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Antineoplastic effects of erufosine on small cell and non-small cell lung cancer cells through induction of apoptosis and cell cycle arrest

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Abstract

Background

Lung cancer (LC) is the most common types of cancer worldwide and is marked by high mortality rate. LC is classified into two major types due to their molecular and histological properties; non-small cell lung cancer (NSCLC) A549 and small cell lung cancer (SCLC). Currently, surgery, chemotherapy and radiation therapy are the most common treatment options of LC. However, the survival rate of LC is still very poor. Therefore, new treatment strategies are urgently needed. Erufosine (ErPC3) is a novel alkylphosphocholine and inhibits the translocation of Akt to the plasma membrane.

Methods and results

In the current study, the effects of ErPC3 in NSCLC cell line A549 and SCLC cell line DMS 114 in terms of cell viability, induction of apoptosis, cell cycle phase distribution, gene and protein expression levels, and migration capacity were investigated. 25 µM ErPC3 exhibited dose-dependent cytotoxicity against in both cancer cells. However, DMS 114 was more sensitive to ErPC3 than A549. Similarly, ErPC3 induced apoptotic cell ratio in DMS114 was significantly greater than A549. 25 µM ErPC3 caused the accumulation of both cell in G2/M phase. The levels of BCL-2 were downregulated and CASPASE 3–7 and BAX were upregulated while p-Akt levels were reduced in A549 and DMS 114 cells treated with 25 µM ErPC3. Besides, ErPC3 displayed anti-migratory effect on A549 and DMS 114.

Conclusion

These findings suggest that ErPC3 may be a promising novel therapeutic candidate for treatment of LC. ErPC3 treatment merits further investigation as potential agent against LC.

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References

  1. Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249

    Article  Google Scholar 

  2. Travis WD, Brambilla E, Burke AP et al (2015) Introduction to the 2015 World Health Organization classification of tumors of the lung, pleura, thymus, and heart. J Thorac Oncol 10:1240–1242

    Article  Google Scholar 

  3. Hecht SS (2003) Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer 3:733–744

    Article  CAS  Google Scholar 

  4. Yu C-J (2018) Letter from Taiwan. Respirology 23:535–537

    Article  Google Scholar 

  5. Ji X, Bossé Y, Landi MT et al (2018) Identification of susceptibility pathways for the role of chromosome 15q25. 1 in modifying lung cancer risk. Nat Commun 9:1–15

    Article  Google Scholar 

  6. Eckel SP, Cockburn M, Shu Y-H et al (2016) Air pollution affects lung cancer survival. Thorax 71:891–898

    Article  Google Scholar 

  7. Gelsomino F, Rossi G, Tiseo M (2014) MET and small-cell lung cancer Cancers (Basel) 6:2100–2115

    Article  Google Scholar 

  8. Yan Y, Su C, Hang M et al (2017) Recombinant Newcastle disease virus rL-RVG enhances the apoptosis and inhibits the migration of A549 lung adenocarcinoma cells via regulating alpha 7 nicotinic acetylcholine receptors in vitro. Virol J 14:190. https://doi.org/10.1186/s12985-017-0852-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. McLean AEB, Barnes DJ, Troy LK (2018) Diagnosing lung cancer: the complexities of obtaining a tissue diagnosis in the era of minimally invasive and personalised medicine. J Clin Med. https://doi.org/10.3390/jcm7070163

    Article  PubMed  PubMed Central  Google Scholar 

  10. Deveraux QL, Schendel SL, Reed JC (2001) Antiapoptotic proteins. The bcl-2 and inhibitor of apoptosis protein families. Cardiol Clin 19:57–74. https://doi.org/10.1016/s0733-8651(05)70195-8

    Article  CAS  PubMed  Google Scholar 

  11. Cheng H, Shcherba M, Pendurti G et al (2014) Targeting the PI3K/AKT/mTOR pathway: potential for lung cancer treatment. Lung Cancer Manag 3:67–75

    Article  CAS  Google Scholar 

  12. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-kinase–AKT pathway in human cancer. Nat Rev Cancer 2:489–501

    Article  CAS  Google Scholar 

  13. Tsao AS, McDonnell T, Lam S et al (2003) Increased phospho-AKT (Ser473) expression in bronchial dysplasia: implications for lung cancer prevention studies. Cancer Epidemiol Prev Biomarkers 12:660–664

    CAS  Google Scholar 

  14. Balsara BR, Pei J, Mitsuuchi Y et al (2004) Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis 25:2053–2059. https://doi.org/10.1093/carcin/bgh226

    Article  CAS  PubMed  Google Scholar 

  15. Tang J-M, He Q-Y, Guo R-X, Chang X-J (2006) Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung Cancer 51:181–191. https://doi.org/10.1016/j.lungcan.2005.10.003

