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Sensitization of A-549 lung cancer cells to Cisplatin by Quinacrine-loaded lipidic nanoparticles via suppressing Nrf2 mediated defense mechanism

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Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) is believed to be responsible for the control mechanisms of cellular defense response and master regulator of antioxidant system by adjustment of endogenous antioxidants, phase II detoxifying enzymes and transporters, so inhibition of Nrf2 could be considered molecule target to overcome drug resistance and cancer progression. By harnessing liposome as an advanced nanoparticles transporter, we formulated Quinacrine known as nrf2 inhibitor into nano-carrier, and sensitized A-549 lung tumor cells to Cisplatin. The aim of this work was to prepare liposome nano-carriers to enhance the bioavailability of Quinacrine and to improve passive targeting in A549 cells. Quinacrine formulation into liposome exposed a mean particle size of 80±5 nm in passive targeting and 110±3 after decoration with chitosan oligosaccharides (COS), respectively. The highest amount of cell death (p<0.05) occurred with the co-incubation of the A549 cells with new formulation and Cisplatin. Additionally, Quinacrine-loaded liposomes declined Nrf2 expression more than Quinacrine alone (p<0.05). Correspondingly, the expression of Nrf2 downstream genes, MRP1, Trx, and bcl2 decreased significantly. Taking all the data into consideration, liposomes containing Quinacrine could ameliorate the effectiveness of Cisplatin by raising the permeability of cancer cells to the abovementioned chemical treatment and might be then given as a candidate to boost the therapeutic protocols in cancer patients.

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References

  • Barta M, Julie A, Powell CA, Wisnivesky JP (2019) Global epidemiology of lung cancer

  • Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424

    Article  Google Scholar 

  • Chang A (2011) Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC. Lung Cancer 71:3–10

    Article  Google Scholar 

  • Chen B, Lu Y, Chen Y, Cheng JJJE (2015) The role of Nrf2 in oxidative stress-induced endothelial injuries 225:R83–R99

    CAS  Google Scholar 

  • Duan L, Perez RE, Chastain PD, Mathew MT, Bijukumar DR, Maki CG (2019) JMJD2 promotes acquired cisplatin resistance in non-small cell lung carcinoma cells Oncogene:1

  • Dubey V, Mishra D, Asthana A, Jain NK (2006) Transdermal delivery of a pineal hormone: melatonin via elastic liposomes Biomaterials 27:3491–3496

    CAS  PubMed  Google Scholar 

  • Erkoc P, Cingöz A, Bagci-Onder T, Kizilel S (2017) Quinacrine mediated sensitization of glioblastoma (GBM) cells to TRAIL through MMP-sensitive PEG hydrogel carriers Macromolecular bioscience 17:1600267

    Google Scholar 

  • Gao A-M, Ke Z-P, Shi F, Sun G-C, Chen H (2013) Chrysin enhances sensitivity of BEL-7402/ADM cells to doxorubicin by suppressing PI3K/Akt/Nrf2 and ERK/Nrf2 pathway. Chemico-biological interactions 206:100–108

    Article  CAS  Google Scholar 

  • García-Pinel B, Porras-Alcalá C, Ortega-Rodríguez A, Sarabia F, Prados J, Melguizo C, López-Romero JM (2019) Lipid-based nanoparticles: application and recent advances in cancer treatment Nanomaterials 9:638

    Google Scholar 

  • Garg T, Goyal AK (2014) Liposomes: targeted and controlled delivery system Drug delivery letters 4:62–71

    CAS  Google Scholar 

  • Gurova K (2009) New hopes from old drugs: revisiting DNA-binding small molecules as anticancer agents. Future Oncol 5:1685–1704

    Article  CAS  Google Scholar 

  • Hajipour H, Hamishehkar H, Nazari Soltan Ahmad S, Barghi S, Maroufi NF, Taheri RA (2018) Improved anticancer effects of epigallocatechin gallate using RGD-containing nanostructured lipid carriers Artificial cells, nanomedicine, and biotechnology 46:283–292

    CAS  PubMed  Google Scholar 

  • Hu X-F, Yao J, Gao S-G, Wang X-S, Peng X-Q, Yang Y-T, Feng X-SJAPJCP (2013) Nrf2 overexpression predicts prognosis and 5-FU resistance in gastric cancer 14:5231–5235

