Bypassing pro-survival and resistance mechanisms of autophagy in EGFR-positive lung cancer cells by targeted delivery of 5FU using theranostic Ag2S quantum dots

2019 ◽  
Vol 7 (46) ◽  
pp. 7363-7376 ◽  
Author(s):  
Fatma Demir Duman ◽  
Yunus Akkoc ◽  
Gozde Demirci ◽  
Nima Bavili ◽  
Alper Kiraz ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Quantum Dots ◽  
Drug Resistance ◽  
Cell Death ◽  
Cancer Cells ◽  
Targeted Delivery ◽  
Resistance Mechanisms ◽  
Lung Cancer Cells ◽  
Ag2s Quantum Dots

Cetuximab tagged, 5FU loaded Ag2S QDs enhanced cell death selectively and overcame drug resistance by suppressing autophagy in strong EGFR overexpressing cancer cells.

scholarly journals Autophagy Regulated by Gain of Function Mutant p53 Enhances Proteasomal Inhibitor-Mediated Cell Death through Induction of ROS and ERK in Lung Cancer Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Heena Saini ◽  
Ifrah Hakeem ◽  
Sudeshna Mukherjee ◽  
Shibasish Chowdhury ◽  
Rajdeep Chowdhury
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Cell Death ◽  
Cancer Cells ◽  
Lung Cancer Cells ◽  
Erk Signaling ◽  
Gain Of Function ◽  
Lung Cancers ◽  
Advanced Therapy ◽  
Proteasomal Inhibitor

Mutations in p53, especially gain of function (GOF) mutations, are highly frequent in lung cancers and are known to facilitate tumor aggressiveness. Yet, the links between mutant GOF-p53 and lung cancers are not well established. In the present study, we set to examine how we can better sensitize resistant GOF-p53 lung cancer cells through modulation of cellular protein degradation machineries, proteasome and autophagy. H1299 p53 null lung cancer cells were stably transfected with R273H mutant GOF-p53 or wild-type (wt) p53 or empty vectors. The presence of R273H-P53 conferred the cancer cells with drug resistance not only against the widely used chemotherapeutic agents like cisplatin (CDDP) or 5-flurouracil (5-FU) but also against potent alternative modes of therapy like proteasomal inhibition. Therefore, there is an urgent need for new strategies that can overcome GOF-p53 induced drug resistance and prolong patient survival following failure of standard therapies. We observed that the proteasomal inhibitor, peptide aldehyde N-acetyl-leu-leu-norleucinal (commonly termed as ALLN), caused an activation of cellular homeostatic machinery, autophagy in R273H-P53 cells. Interestingly, inhibition of autophagy by chloroquine (CQ) alone or in combination with ALLN failed to induce enhanced cell death in the R273H-P53 cells; however, in contrast, an activation of autophagy by serum starvation or rapamycin increased sensitivity of cells to ALLN-induced cytotoxicity. An activated autophagy was associated with increased ROS and ERK signaling and an inhibition of either ROS or ERK signaling resulted in reduced cytotoxicity. Furthermore, inhibition of GOF-p53 was found to enhance autophagy resulting in increased cell death. Our findings provide novel insights pertaining to mechanisms by which a GOF-p53 harboring lung cancer cell is better sensitized, which can lead to the development of advanced therapy against resistant lung cancer cells.

scholarly journals Quantum dots as targeted doxorubicin drug delivery nanosystems in human lung cancer cells

2020 ◽  
Author(s):  
Monika Ruzycka ◽  
Patrycja Kowalik ◽  
Agata Kowalczyk ◽  
Piotr Bujak ◽  
Anna M. Nowicka ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Delivery ◽  
Quantum Dots ◽  
Cancer Cells ◽  
Targeted Delivery ◽  
A549 Cells ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Dna Breaks ◽  
Folate Receptors

