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Remodeling “cold” tumor immune microenvironment via epigenetic-based therapy using targeted liposomes with in situ formed albumin corona

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Acta Pharmaceutica Sinica B 2022年第4期12卷 2057-2073页

作者： Yang He Yuefei Fang Meng Zhang Yuge Zhao Bin Tu Mingjie Shi Bahtiyor Muhitdinov Akmal Asrorov Qin Xu Yongzhuo Huang State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Zhongshan Institute for Drug Discovery Chinese Academy of SciencesZhongshan 528437China Department of Pharmacy the First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China Artemisinin Research Center Guangzhou University of Chinese MedicineGuangzhou 510450China Women’s Hospital School of MedicineZhejiang UniversityHangzhou 310006China Institute of Bioorganic Chemistry Uzbekistan Academy of SciencesTashkent 100125Uzbekistan National Medical Products Administration Key Laboratory for Quality Research and Evaluation of Pharmaceutical ExcipientsShanghai 201203China

There is a close connection between epigenetic regulation,cancer metabolism,and immunology.The combination of epigenetic therapy and immunotherapy provides a promising avenue for cancer management.As an epigenetic regulator of histone acetylation,panobinostat can induce histone acetylation and inhibit tumor cell proliferation,as well as regulate aerobic glycolysis and reprogram intratumoral immune cells.JQ1 is a BRD4 inhibitor that can suppress PD-L1 expression.Herein,we proposed a chemo-free,epigenetic-based combination therapy of panobinostat/JQ1 for metastatic colorectal cancer.A novel targeted binary-drug liposome was developed based on lactoferrin-mediated binding with the LRP-1 receptor.It was found that the tumor-targeted delivery was further enhanced by in situ formation of albumin corona.The lactoferrin modification and endogenous albumin adsorption contribute a dual-targeting effect on the receptors of both LRP-1 and SPARC that were overexpressed in tumor cells and immune cells(e.g.,tumor-associated macrophages).The targeted liposomal therapy was effective to suppress the crosstalk between tumor metabolism and immune evasion via glycolysis inhibition and immune normalization.Consequently,lactic acid production was reduced and angiogenesis inhibited;TAM switched to an anti-tumor phenotype,and the anti-tumor function of the effector CD8+T cells was reinforced.The strategy provides a potential method for remodeling the tumor immune microenvironment(TIME).

关键词： Tumor immune microenvironment Tumor-associated macrophage Epigenetic therapy Immune checkpoint Angiogenesis panobinostat JQ1 Liposome

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ABCB1介导HDAC非选择性抑制剂panobinostat耐药的机制研究

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天津药学 2022年第4期34卷 12-19页

作者：窦永海高晓丽天津市永久医院天津300450 天津市第五中心医院天津300450

目的:探究ABCB1介导非选择性HDAC抑制剂panobinostat(PBST)在肿瘤细胞中耐药的机制。方法:以KB-3-1、SW620、HEK293/pcDNA3.1以及其对应的耐药细胞株KB-C2、SW620/Ad300、HEK293/ABCB1细胞为研究对象,利用MTT法评价panobinostat对上述细胞系中的增殖抑制活性,并利用基于MTT的逆转实验评价已报道的ABCB1逆转药物对PBST的耐药逆转效果。将PBST作用于耐药细胞,利用Western blot方法检测ABCB1蛋白表达情况。并通过免疫荧光法探究PBST对耐药细胞中ABCB1质膜定位的影响。以氚标记的紫杉醇为探针评价PBST在上述细胞中蓄积水平的差异。通过钒敏感的ATP酶活性实验探究PBST对ABCB1的ATP酶活性影响,并采用计算机辅助分子对接模拟PBST和ABCB1活性口袋的结合情况。结果:PBST的抗肿瘤活性在肿瘤多药耐药细胞中显著下调,已报道的ABCB1逆转药物,如verapamil、ibrutinib、nilotinib、lapatinib以及erlotinib,均可不同程度地逆转PBST耐药。在PBST处理后,肿瘤多药耐药细胞中ABCB1的蛋白表达水平上调,但ABCB1的质膜定位未发生显著改变。PBST作用于KB-C2细胞可显著增加氚标紫杉醇的蓄积水平,但不改变亲本细胞KB-3-1中的蓄积。此外,PBST上调ABCB1的ATP酶活性,并可与ABCB1活性口袋稳定结合。结论:PBST可通过上调ABCB1在肿瘤细胞中的表达水平,下调其药物蓄积,介导其耐药,联合ABCB1抑制剂是潜在的逆转耐药策略。