    Google Scholar 

  • Iglesias VS, Giuranno L, Dubois LJ, Theys J, Vooijs M (2018) Drug resistance in non-small cell lung cancer: a potential for NOTCH targeting? Frontiers in oncology 8

  • Ikeda H et al (2002) Activation of mouse Pi-class glutathione S-transferase gene by Nrf2 (NF-E2-related factor 2) and androgen 364:563–570

    CAS  Google Scholar 

  • Kansanen E, Kuosmanen SM, Leinonen H, Levonen A-LJR (2013) The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer 1:45–49

    CAS  Google Scholar 

  • Kaspar JW, Niture SK, AKJFRB J, Medicine (2009) Nrf2: INrf2 (Keap1) signaling in oxidative stress 47:1304–1309

    CAS  Google Scholar 

  • Kim HG, Kim CW, Lee DH, Lee J-S, Oh E-T, Park HJ (2019) Quinacrine-mediated inhibition of Nrf2 reverses hypoxia-induced 5-fluorouracil resistance in colorectal cancer. International journal of molecular sciences 20:4366

    Article  CAS  Google Scholar 

  • Klaunig JEJC (2018) Oxidative Stress and Cancer 24:4771–4778

    CAS  Google Scholar 

  • Li X-T et al (2015) PEGylated VRB plus quinacrine cationic liposomes for treating non-small cell lung cancer Journal of drug targeting 23:232–243

    CAS  PubMed  Google Scholar 

  • Luo Q, Zhao J, Zhang X, Pan W (2011) Nanostructured lipid carrier (NLC) coated with chitosan oligosaccharides and its potential use in ocular drug delivery system International journal of pharmaceutics 403:185–191

    CAS  PubMed  Google Scholar 

  • Mahmoudi S, Ghorbani M, Sabzichi M, Ramezani F, Hamishehkar H, Samadi N (2019) Targeted hyaluronic acid-based lipid nanoparticle for apigenin delivery to induce Nrf2-dependent apoptosis in lung cancer cells. Journal of Drug Delivery Science and Technology 49:268–276

    Article  CAS  Google Scholar 

  • Maroufi NF, Rashidi MR, Vahedian V, Akbarzadeh M, Fattahi A, Nouri M (2020a) Therapeutic potentials of Apatinib in cancer treatment: possible mechanisms and clinical relevance Life sciences 241:117106

    Google Scholar 

  • Maroufi NF et al (2020b) The apatinib inhibits breast cancer cell line MDA-MB-231 in vitro by inducing apoptosis, cell cycle arrest, and regulating nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Breast Cancer 27:613–620

    Article  Google Scholar 

  • Maroufi NF et al (2020c) Targeting cancer stem cells by melatonin: effective therapy for cancer treatment Pathology-Research and Practice 216:152919

    CAS  Google Scholar 

  • Maroufi NF et al (2020d) Sensitization of MDA-MBA231 breast cancer cell to docetaxel by myricetin loaded into biocompatible lipid nanoparticles via sub-G1 cell cycle arrest mechanism. Naunyn Schmiedeberg's Arch Pharmacol 393:1–11

    Article  CAS  Google Scholar 

  • Moghimipour E, Handali S (2012) Utilization of thin film method for preparation of celecoxib loaded liposomes Advanced pharmaceutical bulletin 2:93

    PubMed  Google Scholar 

  • Mohammadian J, Molavi O, Pirouzpanah MB, Rahimi AAR, Samadi N (2018) Stattic enhances the anti-proliferative effect of docetaxel via the Bax/Bcl-2/cyclin B axis in human cancer cells. Process Biochem 69:188–196

    Article  CAS  Google Scholar 

  • Mohammadian J et al (2020) Formulation of Stattic as STAT3 inhibitor in nanostructured lipid carriers (NLCs) enhances efficacy of doxorubicin in melanoma cancer cells. Naunyn Schmiedeberg's Arch Pharmacol 393:2315–2323

    Article  CAS  Google Scholar 

  • Petri S, Körner S, Kiaei MJNri (2012) Nrf2/ARE signaling pathway: key mediator in oxidative stress and potential therapeutic target in ALS 2012

  • Raeisi S, Chavoshi H, Mohammadi M, Ghorbani M, Sabzichi M, Ramezani F (2019) Naringenin-loaded nano-structured lipid carrier fortifies oxaliplatin-dependent apoptosis in HT-29 cell line. Process Biochem 83:168–175

