Skip to main content

Advertisement

SpringerLink
Log in

Aloperine in combination with therapeutic adenoviral vector synergistically suppressed the growth of non-small cell lung cancer

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and ranked top in terms of incidence and mortality in men and women. Recently, improvements in treatment approaches for NSCLC have reported, but still, there is a need to devise innovative treatment strategies, especially to manage the advanced and metastatic stage of NSCLC. Aloperine (ALO), an herbal alkaloid, has exerted anti-cancer effects in many cancers. However, the use of any chemotherapeutic agents is dose limited due to possible adverse effects and drug-resistance issues. Therefore, a combination of chemotherapy with viral-based targeted gene therapy may provide a novel treatment strategy for NSCLC.

Methods/results

In this study, the results of the MTT and flow cytometry-based assays showed that Aloperine–Adbic (adenoviral vector expressing p14ARF/p53) combined treatment on NSCLC cells synergistically produced anti-proliferative effects, induced apoptosis, and arrested cell cycle at the G1 phase. Furthermore, the expression analysis suggested that the p53/p21 pathway might contribute to achieving aforesaid cytotoxic effects. The ALO–Adbic combined treatment prolonged the percent survival of NSCLC xenograft models.

Conclusion

In conclusion, ALO–Adbic combination can produce synergistic anti-cancer effects at low doses, and may offer a more effective and less toxic new treatment strategy for NSCLC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Availability of data and material

The data sets used and/or analyzed following standard procedures during the current study and are available from the corresponding author on reasonable request.

References

  • Andrews P, Howell S (1990) Cellular pharmacology of cisplatin: perspectives on mechanisms of acquired resistance. Cancer Cells (Cold Spring Harbor, NY: 1989) 2:35–43.

  • Bates S, Phillips AC, Clark PA, Stott F, Peters G, Ludwig RL, Vousden KH (1998) p14 ARF links the tumour suppressors RB and p53. Nature 395:124

    Article  CAS  PubMed  Google Scholar 

  • Brennen WN, Chen S, Denmeade SR, Isaacs JT (2013) Quantification of mesenchymal stem cells (MSCs) at sites of human prostate cancer. Oncotarget 4:106

    Article  PubMed  Google Scholar 

  • Brennen WN et al (2017) Mesenchymal stem cell infiltration during neoplastic transformation of the human prostate. Oncotarget 8:46710

    Article  PubMed Central  PubMed  Google Scholar 

  • Chen S et al (2018) Aloperine induces apoptosis and inhibits invasion in MG-63 and U2OS human osteosarcoma cells. Biomed Pharmacother 97:45–52

    Article  CAS  PubMed  Google Scholar 

  • Chou T (1991) The median-effect principle and the combination index for quantitation of synergism and antagonism. Synerg Antagonism Chemother 1:61–102

    Google Scholar 

  • Chou T, Martin N (2005) A computer program for quantitation of synergism and antagonism in drug combinations, and the determination of IC50 and ED50 and LD50 values CompuSyn for Drug Combinations: PC Software and User’s Guide; ComboSyn: Paramus. NJ, USA

    Google Scholar 

  • de Stanchina E et al (1998) E1A signaling to p53 involves the p19ARFtumor suppressor. Genes Dev 12:2434–2442

    Article  PubMed Central  PubMed  Google Scholar 

  • Dulić V et al (1994) p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell 76:1013–1023

    Article  PubMed  Google Scholar 

  • Ferlay J et al (2012) (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN. Int J Cancer 136:E359–E386

    Article  CAS  Google Scholar 

  • Gately D, Howell S (1993) Cellular accumulation of the anticancer agent cisplatin: a review. Br J Cancer 67:1171

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Greenblatt M, Bennett WP, Hollstein M, Harris C (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54:4855–4878

    CAS  PubMed  Google Scholar 

  • Herbst RS, Morgensztern D, Boshoff C (2018) The biology and management of non-small cell lung cancer. Nature 553:446

    Article  CAS  PubMed  Google Scholar 

  • Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53

    Article  CAS  PubMed  Google Scholar 

  • Honda R, Yasuda H (1999) Association of p19ARF with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J 18:22–27

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Huang W-S et al (2017) CIL-102-induced cell cycle arrest and apoptosis in colorectal cancer cells via upregulation of p21 and GADD45. PLoS ONE 12:e0168989

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Huang Y, Tyler T, Saadatmandi N, Lee C, Borgstrom P, Gjerset RA (2003) Enhanced tumor suppression by a p14ARF/p53 bicistronic adenovirus through increased p53 protein translation and stability. Cancer Res 63:3646–3653

    CAS  PubMed  Google Scholar 

  • Jemal A et al (2018) Higher lung cancer incidence in young women than young men in the United States. N Engl J Med 378:1999–2009

    Article  PubMed  PubMed Central  Google Scholar 

  • Kallel H, Kamen AA (2015) Large-scale adenovirus and poxvirus-vectored vaccine manufacturing to enable clinical trials. Biotechnol J 10:741–747

