3-Methyladenine potentiates paclitaxel-induced apoptosis and phosphorylation of cyclin-dependent kinase 1 at thr161 in nasopharyngeal carcinoma cell

Background:Nasopharyngeal carcinoma(NPC)exhibits a significant prevalence in the southern regions of China,and paclitaxel(PTX)is frequently employed as a medication for managing advanced NPC.However,drug resistance is typically accompanied by a poor prognosis.Exploring the synergistic potential of combining multiple chemotherapeutic agents may represent a promising avenue for optimizing treatment efficacy.Methods:This study investigated whether 3-Methyladenine(3-MA)could potentiated the effect of PTX and its potential molecular mechanism.Samples were divided into the following categories:Negative control(NC)with the solvent dimethyl sulfoxide(DMSO,0.5%v/v),PTX(400 nM),3-MA(4 mM),and PTX(400 nM)+3-MA(4 mM).The viability of NPC cells was assessed using both the cell counting kit-8(CCK-8)assay and the colony formation assay.Microscopic observation was performed to identify morphological cell changes.Flow cytometry was used to assess cell cycle status,mitochondrial membrane potential(MMP),and apoptotic cells.Western blotting was conducted to quantify the protein expression.Results:3-MA enhanced PTX-specific inhibition of NPC cell proliferation.PTX,either alone or in combination with 3-MA,caused cell cycle halt at the G2/M phase in the majority of NPC cells,and the combination treatment of PTX with 3-MA induced a higher rate of NPC cell death compared to PTX alone.Western blotting results revealed the combination of PTX with 3-MA heightened activation of cyclin-dependent kinase 1(CDK1),a key molecule in shifting cells from mitotic arrest to apoptosis,led to a reduction in Myeloid Cell Leukemia 1(MCL-1)expression and an increase in Poly(ADP-ribose)polymerase(PARP)cleavage.Conclusion:The concurrent administration of PTX with 3-MA effectively enhances PTX’s inhibitory impact on NPC and activates the apoptosis signal regulated by CDK1.

Paclitaxel induces human KOSC3 oral cancer cell apoptosis through caspase pathways

Background:Paclitaxel is a compound derived from Pacific yew bark that induces various cancer cell apoptosis.However,whether it also has anticancer activities in KOSC3 cells,an oral cancer cell line,is unclear.Methods:3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide,flow cytometry,and western blotting assays were carried out to assess cell viability,subG1 phase of the cell cycle,and apoptosis-related protein expression,respectively.Results:Ourfindings indicate that paclitaxel could inhibit cell viability and increase the expression of apoptotic markers,including plasma membrane blebbing and the cleavage of poly ADP-ribose polymerase in KOSC3 cells.Also,the treatment with paclitaxel remarkably elevated the percentage of the subG1 phase in KOSC3 cells.In addition,treatment with a pan-caspase inhibitor could recover paclitaxel-inhibited cell viability.Moreover,caspase-8,caspase-9,caspase-7,and BH3 interacting domain death agonist(Bid)were activated in paclitaxel-treated KOSC3 cells.Conclusions:Paclitaxel induced apoptosis through caspase cascade in KOSC3 cells.

Hemorrhagic cystitis in gastric cancer after nanoparticle albuminbound paclitaxel:A case report

BACKGROUND The advanced first-line regimen for advanced gastric cancer is based on a combination of fluoropyrimidine and platinum and/or paclitaxel(PTX),forming a two-or three-drug regimen.Compared to conventional PTX,nanoparticle albumin-bound PTX(Nab-PTX)has better therapeutic effects and fewer adverse effects reported in studies.Nab-PTX is a great option for patients presenting with advanced gastric cancer.Herein,we highlight an adverse event(hemorrhagic cystitis)of Nab-PTX in advanced gastric cancer.CASE SUMMARY A 55-year-old male was diagnosed with lymph node metastasis after a laparo-scopic-assisted radical gastrectomy for gastric cancer that was treated by Nab-PTX and S-1(AS).On the 15th day after treatment with AS,he was diagnosed with hemorrhagic cystitis.CONCLUSION Physicians should be aware that hemorrhagic cystitis is a potential adverse event associated with Nab-PTX treatment.