    Article  CAS  Google Scholar 

  • Ren D, Villeneuve NF, Jiang T, Wu T, Lau A, Toppin HA, Zhang DD (2011) Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci 108:1433–1438

    Article  CAS  Google Scholar 

  • Sabzichi M, Ramezani M, Mohammadian J, Ghorbani M, Mardomi A, Najafipour F, Mehdizadeh A (2019) The synergistic impact of quinacrine on cell cycle and anti-invasiveness behaviors of doxorubicin in MDA-MB-231 breast cancer cells. Process Biochem 81:175–181

    Article  CAS  Google Scholar 

  • Tajmohammadi I, Mohammadian J, Sabzichi M, Mahmuodi S, Ramezani M, Aghajani M, Ramezani F (2019) Identification of Nrf2/STAT3 axis in induction of apoptosis through sub-G 1 cell cycle arrest mechanism in HT-29 colon cancer cells. J Cell Biochem 120:14035–14043

    Article  CAS  Google Scholar 

  • Tang X, Wang H, Fan L, Wu X, Xin A, Ren H, Wang XJ (2011) Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs. Free Radic Biol Med 50:1599–1609

    Article  CAS  Google Scholar 

  • Tupal A, Sabzichi M, Bazzaz R, Fathi Maroufi N, Mohammadi M, Pirouzpanah SM, Ramezani F (2019) Application of ɑ-tocotrienol-loaded biocompatible precirol in attenuation of doxorubicin dose-dependent behavior in HUH-7 hepatocarcinoma cell line nutrition and cancer:1-9

  • Wang Y et al (2010) Quinacrine enhances cisplatin-induced cytotoxicity in four cancer cell lines. Chemotherapy 56:127–134

    Article  CAS  Google Scholar 

  • Xia S, Xu S (2005) Ferrous sulfate liposomes: preparation, stability and application in fluid milk. Food Res Int 38:289–296

    Article  CAS  Google Scholar 

  • Zhang L et al (2012) Mitochondrial targeting liposomes incorporating daunorubicin and quinacrine for treatment of relapsed breast cancer arising from cancer stem cells. Biomaterials 33:565–582

    Article  CAS  Google Scholar 

Download references

Funding

This study is funded by the Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

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Author notes

  1. Shahram Ahmadian and Mehdi Sabzichi have equal contribution.

Authors and Affiliations

  1. Laboratory of Emam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran

    Shahram Ahmadian, Jamal Mohammadian, Shiva Mahmoudi & Fatemeh Ramezani

  2. Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Mehdi Sabzichi

  3. Department of Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

    Mohsen Rashidi

  4. Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Nazila Fathi Maroufi, Marjan Ghorbani & Mostafa Mohammadi

  5. Department of Genetic and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, İstanbul, 34755, Turkey

    Mohammadbagher Pirouzpanah & Hossain Bijanpour

Authors
  1. Shahram Ahmadian
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  2. Mehdi Sabzichi
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  3. Mohsen Rashidi
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  4. Jamal Mohammadian
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  5. Shiva Mahmoudi
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  6. Nazila Fathi Maroufi
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  7. Fatemeh Ramezani
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  8. Marjan Ghorbani
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  9. Mostafa Mohammadi
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  10. Mohammadbagher Pirouzpanah
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  11. Hossain Bijanpour
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Contributions

Sh.A and M.S conceived and designed research. M.R, J.M, and Sh.M conducted experiments. N.F.M and F.M analyzed data. M.GH and M.M wrote the manuscript. B.H and M.P are responsible for financial support and are supervisors of project. All authors read and approved the manuscript and all data were generated in-house and that no paper mill was used.

Corresponding authors

Correspondence to Mostafa Mohammadi, Mohammadbagher Pirouzpanah or Hossain Bijanpour.

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Ahmadian, S., Sabzichi, M., Rashidi, M. et al. Sensitization of A-549 lung cancer cells to Cisplatin by Quinacrine-loaded lipidic nanoparticles via suppressing Nrf2 mediated defense mechanism. Naunyn-Schmiedeberg's Arch Pharmacol 394, 1521–1528 (2021). https://doi.org/10.1007/s00210-021-02079-1

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  • DOI: https://doi.org/10.1007/s00210-021-02079-1

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