Antitumor Activity and Mechanism of a Reverse Transcriptase Inhibitor, Dapivirine, in Glioblastoma
- J Cancer. 2018 Jan 1;9(1):117-128. doi: 10.7150/jca.21965.
- 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.
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.