Abstract Background Lung cancer is one of the most frequently diagnosed cancer all over the world and a leading cancer-related mortality. The therapy of lung cancer includes surgery, chemotherapy and radiatherapy and mailny depends on the type and stage of lung cancer characterized based on WHO guidelines. Althought the conventional chemotherapy is the main treatment option for small cell lung cancer (SCLC) and a common treatment for non-SCLC it is characterized with lack of specificity resulting to severe toxicities of normal cells and harmful side effects. Therefore, targeted drug delivery (TDD) systems have been used to reduce the systemic toxicity of some conventional chemotherapies in lung cancer. Quantum dots (QDs) are fascinating nanoscale crystals that can serve as nanocarriers in TDD due to their unique physicochemical properties. Therefore, in this paper, the as-desiged QDs, Ag-In-Zn-S-based nanoconjugates for selective doxorubicin (DOX) targeting to lung cancer cells were developed. The QD nanocrystals were modified with 11-mercaptoundecanoic acid (MUA), L-cysteine (Cys) and lipoic acid (LA) used as drug carriers for targeted delivery of DOX to A549 cells through conjugated folic acid (FA) a self-navigation molecule that docks to the folate receptors on cancer cells. The comprechensive physicochemical, cytotoxicity and genotoxicity studies were performed to characterise the novel QD-based nanocaries and their anticancer cargos. Results The results from FTIR, DLS and fluorescence quenching evidenced the successful attachment of FA to the QDs nanocrystals and DOX to the QDs-FA nanocarriers. UV-vis analysis determined the amount of FA and DOX covalently anchored to the QDs nanocrystal surface. Biological screeining revealed that QDs-FA-DOX nanoconjugates showed higher cytotoxicity in comparison to other forms of the synthesized QD samples, suggesting the cytotoxic effect of liberated DOX from the QD constructs. QD-MUA-FA-DOX occurred to be the most cytotoxic against A549 cells among nanoconjugates. In vitro scratch assay also revealed significant inhibition of A549 migration only due to treatment with QD-MUA-FA-DOX. Studies evidenced that all the nanoconjugates at IC 50 induced significantly more DNA breaks than that observed in non-treated cells. All in all, significant and the greatest cytotoxicity, genotoxicity together with inhibition of migratory potential of A549 cells was observed for QD-MUA-FA-DOX. Conclusion The studies show the therapeutic efficacy of DOX-loaded QD-based cargos suggesting their promising role as novel drug delivery systems navigating to folate receptors in lung cancer cells.

SP1 Mediates MRP1 Upregulation and Multi-Drug Resistance in Human Lung Cancer Cells

2019 ◽  
Author(s):  
Shuli Shao ◽  
Yunjianan Feng ◽  
Yue Xiao ◽  
Yan Li ◽  
Weiwei Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Human Lung ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Multi Drug Resistance ◽  
Human Lung Cancer Cells

Improved Therapeutic Efficacy of Topotecan Against A549 Lung Cancer Cells with Folate-targeted Topotecan Liposomes

2020 ◽  
Vol 21 (11) ◽  
pp. 902-909
Author(s):  
Jingxin Zhang ◽  
Weiyue Shi ◽  
Gangqiang Xue ◽  
Qiang Ma ◽  
Haixin Cui ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Delivery ◽  
Cancer Cells ◽  
Targeted Delivery ◽  
Therapeutic Efficacy ◽  
Drug Delivery Systems ◽  
Lung Tumor ◽  
A549 Cells ◽  
Delivery Systems ◽  
Lung Cancer Cells

Background: Among all cancers, lung cancer has high mortality among patients in most of the countries in the world. Targeted delivery of anticancer drugs can significantly reduce the side effects and dramatically improve the effects of the treatment. Folate, a suitable ligand, can be modified to the surface of tumor-selective drug delivery systems because it can selectively bind to the folate receptor, which is highly expressed on the surface of lung tumor cells. Objective: This study aimed to construct a kind of folate-targeted topotecan liposomes for investigating their efficacy and mechanism of action in the treatment of lung cancer in preclinical models. Methods: We conjugated topotecan liposomes with folate, and the liposomes were characterized by particle size, entrapment efficiency, cytotoxicity to A549 cells and in vitro release profile. Technical evaluations were performed on lung cancer A549 cells and xenografted A549 cancer cells in female nude mice, and the pharmacokinetics of the drug were evaluated in female SD rats. Results: The folate-targeted topotecan liposomes were proven to show effectiveness in targeting lung tumors. The anti-tumor effects of these liposomes were demonstrated by the decreased tumor volume and improved therapeutic efficacy. The folate-targeted topotecan liposomes also lengthened the topotecan blood circulation time. Conclusion: The folate-targeted topotecan liposomes are effective drug delivery systems and can be easily modified with folate, enabling the targeted liposomes to deliver topotecan to lung cancer cells and kill them, which could be used as potential carriers for lung chemotherapy.

Targeted delivery of doxorubicin to A549 lung cancer cells by CXCR4 antagonist conjugated PLGA nanoparticles

2014 ◽  
Vol 88 (2) ◽  
pp. 529-538 ◽  
Author(s):  
Chuda Chittasupho ◽  
Kriengsak Lirdprapamongkol ◽  
Prartana Kewsuwan ◽  
Narong Sarisuta
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Targeted Delivery ◽  
Plga Nanoparticles ◽  
Lung Cancer Cells ◽  
Cxcr4 Antagonist ◽  
A549 Lung

scholarly journals Tubulin acetylation enhances lung cancer resistance to paclitaxel-induced cell death through Mcl-1 stabilization

