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Podophyllotoxin acetate triggers anticancer effects against non-small cell lung cancer cells by promoting cell death via cell cycle arrest, ER stress and autophagy

  • Authors:
    • Jae Yeon Choi
    • Wan Gi Hong
    • Jeong Hyun Cho
    • Eun Mi Kim
    • Jongdoo Kim
    • Chan-Hun Jung
    • Sang-Gu Hwang
    • Hong-Duck Um
    • Jong Kuk Park
  • View Affiliations / Copyright

    Affiliations: Department of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
    Copyright: © Choi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1257-1265
    |
    Published online on: August 13, 2015
       https://doi.org/10.3892/ijo.2015.3123
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Abstract

We previously reported that podophyllotoxin acetate (PA) radiosensitizes NCI-H460 cells. Here, we confirmed that PA treatment also induces cell death among two other non-small cell lung cancer (NSCLC) cell lines: NCI-H1299 and A549 cells (IC50 values = 7.6 and 16.1 nM, respectively). Our experiments further showed that PA treatment was able to induce cell death via various mechanisms. First, PA dose-dependently induced cell cycle arrest at G2/M phase, as shown by accumulation of the mitosis-related proteins, p21, survivin and Aurora B. This G2/M phase arrest was due to the PA-induced inhibition of microtubule polymerization. Together, the decreased microtubule polymerization and increased cell cycle arrest induced DNA damage (reflected by accumulation of γ-H2AX) and triggered the induction of intrinsic and extrinsic apoptotic pathways, as shown by the time-dependent activations of caspase-3, -8 and -9. Second, PA time-dependently activated the pro-apoptotic ER stress pathway, as evidenced by increased expression levels of BiP, CHOP, IRE1-α, phospho-PERK, and phospho-JNK. Third, PA activated autophagy, as reflected by time-dependent increases in the expression levels of beclin-1, Atg3, Atg5 and Atg7, and the cleavage of LC3. Collectively, these results suggest a model wherein PA decreases microtubule polymerization and increases cell cycle arrest, thereby inducing apoptotic cell death via the activation of DNA damage, ER stress and autophagy.
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View References

1 

Cragg GM, Grothaus PG and Newman DJ: Impact of natural products on developing new anti-cancer agents. Chem Rev. 109:3012–3043. 2009. View Article : Google Scholar : PubMed/NCBI

2 

Gordaliza M, García PA, del Corral JM, Castro MA and Gómez-Zurita MA: Podophyllotoxin: Distribution, sources, applications and new cytotoxic derivatives. Toxicon. 44:441–459. 2004. View Article : Google Scholar : PubMed/NCBI

3 

Guerram M, Jiang Z-Z and Zhang L-Y: Podophyllotoxin, a medicinal agent of plant origin: Past, present and future. Chin J Nat Med. 10:161–169. 2012. View Article : Google Scholar

4 

Choi JY, Cho HJ, Hwang SG, Kim WJ, Kim JI, Um HD and Park JK: Podophyllotoxin acetate enhances γ-ionizing radiation-induced apoptotic cell death by stimulating the ROS/p38/caspase pathway. Biomed Pharmacother. 70:111–118. 2015. View Article : Google Scholar : PubMed/NCBI

5 

Kuo CC, Hsieh HP, Pan WY, Chen CP, Liou JP, Lee SJ, Chang YL, Chen LT, Chen CT and Chang JY: BPR0L075, a novel synthetic indole compound with antimitotic activity in human cancer cells, exerts effective antitumoral activity in vivo. Cancer Res. 64:4621–4628. 2004. View Article : Google Scholar : PubMed/NCBI

6 

Park JK, Jung HY, Park SH, Kang SY, Yi MR, Um HD and Hong SH: Combination of PTEN and gamma-ionizing radiation enhances cell death and G(2)/M arrest through regulation of AKT activity and p21 induction in non-small-cell lung cancer cells. Int J Radiat Oncol Biol Phys. 70:1552–1560. 2008. View Article : Google Scholar : PubMed/NCBI