    Article  PubMed  Google Scholar 

  16. Scrima M, De Marco C, Fabiani F et al (2012) Signaling networks associated with AKT activation in non-small cell lung cancer (NSCLC): new insights on the role of phosphatydil-inositol-3 kinase. PLoS ONE 7:e30427. https://doi.org/10.1371/journal.pone.0030427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Papadimitrakopoulou V, Adjei AA (2006) The Akt/mTOR and mitogen-activated protein kinase pathways in lung cancer therapy. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 1:749–751

    Google Scholar 

  18. Tripathi SC, Fahrmann JF, Celiktas M et al (2017) MCAM mediates chemoresistance in small-cell lung cancer via the PI3K/AKT/SOX2 signaling pathway. Cancer Res 77:4414–4425

    Article  CAS  Google Scholar 

  19. Chometon G, Cappuccini F, Raducanu A et al (2014) The membrane-targeted alkylphosphocholine erufosine interferes with survival signals from the extracellular matrix. Anti-Cancer Agents Med Chem (Formerly Curr Med Chem Agents) 14:578–591

    Article  CAS  Google Scholar 

  20. van Blitterswijk WJ, Verheij M (2013) Anticancer mechanisms and clinical application of alkylphospholipids. Biochim Biophys Acta 1831:663–674

    Article  Google Scholar 

  21. Yosifov DY, Konstantinov SM, Berger MR, Erucylphospho-N N (2009) N-trimethylpropylammonium shows substantial cytotoxicity in multiple myeloma cells. Ann N Y Acad Sci 1171:350

    Article  CAS  Google Scholar 

  22. Rudner J, Ruiner C-E, Handrick R et al (2010) The Akt-inhibitor Erufosine induces apoptotic cell death in prostate cancer cells and increases the short term effects of ionizing radiation. Radiat Oncol 5:1–12

    Article  Google Scholar 

  23. Martelli AM, Papa V, Tazzari PL et al (2010) Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK-and PP2A-dependent mechanisms. Leukemia 24:687–698

    Article  CAS  Google Scholar 

  24. Kaleagasioglu F, Berger MR (2014) Differential effects of erufosine on proliferation, wound healing and apoptosis in colorectal cancer cell lines. Oncol Rep 31:1407–1416

    Article  CAS  Google Scholar 

  25. Dineva IK, Zaharieva MM, Konstantinov SM et al (2012) Erufosine suppresses breast cancer in vitro and in vivo for its activity on PI3K, c-Raf and Akt proteins. J Cancer Res Clin Oncol 138:1909–1917

    Article  CAS  Google Scholar 

  26. Veenman L, Alten J, Linnemannstöns K et al (2010) Potential involvement of F 0 F 1-ATP (synth) ASE and reactive oxygen species in apoptosis induction by the antineoplastic agent erucylphosphohomocholine in glioblastoma cell lines. Apoptosis 15:753–768

    Article  CAS  Google Scholar 

  27. Ansari SS, Sharma AK, Soni H et al (2018) Induction of ER and mitochondrial stress by the alkylphosphocholine erufosine in oral squamous cell carcinoma cells. Cell Death Dis 9:1–15

    Article  CAS  Google Scholar 

  28. Königs SK, Pallasch CP, Lindner LH et al (2010) Erufosine, a novel alkylphosphocholine, induces apoptosis in CLL through a caspase-dependent pathway. Leuk Res 34:1064–1069

    Article  Google Scholar 

  29. Avsar Abdik E, Kaleagasioglu F, Abdik H et al (2019) ABT-737 and erufosine combination against castration-resistant prostate cancer: a promising but cell-type specific response associated with the modulation of anti-apoptotic signaling. Anticancer Drugs 30:383–393

    Article  CAS  Google Scholar 

  30. Bade BC, Dela Cruz CS (2020) Lung cancer 2020: epidemiology, etiology, and prevention. Clin Chest Med 41:1–24. https://doi.org/10.1016/j.ccm.2019.10.001

    Article  PubMed  Google Scholar 

  31. Subramanian J, Regenbogen T, Nagaraj G et al (2013) Review of ongoing clinical trials in non-small-cell lung cancer: a status report for 2012 from the ClinicalTrials.gov Web site. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 8:860–865. https://doi.org/10.1097/JTO.0b013e318287c562

    Article  Google Scholar 

  32. Semenova E, Böttger F, Song JY et al (2018) PO-338 Tumour heterogeneity underlies differential cisplatin sensitivity in mouse models of SCLC. ESMO Open 3:A360–A361

    Article  Google Scholar 

  33. Sarvi S, Mackinnon AC, Avlonitis N et al (2014) CD133+ cancer stem-like cells in small cell lung cancer are highly tumorigenic and chemoresistant but sensitive to a novel neuropeptide antagonist. Cancer Res 74:1554–1565

    Article  CAS  Google Scholar 

  34. Thomas A, Chen Y, Yu T et al (2015) Trends and characteristics of young non-small cell lung cancer patients in the United States. Front Oncol 5:113. https://doi.org/10.3389/fonc.2015.00113

