Newly synthesized podophyllotoxin derivative, LJ12, induces apoptosis and mitotic catastrophe in non-small cell lung cancer cells in vitro

Hui,Ling; Sang,Chunyan; Wang,Donghong; Wang,Xiaohui; Wang,Meiliang; Jia,Qinghua; Ma,Mingren; Chen,Shiwu

doi:10.3892/mmr.2015.4561

Newly synthesized podophyllotoxin derivative, LJ12, induces apoptosis and mitotic catastrophe in non-small cell lung cancer cells in vitro

Authors:
- Ling Hui
- Chunyan Sang
- Donghong Wang
- Xiaohui Wang
- Meiliang Wang
- Qinghua Jia
- Mingren Ma
- Shiwu Chen
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Affiliations: Experimental Center of Medicine, General Hospital of Lanzhou Military Area Command, Lanzhou, Gansu 730050, P.R. China, School of Pharmacy, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
Published online on: November 12, 2015 https://doi.org/10.3892/mmr.2015.4561
Pages: 339-346

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Abstract

Deoxypodophyllotoxin (DPT), an active compound isolated from a number of herbs and used in traditional medicine, has been reported to exhibit promising anti‑tumor activity. A newly synthesized derivative, N-(1-oxyl‑4'-demethyl-4-deoxyp odophyllic)-L‑methine-4'-piperazine carbamate (LJ12) may have improved antitumor activity and fewer side effects. The present study assessed the effect of LJ12 on cell viability, apoptosis, cell cycle distribution and mitotic catastrophe in A549 human lung cancer cells in vitro. The molecular mechanisms underlying the antitumor activity of LJ12 were also examined. The results demonstrated that LJ12 reduced A549 cell viability in a time‑ and dose‑dependent manner, with a lower half maximal inhibitory concentration of ~0.1 µM, compared with another known DPT derivative, etoposide (10 µM). Flow cytometric analysis showed that LJ12 induced tumor cell arrest at the G2/M phase of the cell cycle. The present study also observed an expected concomitant decrease in the numbers of cells cells in the G0/G1 and S phases. LJ12 was found to upregulate the protein expression levels of Cdc2 and Cyclin B1. Furthermore, LJ12 induced tumor cell apoptosis and the protein expression of B cell lymphoma‑2‑associated X protein, caspase‑3 and p53. The present study also observed the formation of giant, multinucleated cells, indicating that LJ12 induced mitotic catastrophe in the tumor cells. These results indicated that LJ12 has anti‑non‑small cell lung cancer activity in vitro. Further investigations aim to develop LJ12 as a therapeutic agent for the treatment of lung cancer.

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