Ganoderma lucidum spore oil enhances the effect of paclitaxel,improves the tolerance to paclitaxel and prolongs the survival in Lewis tumor-bearing mice

Purpose:This study aims to investigate whether Ganoderma lucidum spore oil(GLSO)could enhance the effect of paclitaxel(PTX),improve the tolerance to PTX and prolong the overall survival of Lewis tumor-bearing mice,which has never been reported before.Methods:The tumor,spleen,and thymus were weighed at the end of the experiment.Whole blood was collected for hematological index analysis,and the intact femur was removed to determine the bone marrow nucleated cell count(BMN).The percentage of lymphocytes in the spleen of mice was detected by flow cytometry,the activity of NK cells was detected by LDH assay,and the proliferation index of lymphocytes was determined by CCK-8 assay.The overall and mean survival time and life extension rate were calculated using SPSS software.Results:Our data showed that GLSO could enhance the anti-tumor effect of PTX and prolong the survival of mice.The underlying mechanisms of the above effects might be related to the toxic reduction effect of GLSO by relieving hematotoxicity,myelosuppression and immunosuppression.Specifically,GLSO could increase the number of blood cells and bone marrow cells,alleviate the thymic index,and elevate the number and activity of NK cells in mice treated with PTX.Conclusion:GLSO may enhance the efficacy of PTX by boosting the activity of immune NK cells and prolong survival by counteracting PTX-induced bone marrow alterations and improving hematopoiesis.These findings suggested the promising role of GLSO in combination with PTX to extend the survival and increase the tolerance of patients in clinical chemotherapy of lung cancer.

沉默MPZL1调控β-catenin对A549/Tax细胞干性及耐药性的影响

目的探讨髓磷脂蛋白零样蛋白1(MPZL1)沉默后是否通过调控β-catenin表达对A549/Tax耐药性和细胞干性产生影响。方法采用不同浓度阿霉素和紫杉醇处理A549和A549紫杉醇耐药性(A549/Tax)细胞,观察两种细胞的耐药性差异。实时荧光定量聚合酶链式反应(qRT-PCR)和Western blot检测A549和A549/Tax细胞中MPZL1的表达量差异。对A549/Tax细胞沉默或者过表达MPZL1,进一步将细胞分为对照(control)组、短发卡RNA阴性对照(sh-NC)组、MPZL1沉默(sh-MPZL1)组、过表达阴性对照(OE-NC)组、MPZL1过表达(OE-MPZL1)组,运用细胞计数试剂盒8(CCK-8)和平板克隆实验分别检测MPZL1的表达变化对A549/Tax细胞增殖和克隆形成能力的影响。Western blot检测Wnt/β-catenin抑制剂XAV939和激活剂CHIR-99201处理细胞后,不同蛋白的表达变化。结果A549/Tax细胞对阿霉素和紫杉醇的半数抑制浓度(IC 50)较A549细胞明显增加(P<0.01)。MPZL1在A549/Tax中呈更高的表达趋势。MPZL1敲除后A549/Tax对阿霉素和紫杉醇的IC 50分别为2.731 mg/ml和4.939μg/ml,较阴性对照组的4.541 mg/ml和13.55μg/ml降低(P<0.01)。CCK-8和克隆形成实验结果显示,MPZL1敲除抑制肺癌A549/Tax细胞的增殖活力和克隆形成能力(P<0.05);Western blot结果显示,与阴性对照组相比,MPZL1、肿瘤干性相关蛋白(CD44和CD133)、多药耐药蛋白1(MDR1)、肺耐药相关蛋白(LRP)和β-catenin在sh-MPZL1中的表达水平明显减少(P<0.01)。此外,XAV939可抑制MPZL1、CD44、CD133、MDR1、LRP和β-catenin的表达。CHIR-99201处理细胞后部分逆转敲除MPZL1对上述蛋白的抑制作用。结论MPZL1在肺癌A549/Tax细胞中高表达。敲除MPZL1可抑制肿瘤干性和细胞增殖,增强肺癌A549/Tax细胞对阿霉素和紫杉醇的敏感性。

