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J Cancer. 2018 Jan 1;9(1):117-128. doi: 10.7150/jca.21965. eCollection 2018.

Antitumor Activity and Mechanism of a Reverse Transcriptase Inhibitor, Dapivirine, in Glioblastoma.

Liu W1, Song XL2, Zhao SC3, He M4, Wang H5,6, Chen Z5,6, Xiang W5,6, Yi G5,6, Qi S5,6, Liu Y5,6.

Author information

1
First College of Clinical Medicine, Southern Medical University, Guangzhou 510515, China.
2
Department of Radiotherapy, Guangzhou Medical University Cancer Institute and Hospital, Guangzhou 510095, China.
3
Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
4
Center for Clinical Medical Education, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
5
Department of Neurosurgery, Nanfang hospital, Southern Medical University, Guangzhou 510515, China.
6
Laboratory for Precision Neurosurgery, Nanfang hospital, Southern Medical University, Guangzhou 510515, China.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:

Dapivirine is one of reverse transcriptase inhibitors (RTIs). It is the prototype of diarylpyrimidines (DAPY), formerly known as TMC120 or DAPY R147681 (IUPAC name: 4- [[4-(2, 4, 6-trimethylphenyl) amino]-2-pyrimidinyl] amino]-benzonitrile; CAS no.244767-67-7).

AIM:

The purpose of this study is to investigate the antitumor activity of dapivirine, one of the RTIs, on U87 glioblastoma (GBM) cells in vitro and in vivo.

MATERIALS AND METHODS:

U87 GBM cells were cultured and treated with or without dapivirine. Cell viability was evaluated by CCK-8 (Cell Counting Kit 8, CCK-8) assay; apoptosis was analyzed by flow cytometry; cell migration was evaluated by Boyden Chamber assay; Western blotting was performed to detect proteins related to apoptosis, epithelial-to-mesenchymal transition and autophagy. PathScan intracellular signaling array kit was used to detect important and well-characterized signaling molecules. Tumor xenograft model in nude mice was used to evaluate the antitumorigenic effect in vivo.

RESULTS:

Dapivirine weakened proliferation of glioma cells and induced the apoptosis of U87 glioblastoma cells. Furthermore, dapivirine regulated autophagy and induced Akt, Bad and SAPK/JNK activations. Moreover, the inhibition of glioma cell growth by dapivirine was also observed in nude mice in vivo.

CONCLUSION:

In summary, in our study dapivirine exposure induces stress, resulting in JNK and PI3K/Akt pathway activation through diminished inhibition of the apoptosis and autophagy cascade in U87 GBM cells, which inhibits cell growth in vitro and in vivo.

KEYWORDS:

Antitumor activity; Autophagy; Dapivirine; Drug metabolism; Glioblastoma

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

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