7 

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T and Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 58:71–96. 2008. View Article : Google Scholar : PubMed/NCBI

8 

Begg AC, Stewart FA and Vens C: Strategies to improve radio-therapy with targeted drugs. Nat Rev Cancer. 11:239–253. 2011. View Article : Google Scholar : PubMed/NCBI

9 

Tsai CM, Chang KT, Perng RP, Mitsudomi T, Chen MH, Kadoyama C and Gazdar AF: Correlation of intrinsic chemoresistance of non-small-cell lung cancer cell lines with HER-2/neu gene expression but not with ras gene mutations. J Natl Cancer Inst. 85:897–901. 1993. View Article : Google Scholar : PubMed/NCBI

10 

Xin Y, Yin F, Qi S, Shen L, Xu Y, Luo L, Lan L and Yin Z: Parthenolide reverses doxorubicin resistance in human lung carcinoma A549 cells by attenuating NF-κB activation and HSP70 up-regulation. Toxicol Lett. 221:73–82. 2013. View Article : Google Scholar : PubMed/NCBI

11 

Breen L, Heenan M, Amberger-Murphy V and Clynes M: Investigation of the role of p53 in chemotherapy resistance of lung cancer cell lines. Anticancer Res. 27A:1361–1364. 2007.

12 

Jung IL, Kang HJ, Kim KC and Kim IG: PTEN/pAkt/p53 signaling pathway correlates with the radioresponse of non-small cell lung cancer. Int J Mol Med. 25:517–523. 2010.PubMed/NCBI

13 

Jordan MA and Wilson L: Microtubules as a target for anticancer drugs. Nat Rev Cancer. 4:253–265. 2004. View Article : Google Scholar : PubMed/NCBI

14 

Montecucco A and Biamonti G: Cellular response to etoposide treatment. Cancer Lett. 252:9–18. 2007. View Article : Google Scholar

15 

Kaufmann SH: Cell death induced by topoisomerase-targeted drugs: More questions than answers. Biochim Biophys Acta. 1400:195–211. 1998. View Article : Google Scholar : PubMed/NCBI

16 

Elmore S: Apoptosis: A review of programmed cell death. Toxicol Pathol. 35:495–516. 2007. View Article : Google Scholar : PubMed/NCBI

17 

Bicknell AA, Babour A, Federovitch CM and Niwa M: A novel role in cytokinesis reveals a housekeeping function for the unfolded protein response. J Cell Biol. 177:1017–1027. 2007. View Article : Google Scholar : PubMed/NCBI

18 

Chen JY, Tang YA, Li WS, Chiou YC, Shieh JM and Wang YC: A synthetic podophyllotoxin derivative exerts anti-cancer effects by inducing mitotic arrest and pro-apoptotic ER stress in lung cancer preclinical models. PLoS One. 8:e620822013. View Article : Google Scholar : PubMed/NCBI

19 

Schröder M and Kaufman RJ: ER stress and the unfolded protein response. Mutat Res. 569:29–63. 2005. View Article : Google Scholar

20 

Gills JJ, Lopiccolo J and Dennis PA: Nelfinavir, a new anti-cancer drug with pleiotropic effects and many paths to autophagy. Autophagy. 4:107–109. 2008. View Article : Google Scholar

21 

Terés S, Lladó V, Higuera M, Barceló-Coblijn G, Martin ML, Noguera-Salvà MA, Marcilla-Etxenike A, García-Verdugo JM, Soriano-Navarro M, Saus C, et al: 2-Hydroxyoleate, a nontoxic membrane binding anticancer drug, induces glioma cell differentiation and autophagy. Proc Natl Acad Sci USA. 109:8489–8494. 2012. View Article : Google Scholar : PubMed/NCBI

22 

Galluzzi L, Pietrocola F, Levine B and Kroemer G: Metabolic control of autophagy. Cell. 159:1263–1276. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Yang ZJ, Chee CE, Huang S and Sinicrope FA: The role of autophagy in cancer: Therapeutic implications. Mol Cancer Ther. 10:1533–1541. 2011. View Article : Google Scholar : PubMed/NCBI