Comparing effectiveness and safety of paclitaxel plus raltitrexed vs. paclitaxel alone in second-line palliative chemotherapy for metastatic gastric adenocarcinoma: A randomized phase Ⅱ clinical trial

Objective:Paclitaxel(P)is a standard second-line chemotherapy in the treatment of advanced gastric cancer.This study compared the clinical outcome of a paclitaxel plus raltitrexed(RP)regimen as second-line treatment in metastatic gastric cancer(MGC)patients.Methods:An open,randomized,multi-center phase Ⅱ clinical trial was conducted involving 148 patients who were randomly assigned and treated with RP[raltitrexed(3 mg/m^(2)on day 1)and paclitaxel(135 mg/m^(2)on day 1 every 3 weeks)]or P[paclitaxel(135 mg/m^(2)on day 1 every 3 weeks)]as 2nd-line chemotherapy.The primary endpoint was progression-free survival(PFS).The secondary endpoints were the overall response rate(ORR),overall survival(OS),and safety.Results:PFS had a tendency to be prolonged with RP compared to P(2.7 months vs.1.7 months;P=0.148).OS was also prolonged with RP compared to P(10.2 months vs.6.1 months;P=0.140).The ORR was equal in the RP and P groups(6.8%and 4.0%;P=0.72).The disease control rate(DCR)in the RP and P groups was 56.2%and 36.0%,respectively.Grade 3-4 treatment-related adverse events occurred in 36.2%(RP)and 28.2%(P)of patients.Frequent grade 3-4 toxicities for RP and P were neutropenia(11.0%and 4.0%),anemia(1.4%and 4.0%),and thrombocytopenia(1.4%and 5.3%),and all grades of peripheral neurotoxicity(12.3%vs.17.3%).All grades of hepatic toxicity were demonstrated for the RP and P groups based on elevated aminotransferase levels(27.4%and 14.1%).Subgroup analysis shows if MGC was combined with ascites or peritoneal involvement,the OS of the RP regimen was longer(P=0.05).Conclusions:Second-line palliative chemotherapy with RP was shown to prolong the PFS and OS,especially among patients with ascites or peritoneal involvement,which warrants confirmation using larger sample studies.

The Combination of Artesunate and Paclitaxel in 1:1 Ratio Induces Apoptosis and Morphology Change on Human Prostate Cancer Cell Lines

The combination of Artesunate (ART) and Paclitaxel (PTX) in two human prostate cancer (PCa) cell lines (PC-3 and LNCaP) was evaluated to investigate the effects on proliferation, apoptosis and morphological changes. The half maximal inhibitory concentration (IC50) values that were observed by ART and PTX on both LNCaP and PC-3 cell lines at 72-and 120-hour exposure were used to assess these effects. Early and late apoptosis was detected in Annexin V-FITC/PI assay revealed a shift in population of cells towards early and mid-apoptosis with ART + PTX than with ART and PTX individually. More effects were observed on LNCaP cell lines at both 72-hour and 120-hour exposure. The results for the Caspase 3/7 activity assay showed shift of viable population in all induced samples compared to control. Morphological changes occurred in both cell lines;this was validated in qualitative assessment when examined under the inverted microscope. These findings indicated that ART + PTX suppressed PCa cell proliferation in a dose- and time-dependent manner.

