A novel anti-cancer role of β-apopicropodophyllin against non-small cell lung cancer cells

Ju Yeon Kim, Jeong Hyun Cho, Jong Ryoo Choi, Hyun Jin Shin, Jie Young Song, Sang Gu Hwang, Hong Duck Um, Young Do Yoo, Joon Kim, Jong Kuk Park

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

We previously reported that podophyllotoxin acetate (PA) inhibits the growth and proliferation of non-small cell lung cancer (NSCLC) cells and also makes them more sensitive to radiation and chemotherapeutic agents. In an attempt to enhance PA activity, we synthesized 34 derivatives based on podophyllotoxin (PPT). Screening of the derivative compounds for anti-cancer activity against NSCLC led to the identification of β-apopicropodophyllin (APP) as a strong anti-cancer agent. In addition to its role as an immunosuppressive regulator of the T-cell mediated immune response, the compound additionally showed anti-cancer activity against A549, NCI-H1299 and NCI-460 cell lines with IC50 values of 16.9, 13.1 and 17.1 nM, respectively. The intracellular mechanisms underlying the effects of APP were additionally examined. APP treatment caused disruption of microtubule polymerization and DNA damage, which led to cell cycle arrest, as evident from accumulation of phospho-CHK2, p21, and phospho-Cdc2. Moreover, APP stimulated the pro-apoptotic ER stress signaling pathway, indicated by elevated levels of BiP, phospho-PERK, phospho-eIF2α CHOP and ATF4. We further observed activation of caspase-3, -8 and -9, providing evidence that both intrinsic and extrinsic apoptotic pathways were triggered. In vivo, APP inhibited tumor growth of NSCLC xenografts in nude mice by promoting apoptosis. Our results collectively support a novel role of APP as an anticancer agent that evokes apoptosis by inducing microtubule disruption, DNA damage, cell cycle arrest and ER stress.

Original languageEnglish
Pages (from-to)39-49
Number of pages11
JournalToxicology and Applied Pharmacology
Volume357
DOIs
Publication statusPublished - 2018 Oct 15

Fingerprint

Podophyllotoxin
Non-Small Cell Lung Carcinoma
Cells
Cell Cycle Checkpoints
Microtubules
DNA Damage
Neoplasms
Acetates
Apoptosis
Caspase 8
Immunosuppressive Agents
Growth
Heterografts
Nude Mice
Caspase 3
Polymerization
Antineoplastic Agents
Inhibitory Concentration 50
Derivatives
T-cells

Keywords

  • Anti-cancer drug
  • Drug repositioning
  • Non-small cell lung cancer cells
  • Podophyllotoxin derivatives
  • β-apopicropodophyllin

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Kim, J. Y., Cho, J. H., Choi, J. R., Shin, H. J., Song, J. Y., Hwang, S. G., ... Park, J. K. (2018). A novel anti-cancer role of β-apopicropodophyllin against non-small cell lung cancer cells. Toxicology and Applied Pharmacology, 357, 39-49. https://doi.org/10.1016/j.taap.2018.08.022

A novel anti-cancer role of β-apopicropodophyllin against non-small cell lung cancer cells. / Kim, Ju Yeon; Cho, Jeong Hyun; Choi, Jong Ryoo; Shin, Hyun Jin; Song, Jie Young; Hwang, Sang Gu; Um, Hong Duck; Yoo, Young Do; Kim, Joon; Park, Jong Kuk.

In: Toxicology and Applied Pharmacology, Vol. 357, 15.10.2018, p. 39-49.

Research output: Contribution to journalArticle

Kim, Ju Yeon ; Cho, Jeong Hyun ; Choi, Jong Ryoo ; Shin, Hyun Jin ; Song, Jie Young ; Hwang, Sang Gu ; Um, Hong Duck ; Yoo, Young Do ; Kim, Joon ; Park, Jong Kuk. / A novel anti-cancer role of β-apopicropodophyllin against non-small cell lung cancer cells. In: Toxicology and Applied Pharmacology. 2018 ; Vol. 357. pp. 39-49.
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abstract = "We previously reported that podophyllotoxin acetate (PA) inhibits the growth and proliferation of non-small cell lung cancer (NSCLC) cells and also makes them more sensitive to radiation and chemotherapeutic agents. In an attempt to enhance PA activity, we synthesized 34 derivatives based on podophyllotoxin (PPT). Screening of the derivative compounds for anti-cancer activity against NSCLC led to the identification of β-apopicropodophyllin (APP) as a strong anti-cancer agent. In addition to its role as an immunosuppressive regulator of the T-cell mediated immune response, the compound additionally showed anti-cancer activity against A549, NCI-H1299 and NCI-460 cell lines with IC50 values of 16.9, 13.1 and 17.1 nM, respectively. The intracellular mechanisms underlying the effects of APP were additionally examined. APP treatment caused disruption of microtubule polymerization and DNA damage, which led to cell cycle arrest, as evident from accumulation of phospho-CHK2, p21, and phospho-Cdc2. Moreover, APP stimulated the pro-apoptotic ER stress signaling pathway, indicated by elevated levels of BiP, phospho-PERK, phospho-eIF2α CHOP and ATF4. We further observed activation of caspase-3, -8 and -9, providing evidence that both intrinsic and extrinsic apoptotic pathways were triggered. In vivo, APP inhibited tumor growth of NSCLC xenografts in nude mice by promoting apoptosis. Our results collectively support a novel role of APP as an anticancer agent that evokes apoptosis by inducing microtubule disruption, DNA damage, cell cycle arrest and ER stress.",
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