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Onsurang Wattanathamsan ◽  
Rawikorn Thararattanobon ◽  
Ratchanee Rodsiri ◽  
Pithi Chanvorachote ◽  
Chanida Vinayanuwattikun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Trichostatin A ◽  
Primary Lung Cancer ◽  
Lung Cancer Cells ◽  
Cancer Resistance ◽  
Apoptosis Resistance ◽  
Tubulin Acetylation ◽  
Cancer Aggressiveness

AbstractThe posttranslational modifications (PTMs) of microtubules have been reported to play an important role in cancer aggressiveness, including apoptosis resistance. In this study, we aimed to investigate the biological role of microtubule PTMs in the regulation of paclitaxel responsiveness. The acetylated tubulin (Ace-tub) level was strongly associated with paclitaxel sensitivity, as observed in patient-derived primary lung cancer cells and xenografted immunodeficient mice. We showed that paclitaxel-resistant H460 lung cancer cells, generated by a stepwise increase in paclitaxel, exhibited markedly increased tubulin acetylation and consequently acquired paclitaxel resistance. Upregulation of tubulin acetylation by overexpression of α-tubulin acetyltransferase 1 wild-type (αTAT1wt), an enzyme required for acetylation, or by treatment with trichostatin A (TSA), a histone deacetylase 6 (HDAC6) inhibitor, significantly attenuated paclitaxel-induced apoptosis. Investigation of the underlying mechanism revealed that the levels of antiapoptotic Mcl-1 appeared to increase in αTAT1wt-overexpressing and TSA-treated cells compared to control cells, whereas the levels of other antiapoptotic regulatory proteins were unchanged. On the other hand, decreased tubulin acetylation by αTAT1 RNA interference downregulated Mcl-1 expression in patient-derived primary lung cancer and paclitaxel-resistant lung cancer cells. A microtubule sedimentation assay demonstrated that Mcl-1 binds to microtubules preferentially at Ace-type, which prolongs the Mcl-1 half-life (T1/2). Furthermore, immunoprecipitation analysis revealed that polyubiquitination of Mcl-1 was extensively decreased in response to TSA treatment. These data indicate that tubulin acetylation enhances the resistance to paclitaxel-induced cell death by stabilizing Mcl-1 and protecting it from ubiquitin–proteasome-mediated degradation.

AMD3100-tagged nano-gold as a targeting nanocarrier for delivery of doxorubicin into lung cancer cells

2021 ◽  
Vol 11 (5) ◽  
pp. 618-626
Author(s):  
Yali Liu ◽  
Changpeng Hu ◽  
Min Zhou ◽  
Qian Zhang ◽  
Qin Tang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Targeted Delivery ◽  
Acquired Resistance ◽  
Lung Cancer Cells ◽  
Cxcr4 Antagonist ◽  
Au Nps ◽  
Nano Gold ◽  
Dependent Model ◽  
Doxorubicin Release

Doxorubicin (DOX) is widely used as a traditional chemotherapy drug in tumor treatment, but its dose-dependent side effects make it susceptible to acquired resistance. CXCR4 is a chemokine receptor that has high expression in many cancers, including lung cancer. In this work, we studied the possibility of using CXCR4 antagonist, AMD3100, as a targeting molecule to targeted delivery of DOX to CXCR4 expressing lung cancer cells through conjugated gold nanoparticles (Au NPs). DOX was intercalated inside the pH-responsive doublestrand DNA (dsDNA) and then conveniently loaded onto the Au NPs. The CXCR4 antagonist, AMD3100, was bonded with LA-PEG, and then conjugated to the surface of Au-S bond. The doxorubicin release from AuNPs@DOX@AMD3100 NPs was in a pH-dependent model, and specificity of AuNPs@DOX@AMD3100 nanoparticle was verified by using free DOX and Au@DOX NPs as control. Results in this work not only confirmed the possibility of using AMD3100 as a targeting ligand for tumor-targeted treatment, but also suggested that the non-toxic Au NPs is a prospect nanocarrier for target design of cancer therapy.

A synthetic 2,3-diarylindole induces cell death via apoptosis and autophagy in A549 lung cancer cells

2016 ◽  
Vol 26 (9) ◽  
pp. 2119-2123 ◽  
Author(s):  
Thanya Rukkijakan ◽  
Lukana Ngiwsara ◽  
Kriengsak Lirdprapamongkol ◽  
Jisnuson Svasti ◽  
Nared Phetrak ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Lung Cancer Cells ◽  
A549 Lung

Biological Effects of125I Seeds Radiation on A549 Lung Cancer Cells: G2/M Arrest and Enhanced Cell Death

2014 ◽  
Vol 32 (6) ◽  
pp. 209-217 ◽  
Author(s):  
Ang Qu ◽  
Hao Wang ◽  
Jinna Li ◽  
Junjie Wang ◽  
Jingjia Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Biological Effects ◽  
Lung Cancer Cells ◽  
A549 Lung
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