Anti-tumor Effect of Paclitaxel Enhanced by Psoralen at the Cellular Level

[Objectives]To explore the effect of psoralen combined with paclitaxel on the apoptosis of MCF-7 cells.[Methods]The effects of different concentrations of psoralen,paclitaxel,or the combination of psoralen and paclitaxel on cell viability were detected using CCK-8 assay kit.Cell cycle distribution and apoptosis after 24 h of psoralen(0.16,0.32,0.64 mmol/L),paclitaxel(0.1μmol/L),combined action of psoralen(0.32 mmol/L)and paclitaxel(0.1μmol/L)were detected using flow cytometry.[Results]Lower concentration of psoralen(0.04-0.32 mmol/L)showed no significant inhibitory effect on cells.After combined with paclitaxel,the inhibitory effect on MCF-7 cell proliferation was significantly higher than that of the group treated alone.Compared with the paclitaxel group,the cell apoptosis rate in the drug combination group was significantly increased.Different low concentrations of psoralen can block the cell cycle of MCF-7 at G 0/G 1 phase,while paclitaxel can block the cell cycle at G 2/M phase.After combined action,the number of cells blocked at G 2/M phase decreased.[Conclusions]Overall,the combined effect of psoralen and paclitaxel can enhance anti-tumor ability by inhibiting cell proliferation,inducing apoptosis,and blocking cell cycle.

Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer

Background:Unresectable locally advanced or metastatic triple-negative(hormone-receptor-negative and human epidermal growth factor receptor 2[HER2]-negative)breast cancer is an aggressive disease with poor outcomes.Nanoparticle albumin-bound(nab)-paclitaxel may enhance the anticancer activity of atezolizumab.

TAX1BP1 and FIP200 orchestrate non-canonical autophagy of p62 aggregates for mouse neural stem cell maintenance

Autophagy plays a pivotal role in diverse biological processes,including the maintenance and differentiation of neural stem cells(NSCs).Interestingly,while complete deletion of Fip200 severely impairs NSC maintenance and differentiation,inhibiting canonical autophagy via deletion of core genes,such as Atg5,Atg16l1,and Atg7,or blockade of canonical interactions between FIP200 and ATG13(designated as FIP200-4A mutant or FIP200 KI)does not produce comparable detrimental effects.This highlights the likely critical involvement of the non-canonical functions of FIP200,the mechanisms of which have remained elusive.Here,utilizing genetic mouse models,we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1,primarily via TAX1BP1 in NSCs.Conditional deletion of Tax1bp1 in fip200hGFAP conditional knock-in(cKI)mice led to NSC deficiency,resembling the fip200hGFAP conditional knockout(cKO)mouse phenotype.Notably,reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200hGFAP cKI mice but also led to a marked reduction in p62 aggregate accumulation.Conversely,a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration.Furthermore,conditional deletion of Tax1bp1 in fip200hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200hGFAP cKO mice.Collectively,these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function,presenting novel therapeutic targets for neurodegenerative diseases.

Effect of Property Tax on Optimization and Upgrading of Industrial Structure

China's economic growth and economic development has entered a new stage,and the optimization and upgrading of industrial structure is the core driving force for China to achieve high-quality economic development during the"14 th Five-Year Plan"period.Property tax has a conductive effect on the upgrading of industrial structure.Therefore,from the perspective of property tax and industrial structure adjustment and the relationship between them,this study summarizes the relevant research of domestic and foreign scholars.On the basis of the research,the paper puts forward some relevant policy suggestions on improving China's property tax and promoting the optimization and upgrading of China's industrial structure.

Exploring Corporate Tax Compliance in the Era of Digital Tax Collection and Administration:Insights from the“Golden Tax Phase Four”Project

This article primarily examines the current state of tax collection and management,alongside other associated issues.It integrates insights from China’s“14th Five-Year Plan”and anticipates the imminent implementation of the“Golden Tax Phase Four.”With this backdrop,the article offers recommendations for advancing the reform of the tax collection and management system,fostering the development of intelligent taxation,and accelerating the modernization of tax collection and management in China.

Research on Tax Risk Regulation and Strategic Management in the Context of Big Data

With the rapid development of big data,big data has been more and more applied in all walks of life.Under the big data environment,massive big data provides convenience for regional tax risk control and strategic decision-making but also increases the difficulty of data supervision and management.By analyzing the status quo of big data and tax risk management,this paper finds many problems and puts forward effective countermeasures for tax risk supervision and strategic management by using big data.