    Article  PubMed  PubMed Central  Google Scholar 

  35. Dela Cruz CS, Tanoue LT, Matthay RA (2011) Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med 32:605–644. https://doi.org/10.1016/j.ccm.2011.09.001

    Article  PubMed  Google Scholar 

  36. Islam KMM, Jiang X, Anggondowati T et al (2015) Comorbidity and survival in lung cancer patients. Cancer Epidemiol Biomark Prev 24:1079–1085. https://doi.org/10.1158/1055-9965.EPI-15-0036

    Article  Google Scholar 

  37. Qu Q, Jiang S, Li X (2020) LncRNA TBX5-AS1 regulates the tumor progression through the PI3K/AKT pathway in non-small cell lung cancer. Onco Targets Ther 13:7949

    Article  CAS  Google Scholar 

  38. Sabari JK, Lok BH, Laird JH et al (2017) Unravelling the biology of SCLC: implications for therapy. Nat Rev Clin Oncol 14:549–561

    Article  CAS  Google Scholar 

  39. Fiegl M, Lindner LH, Juergens M et al (2008) Erufosine, a novel alkylphosphocholine, in acute myeloid leukemia: single activity and combination with other antileukemic drugs. Cancer Chemother Pharmacol 62:321–329

    Article  CAS  Google Scholar 

  40. Lemeshko VV, Kugler W (2007) Synergistic inhibition of mitochondrial respiration by anticancer agent erucylphosphohomocholine and cyclosporin A. J Biol Chem 282:37303–37307

    Article  CAS  Google Scholar 

  41. Kapoor V, Zaharieva MM, Das SN, Berger MR (2012) Erufosine simultaneously induces apoptosis and autophagy by modulating the Akt–mTOR signaling pathway in oral squamous cell carcinoma. Cancer Lett 319:39–48

    Article  CAS  Google Scholar 

  42. Pervaiz A, Akhtar MS, Mahmood S, et al (2018) Molecular basis of cell cycle arrest induced by erufosine in metastatic breast cancer cells.

  43. Steelman LS, Navolanic PM, Sokolosky ML et al (2008) Suppression of PTEN function increases breast cancer chemotherapeutic drug resistance while conferring sensitivity to mTOR inhibitors. Oncogene 27:4086–4095

    Article  CAS  Google Scholar 

  44. Sinnberg T, Lasithiotakis K, Niessner H et al (2009) Inhibition of PI3K-AKT-mTOR signaling sensitizes melanoma cells to cisplatin and temozolomide. J Invest Dermatol 129:1500–1515. https://doi.org/10.1038/jid.2008.379

    Article  CAS  PubMed  Google Scholar 

  45. Matsuoka T, Yashiro M (2014) The role of PI3K/Akt/mTOR signaling in gastric carcinoma. Cancers (Basel) 6:1441–1463. https://doi.org/10.3390/cancers6031441

    Article  CAS  Google Scholar 

  46. Barrett D, Brown VI, Grupp SA, Teachey DT (2012) Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies. Pediatr Drugs 14:299–316

    Google Scholar 

  47. Li X, Li C, Guo C, et al (2021) PI3K/Akt/mTOR signaling orchestrates the phenotypic transition and chemoresistance of small cell lung cancer. J Genet Genomics. https://doi.org/10.1016/j.jgg.2021.04.001

  48. Wu L, Yang W, Zhang S, Lu J (2015) Alpinetin inhibits lung cancer progression and elevates sensitization drug-resistant lung cancer cells to cis-diammined dichloridoplatium. Drug Des Devel Ther 9:6119

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Fulda S, Debatin K-M (2013) Caspase activation in cancer therapy. In: Madame curie bioscience database. Landes bioscience

  50. Ansari SS, Akgün N, Berger MR (2017) Erufosine increases RhoB expression in oral squamous carcinoma cells independent of its tumor suppressive mode of action - a short report. Cell Oncol 40:89–96. https://doi.org/10.1007/s13402-016-0302-8

    Article  CAS  Google Scholar 

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Acknowledgements

This study was funded by Yeditepe University. The author thanks to Prof. Fikrettin Şahin for providing laboratory facilities and Prof. Ferda Kaleagasıoglu and Prof. Martin Berger for providing Erufosine.

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Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Istanbul Sabahattin Zaim University, Istanbul, Turkey

    Hüseyin Abdik

  2. Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, Istanbul, Turkey

    Hüseyin Abdik

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HA: Investigation, Methodology, Validation, Visualization, Writing—original draft.

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Abdik, H. Antineoplastic effects of erufosine on small cell and non-small cell lung cancer cells through induction of apoptosis and cell cycle arrest. Mol Biol Rep 49, 2963–2971 (2022). https://doi.org/10.1007/s11033-022-07117-6

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  • DOI: https://doi.org/10.1007/s11033-022-07117-6

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