关键词： panobinostat 肿瘤耐药 ABC转运蛋白B1亚家族药物蓄积

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Al-Akidi Therapeutic Protocol for Severe Infections Associated with Covid-19:Potential and Effective Treatment by Levofloxacin and Vitamin D3 and Zinc(Part 1)

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Journal of Pharmacy and Pharmacology 2022年第4期10卷 105-119页

作者： Shakir Mahmood Alwan Department of Pharmacy Al-Farabi University CollegeBaghdadIraq

Background:The emergence of Coronavirus SARS-CoV-2 evoked an unprecedented threat globally.Ever since the spread of this pandemic research and clinical trials have concentrated on the repurposing of already exciting FDA drugs to find a successful candidate to combat Covid-19.Objective:The objective of this study is to propose a therapeutic protocol that may have a potential solution to treat the severe infections associated with coronavirus.The clinical application of this protocol(Al-Akidi Therapeutic Protocol,A-TP)is highly recommended,as there are several scientific evidences that support this trusted protocol to be of great potential.Methods and Materials:This A-TP includes the use of one of the respiratory Fluoroquinolones(Levofloxacin or Moxifloxacin)in doses of 500 mg twice daily for 7-10 days,together with high doses of Vitamin D3(10000 IU/day)and Zinc(50 mg daily)for few weeks.This protocol is based on the previous antiviral activity of those Fluoroquinolones towards few viruses,the potent antibacterial activity on respiratory infections and high available concentrations in the lungs.It is also based on molecular docking of Levofloxacin and Moxifloxacin on various viral enzymes.Results:Molecular docking showed encouraging and very interesting docking scores and binding affinity of Levofloxacin and Moxifloxacin to certain viral enzymes,such as,RNA dependent RNA polymerase(RdRp),3-Cysteine-Like protease,Neuraminidase,Replicase polyproteins and Trans-Membrane Protease Serine 2 inhibitor(TMPRSS2).The highly expected clinical results of using this protocol are:reduce infection,control of temperature,improve breathing with less dependent on supplemented oxygen,and remarkable reduction of the pro-inflammatory cytokine storm,and hence,reduce hospitalization and mortality.Conclusion:Levofloxacin is highly recommended in managing the severe infections associated with Corona virus and has a remarkable reduction of pro-inflammatory cytokine storm as an immuomodulating agent.Levofloxacin is superior in this protocol

关键词： Covid-19 Levofloxacin Moxifloxacin ACE2 docking protocol viral enzymes 3CL pro-1 Camostat panobinostat Oseltamivir acid

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抗癌药帕比司他

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药学进展 2007年第9期31卷 430-430页

由诺华公司(Novartis)研制开发的抗癌药帕比司他(panobinostat,曾用代号LBH-589;NVP-LBH-589)是一种小分子的组蛋白去乙酰酶(Histone Deacetylase,HDAC)抑制剂,能阻断癌症和与癌症发生有关的多种病理通路,降低癌细胞的存活,诱导癌细胞... 详细信息

由诺华公司(Novartis)研制开发的抗癌药帕比司他(panobinostat,曾用代号LBH-589;NVP-LBH-589)是一种小分子的组蛋白去乙酰酶(Histone Deacetylase,HDAC)抑制剂,能阻断癌症和与癌症发生有关的多种病理通路,降低癌细胞的存活,诱导癌细胞的凋亡。panobinostat的化学结构为:CAS:404950-80-7药理、药效panobinostat能浓度依赖性地增加组蛋白和微管蛋白的过乙酰化,引发细胞周期终止和细胞凋亡。panobinostat对人工培养的、药物敏感或多药耐药的骨髓瘤细胞系,如对地塞米松敏感和不敏感的MM.1S、MM1R细胞,对苯丙氨酸氮芥或阿霉素敏感和不敏感的RPMI8226、U266、U266LR7、U266DOX4细胞以及对苯丙酸氮芥、阿霉素及米妥蒽醌耐药的一些细胞系的增值均有抑制作用,其半数有效量(IC50)均在100nmol/L以下,而且,该药对正常的淋巴细胞和骨髓细胞的细胞毒性作用明显小于对多发性骨髓瘤细胞的作用。另外,panobinostat对慢性髓细胞白血病(CML)细胞系的K-562和急性髓细胞白血病(AML)细胞系的MV-4-...

关键词：帕比司他 panobinostat 抗癌药

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