    Article  CAS  PubMed  Google Scholar 

  • Kannan K et al (2000) The p16INK4alpha/p19ARF gene mutations are infrequent and are mutually exclusive to p53 mutations in Indian oral squamous cell carcinomas. Int J Oncol 16:585–675

    CAS  PubMed  Google Scholar 

  • Kelland L (2007) The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 7:573

    Article  CAS  PubMed  Google Scholar 

  • Kim MS et al (2014) Naproxen induces cell-cycle arrest and apoptosis in human urinary bladder cancer cell lines and chemically induced cancers by targeting PI3K. Cancer Prev Res 7:236–245

    Article  CAS  Google Scholar 

  • Lee Y-R, Chen S-H, Lin C-Y, Chao W-Y, Lim Y-P, Yu H-I, Lu C-H (2018) Vitro antitumor activity of aloperine on human thyroid cancer cells through caspase-dependent apoptosis. Int J Mol Sci 19:312

    Article  PubMed Central  CAS  Google Scholar 

  • Liang L, Wang X-Y, Zhang X-H, Ji B, Yan H-C, Deng H-Z, Wu X-R (2012) Sophoridine exerts an anti-colorectal carcinoma effect through apoptosis induction in vitro and in vivo. Life Sci 91:1295–1303

    Article  CAS  PubMed  Google Scholar 

  • Ling Z et al (2018) Aloperine executes antitumor effects through the induction of apoptosis and cell cycle arrest in prostate cancer in vitro and in vivo. OncoTargets Ther 11:2735

    Article  Google Scholar 

  • Liu J-S et al (2019) Aloperine induces apoptosis and G2/M cell cycle arrest in hepatocellular carcinoma cells through the PI3K/Akt signaling pathway. Phytomedicine 61:152843

    Article  CAS  PubMed  Google Scholar 

  • Maher A, Miake-Lye I, Beroes J, Shekelle P (2012) Treatment of metastatic non-small cell lung cancer: a systematic review of comparative effectiveness and cost-effectiveness

  • Miller KD et al (2016) Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 66:271–289

    Article  PubMed  Google Scholar 

  • Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. In: Mayo clinic proceedings, 2008, vol 5. Elsevier, pp 584–594

  • Muhammad T, Sakhawat A, Khan AA, Ma L, Gjerset RA, Huang Y (2019) Mesenchymal stem cell-mediated delivery of therapeutic adenoviral vectors to prostate cancer. Stem Cell Res Ther 10:190

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Muthana M et al (2011) Use of macrophages to target therapeutic adenovirus to human prostate tumors. Can Res 71:1805–1815

    Article  CAS  Google Scholar 

  • Myers TJ, Granero-Molto F, Longobardi L, Li T, Yan Y, Spagnoli A (2010) Mesenchymal stem cells at the intersection of cell and gene therapy. Expert Opin Biol Ther 10:1663–1679

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Palmero I, Pantoja C, Serrano M (1998) p19 ARF links the tumour suppressor p53 to Ras. Nature 395:125

    Article  CAS  PubMed  Google Scholar 

  • Pinyol M et al (2000) INK4a/ARFLocus alterations in human non-Hodgkin's lymphomas mainly occur in tumors with wild-type p53 gene. Am J Pathol 156:1987–1996

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Planas-Silva MD, Weinberg RA (1997) The restriction point and control of cell proliferation. Curr Opin Cell Biol 9:768–772

    Article  CAS  PubMed  Google Scholar 

  • Ramalingam S, Belani C (2008) Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions. Oncologist 13:5–13

    Article  CAS  PubMed  Google Scholar 

  • Sakhawat A, Liu Y, Ling Ma TM, Wang S, Zhang L, Cong X, Huang Y (2017) Upregulation of Coxsackie adenovirus receptor sensitizes cisplatin-resistant lung cancer cells to CRAd-induced inhibition. J Cancer 8:1425

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Sarkar D, Vemula PK, Zhao W, Gupta A, Karnik R, Karp JM (2010) Engineered mesenchymal stem cells with self-assembled vesicles for systemic cell targeting. Biomaterials 31:5266–5274

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Schweizer MT et al (2019) A phase I study to assess the safety and cancer-homing ability of allogeneic bone marrow-derived mesenchymal stem cells in men with localized prostate cancer. Stem Cells Trans Med 8:441–449

    Article  CAS  Google Scholar 

  • Serakinci N, Cagsin H (2019a) Programming hMSCs into potential genetic therapy in cancer critical reviews™ in eukaryotic gene expression 29

  • Serakinci N, Cagsin H (2019b) Turning stem cells homing potential into cancer specific drug delivery machines. Ann Transl Med 7

  • Song X-l et al (2017) Casticin induces apoptosis and G0/G1 cell cycle arrest in gallbladder cancer cells. Cancer Cell Int 17:9

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Spiro SG, Porter JC (2002) Lung cancer—where are we today? Current advances in staging and nonsurgical treatment. Am J Respir Crit Care Med 166:1166–1196

