×10^(-3)min^(-1)for 40-350 nm with an average lifetime of more than one day.A series of toluene photooxidation experiments were carried out in absence of NO_xunder dry *** results of the simulation experiments demonstrated that the chamber is well designed to simulate photolysis progress in the atmosphere.

关键词： Smog chamber Gas-phase oxidation Chamber characterization Chemical mechanism

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Regulation of PM_(2.5)on mitochondrial damage in H9c2 cells through miR-421/SIRT3 pathway and protective effect of miR-421 inhibitor and resveratrol

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Journal of Environmental Sciences 2024年第4期138卷 288-300页

作者： Shanshan Chen Wenqi Chen Zhiping Li Jianwei Yue Ken kin Lam Yung Ruijin Li Institute of Environmental Science Shanxi UniversityTaiyuan 030006China Institute of Judicial Identification Techniques for Environmental Damage Shanxi University and Shanxi Unisdom Testing Technology Co.Ltd.Taiyuan 030006China Department of Biology Hong Kong Baptist UniversityHong KongChina Shanxi Yellow River Laboratory Taiyuan 030006China

Fine particulate matter(PM_(2.5))exposure is associated with cardiovascular disease(CVD)morbidity and *** are sensitive targets of PM_(2.5),and mitochondrial dysfunction is closely related to the occurrence of *** epigenetic mechanism of PM_(2.5)-triggered mitochondrial injury of cardiomyocytes is *** study focused on the mi R-421/SIRT3 signaling pathway to investigate the regulatory mechanism in cardiac mitochondrial dynamics imbalance in rat H9c2 cells induced by PM_(2.5).Results illustrated that PM_(2.5)impaired mitochondrial function and caused dynamics homeostasis ***,PM_(2.5)up-regulated mi R-421 and down-regulated SIRT3 gene expression,along with decreasing p-FOXO3a(SIRT3 downstream target gene)and p-Parkin expression and triggering abnormal expression of fusion gene OPA1 and fission gene ***,mi R-421 inhibitor(mi R-421i)and resveratrol significantly elevated the SIRT3 levels in H9c2 cells after PM_(2.5)exposure and mediated the expression of SOD2,OPA1 and Drp1,restoring the mitochondrial morphology and *** suggests that mi R-421/SIRT3 pathway plays an epigenetic regulatory role in mitochondrial damage induced by PM_(2.5)and that mi R-421i and resveratrol exert protective effects against PM_(2.5)-incurred cardiotoxicity.

关键词： Fine particulate matter Rat H9c2 cells Mitochondrial damage MiR-421 SIRT3 Resveratrol

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Well-Posedness of Stochastic Continuity Equations on Riemannian Manifolds

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Chinese Annals of Mathematics,Series B 2024年第1期45卷 81-122页

作者： Luca GALIMBERTI kenneth H.KARLSEN Department of Mathematical Sciences NTNU Norwegian University of Science and TechnologyN-7491 TrondheimNorway Department of mathematics University of OsloP.O.Box 1053BlindernN-0316 OsloNorway

The authors analyze continuity equations with Stratonovich stochasticity,■ρ+divh[ρo(u(t,x)+∑_(i=1)^(N)a_(i)(x)w_(i)(t))]=0defined on a smooth closed Riemannian manifold M with metric *** velocity field u is perturbed by Gaussian noise terms Wi(t),:WN(t)driven by smooth spatially dependent vector fields a1(x),...,aN(x)on *** velocity u belongs to L_(t)^(1)W_(x)^(1,2)with divh u bounded in Lf,for p>d+2,where d is the dimension of M(they do not assume div_(h) u∈L_(t,x)^(∞)).For carefully chosen noise vector fields ai(and the number N of them),they show that the initial-value problem is well-posed in the class of weak L^(2) solutions,although the problem can be ill-posed in the deterministic case because of concentration *** proof of this“regularization by noise”result is based on a L^(2) estimate,which is obtained by a duality method,and a weak compactness argument.

关键词： Stochastic continuity equation Riemannian manifold Hyperbolic equa-tion Non-smooth velocity field Weak solution Existence Uniqueness

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