Taxation Models and Improvement Proposals for Personal Income Tax in the Sharing Economy

As an innovative economic model,the sharing economy has seen rapid growth globally in recent years.It has not only brought a profound impact on traditional economies but also injected new vitality and momentum into the sustainable development of the social economy.However,for the sharing economy,the process of collecting personal income tax is facing several issues,such as the ambiguity of tax policies regarding personal income,challenges in identifying taxpayers,and difficulties in defining income.To achieve the fairness and efficiency of personal income tax collection in the sharing economy,this study proposes optimized regulatory mechanisms and conducts in-depth discussions on the adjustment of personal income tax policies,innovation in tax management technology,and improvement in the quality of personal income tax services.

Analysis and Innovative Strategies of Tax Preferential Policies to Promote the Sustainable Development of Small-Scale Individual Businesses

This study conducted an in-depth analysis of the current tax preferential policies for small-scale individual businesses and compared them with similar policies both domestically and internationally,aiming to reveal the advantages and disadvantages of the current system.After examining the impact of these tax preferential policies on the economic status of individual business owners and the broader social economy,this article proposes a set of innovative tax preferential strategies based on theoretical foundations.By developing these innovative strategies and clarifying their implementation paths,the aim is to promote the sustainable and healthy development of small-scale individual businesses,thereby fostering comprehensive socio-economic progress.The conclusion of this study not only summarizes policy recommendations with practical significance but also provides theoretical support for the optimization and innovation of future related systems.

紫杉醇(Paclitaxel)治疗晚期鼻咽癌的临床研究

评价紫杉醇对晚期鼻咽癌的客观疗效及毒副反应。方法 :采用紫杉醇175mg/m2,3h静脉滴注 (每3周1次 )方案共治疗晚期鼻咽癌病人22例 ,所有病人均接受两个疗程以上的化疗。结果 :22例病人均可评价疗效 ,有7例病人达到PR ,有效率为31 .82 %。主要毒副反应为骨髓抑制、恶心和呕吐、肌痛和关节痛、脱发等。大部分病人为Ⅰ～Ⅱ度反应 ,病人耐受良好。经常规预防用药后 ,未观察到有严重的过敏反应。结论 :紫杉醇是一种对晚期鼻咽癌有效的化疗药物 ,该剂量的紫杉醇临床使用较为安全 ,值得进一步的临床研究。

Preparation,physicochemical characterization and cyctotoxicity of solid dispersion of paclitaxel and polyvinylpyrrolidone

The objective of this study was to prepare and characterize paclitaxel-polyvinylpyrrolidone （PTX-PVP） solid dispersions with the intention of improving its solubility and dissolution properties. The PTX-PVP solid dispersion systems were prepared by solvent method. The release rate ofpaclitaxel was determined from dissolution studies and the physicochemical properties of solid dispersion were investigated by differential scanning calorimetry （DSC）, powder X-ray diffraction （PXRD） and scanning electron microscopy （SEM）. The cytotoxicities ofpaclitaxel in solid dispersion to the SKOV-3 cells were assayed by a SRB staining method. The results showed that the solubility and dissolution rate of paclitaxel were significantly improved in solid dispersion system compared with that of the pure drug and physical mixture. The results of DSC and PXRD showed that the paclitaxel in solid dispersion was amorphous form. No paclitaxel crystals in the solid dispersions was found during SEM analysis. Cytotoxicity study suggested that the inhibitory rates of PTX-PVP solid dispersion to SKOV-3 cells were higher than that of pure paclitaxel. The solubility and dissolution of paclitaxel were improved by solid dispersion technique. In vitro cytotoxicity of paclitaxel in solid dispersion was higher than that of pure drug.