    Article  PubMed  Google Scholar 

  • Thomas A, Liu SV, Subramaniam DS, Giaccone G (2015) Refining the treatment of NSCLC according to histological and molecular subtypes. Nat Rev Clin Oncol 12:511

    Article  CAS  PubMed  Google Scholar 

  • Tian D, Li Y, Li X, Tian Z (2018) Aloperine inhibits proliferation, migration and invasion and induces apoptosis by blocking the Ras signaling pathway in human breast cancer cells. Mol Med Rep 18:3699–3710

    CAS  PubMed Central  PubMed  Google Scholar 

  • Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108

    Article  PubMed  Google Scholar 

  • Torre LA, Sauer AMG, Chen MS Jr, Kagawa-Singer M, Jemal A (2016) Siegel RL (2016) Cancer statistics for Asian Americans, Native Hawaiians, and Pacific Islanders converging incidence in males and females CA. Cancer J Clin 66:182–202

    Article  Google Scholar 

  • Wang H, Guo S, Qian D, Qian Y, Duan JA (2012) Comparative analysis of quinolizidine alkaloids from different parts of Sophora alopecuroides seeds by UPLC–MS/MS. J Pharmaceut Biomed Anal 67:16–21

    Article  CAS  Google Scholar 

  • Wang H et al (2015) Aloperine executes antitumor effects against multiple myeloma through dual apoptotic mechanisms. J Hematol Oncol 8:26

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Williams GH, Stoeber K (2012) The cell cycle and cancer. J Pathol 226:352–364

    Article  CAS  PubMed  Google Scholar 

  • Wu X, Bayle JH, Olson D, Levine AJ (1993) The p53-mdm-2 autoregulatory feedback loop. Genes Dev 7:1126–1132

    Article  CAS  PubMed  Google Scholar 

  • Xu Z et al. (2017) Reducing autophagy and inducing G1 phase arrest by aloperine enhances radio-sensitivity in lung cancer cells. Oncol Rep

  • Yuan X-Y, Liu W, Zhang P, Wang R-Y, Guo J-Y (2010) Effects and mechanisms of aloperine on 2, 4-dinitrofluorobenzene-induced allergic contact dermatitis in BALB/c mice. Eur J Pharmacol 629:147–152

    Article  CAS  PubMed  Google Scholar 

  • Zhang L et al (2001) Effects of matrine on proliferation and differentiation in K-562 cells. Leukemia Res 25:793–800

    Article  CAS  Google Scholar 

  • Zhang Z et al (2012) Effects of matrine on proliferation and apoptosis in gallbladder carcinoma cells (GBC-SD). Phytother Res 26:932–937

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Jiang J, Tan R (1998) Effects of matrine on telomerase activity and cell cycle in K562 cell. Chin J Oncol 20:328–329

    CAS  Google Scholar 

  • Zhang L, Zheng Y, Deng H, Liang L, Peng J (2014) Aloperine induces G2/M phase cell cycle arrest and apoptosis in HCT116 human colon cancer cells. Int J Mol Med 33:1613–1620

    Article  PubMed  CAS  Google Scholar 

  • Zhou C, Gao H, Sun X, Shi H, Liu W, Yuan H, Wang Z (1989) Anti-inflammatory and anti-allergic action of aloperine. Acta Pharmacol Sin 10:360–365

    CAS  Google Scholar 

Download references

Acknowledgements

We are very thankful to Ming Zhao in Torrey Pines Institute for Molecular Studies for her technical assistance, and Beijing Inmay Future Biopharma Inc. to provide experimental materials.

Funding

This research was funded by National Natural Science Foundation OF China (Grant # 81472209) and Key Programs of Beijing Municipal Science and Technology Commission (Grant # K2015311201501).

Author information

Authors and Affiliations

  1. College of Life Sciences and Bio-Engineering, Beijing University of Technology, Beijing, 100022, China

    Tahir Muhammad, Aamir Ali Khan, Hua Huang, Yinghui Huang & Juan Wang

  2. Beijing Institute of Technology, Beijing, 100124, China

    Ali Sakhawat

  3. Quaid-I-Azam University, Islamabad, 44000, Pakistan

    Haroon Rashid Khan

Authors
  1. Tahir Muhammad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ali Sakhawat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aamir Ali Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hua Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haroon Rashid Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yinghui Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Juan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TM and AS contributed in designing and conducting experiments in this study. KAA also performed experiments. HH and HRK assisted in data analysis and manuscript writing. WJ and YH overall supervised the research work.

Corresponding author

Correspondence to Juan Wang.

Ethics declarations

Conflict of interest

Authors declared no conflict of interest.

Ethical approval

Study was approved by ethical committee of Beijing University of Technology (approval number IRB-1507).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file 1 (DOCX 991 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Muhammad, T., Sakhawat, A., Khan, A.A. et al. Aloperine in combination with therapeutic adenoviral vector synergistically suppressed the growth of non-small cell lung cancer. J Cancer Res Clin Oncol 146, 861–874 (2020). https://doi.org/10.1007/s00432-020-03157-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-020-03157-2

Keywords

Search

Navigation