24 

Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K, Agholme L, Agnello M, Agostinis P, Aguirre-Ghiso JA, et al: Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 8:445–544. 2012. View Article : Google Scholar : PubMed/NCBI

25 

Yan CH, Yang YP, Qin ZH, Gu ZL, Reid P and Liang ZQ: Autophagy is involved in cytotoxic effects of crotoxin in human breast cancer cell line MCF-7 cells. Acta Pharmacol Sin. 28:540–548. 2007. View Article : Google Scholar : PubMed/NCBI

26 

Abedin MJ, Wang D, McDonnell MA, Lehmann U and Kelekar A: Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death Differ. 14:500–510. 2007. View Article : Google Scholar

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Copy and paste a formatted citation
Spandidos Publications style
Choi JY, Hong WG, Cho JH, Kim EM, Kim J, Jung C, Hwang S, Um H and Park JK: Podophyllotoxin acetate triggers anticancer effects against non-small cell lung cancer cells by promoting cell death via cell cycle arrest, ER stress and autophagy. Int J Oncol 47: 1257-1265, 2015.
APA
Choi, J.Y., Hong, W.G., Cho, J.H., Kim, E.M., Kim, J., Jung, C. ... Park, J.K. (2015). Podophyllotoxin acetate triggers anticancer effects against non-small cell lung cancer cells by promoting cell death via cell cycle arrest, ER stress and autophagy. International Journal of Oncology, 47, 1257-1265. https://doi.org/10.3892/ijo.2015.3123
MLA
Choi, J. Y., Hong, W. G., Cho, J. H., Kim, E. M., Kim, J., Jung, C., Hwang, S., Um, H., Park, J. K."Podophyllotoxin acetate triggers anticancer effects against non-small cell lung cancer cells by promoting cell death via cell cycle arrest, ER stress and autophagy". International Journal of Oncology 47.4 (2015): 1257-1265.
Chicago
Choi, J. Y., Hong, W. G., Cho, J. H., Kim, E. M., Kim, J., Jung, C., Hwang, S., Um, H., Park, J. K."Podophyllotoxin acetate triggers anticancer effects against non-small cell lung cancer cells by promoting cell death via cell cycle arrest, ER stress and autophagy". International Journal of Oncology 47, no. 4 (2015): 1257-1265. https://doi.org/10.3892/ijo.2015.3123
Copy and paste a formatted citation
x
Spandidos Publications style
Choi JY, Hong WG, Cho JH, Kim EM, Kim J, Jung C, Hwang S, Um H and Park JK: Podophyllotoxin acetate triggers anticancer effects against non-small cell lung cancer cells by promoting cell death via cell cycle arrest, ER stress and autophagy. Int J Oncol 47: 1257-1265, 2015.
APA
Choi, J.Y., Hong, W.G., Cho, J.H., Kim, E.M., Kim, J., Jung, C. ... Park, J.K. (2015). Podophyllotoxin acetate triggers anticancer effects against non-small cell lung cancer cells by promoting cell death via cell cycle arrest, ER stress and autophagy. International Journal of Oncology, 47, 1257-1265. https://doi.org/10.3892/ijo.2015.3123
MLA
Choi, J. Y., Hong, W. G., Cho, J. H., Kim, E. M., Kim, J., Jung, C., Hwang, S., Um, H., Park, J. K."Podophyllotoxin acetate triggers anticancer effects against non-small cell lung cancer cells by promoting cell death via cell cycle arrest, ER stress and autophagy". International Journal of Oncology 47.4 (2015): 1257-1265.
Chicago
Choi, J. Y., Hong, W. G., Cho, J. H., Kim, E. M., Kim, J., Jung, C., Hwang, S., Um, H., Park, J. K."Podophyllotoxin acetate triggers anticancer effects against non-small cell lung cancer cells by promoting cell death via cell cycle arrest, ER stress and autophagy". International Journal of Oncology 47, no. 4 (2015): 1257-1265. https://doi.org/10.3892/ijo.2015.3123
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