紫杉醇(Paclitaxel,紫素)治疗恶性肿瘤Ⅲ期临床研究报告

为了对紫杉醇的临床应用价值和药物不良反应进行进一步评价，根据协作组共同制定的Ⅲ期临床试用计划通过前瞻性多中心１６单位进行临床研究。共收治２４３例恶性肿瘤患者，均为有病理或细胞学证实的中晚期病人。单药治疗：所选病人大多为一般状况较好，首次治疗的晚期患者。应用紫杉醇１５０～１７５理学ｍｇ·ｍ－２，静脉滴注，３～５ｈ，每３～４周一次，２～３周期为一疗程。联合化疗主要为经手术、化疗、放疗后的晚期患者，所用方案为：紫杉醇静脉滴注１３５ｍｇ·ｍ－２，卵巢癌加顺铂８０ｍｇ·ｍ－２；乳腺癌加阿霉素４０ｍｇ·ｍ－２；肺癌加顺铂８０ｍｇ·ｍ－２或静脉滴注卡铂３５０ｍｇ·ｍ－２；食管癌加静脉滴注顺铂８０ｍｇ·ｍ－２，第１周和平阳霉素８ｍｇ，肌注２周，第１、２周使用。均每３周重复一次，２～３周期为一个疗程。结果本组可统计近期疗效的１９０例，治后完全缓解１４例，部分缓解７３例，无变化７７例，进展２６例，总有效率为４５．８％。卵巢癌单药治疗的有效比为３／４，与顺铂联合应用的有效率为３０％（６／２０）；乳腺癌单药治疗为６２．５％（１０／１６），与阿霉素联合应用为６０．０（２４／４０）；食管癌单用有效比为４／５，与顺铂及平阳霉素联合应用为?

条件培养液对红豆杉细胞Paclitaxel生产的促进作用

在两步法红豆杉 ( Taxus chinensis)细胞悬浮培养体系的生产阶段 ,加入从生长阶段悬浮培养物中制得的条件培养液 ( Conditioned Medium,CM) ,既能促进细胞的生长 ,又能提高紫杉醇 ( paclitaxel)的产率 ;解决了生产培养时 ,细胞生长受抑制的问题 .特别是 ,取自生长 1 2 d的细胞悬浮培养物的 CM按体积分数为2 5%添加到新鲜生产培养基中时 ,可使细胞紫杉醇最高产量达 2 8.5mg/ L,细胞干重达 32 .2 g/ L,分别是对照的 2 .4倍和 2 .2倍 .对 CM中的蔗糖、果糖、NO- 3 和 PO3- 4

DL1106与doxorubicin和paclitaxel协同作用及其机制研究

目的探讨DL1106与doxorubicin和paclitaxel对三阴性乳腺癌细胞协同作用效果及研究机制。方法将三阴性乳腺癌细胞MDA-MB-231和BT549分为4组,对照组,DL1106,DL1106+doxorubicin,DL1106+paclitaxel组作用24和48 h。用流式细胞仪检测细胞凋亡率和细胞周期;用JC-1检测细胞膜电位;用Caspase-Glo?3/7 assay检测细胞内胱天蛋白酶活性;用Western blotting检测细胞周期、细胞凋亡相关蛋白表达。采用si RNA技术敲低P53和PUMA的表达后检测药物联合对细胞的作用效果。结果与DL1106单独作用组细胞相比,DL1106与doxorubicin和paclitaxel联合作用组的细胞在48 h后凋亡率显著下降。DL1106与doxorubicin和paclitaxel联合作用导致细胞膜电位大幅下降并使细胞内胱天蛋白酶活性显著升高。同对照组相比,DL1106,DL1106+doxorubicin,DL1106+paclitaxel作用组的细胞均抑制MDM2的表达,促进P53和PUMA的表达。DL1106+doxorubicin,DL1106+paclitaxel协同作用抑制细胞Cyclin D1和Bcl-2的表达,促进BAX的表达。用P53si RNA和PUMA si RNA分别敲低细胞P53和PUMA的表达后,发现DL1106+doxorubicin,DL1106+paclitaxel联合作用效果明显减弱。结论 DL1106与doxorubicin和paclitaxel对三阴性乳腺癌细胞均具有协同作用,且这种协同作用通过P53/PUMA/BAX/caspase途径发挥作用。