Open Access

Pterostilbene modulates the suppression of multidrug resistance protein 1 and triggers autophagic and apoptotic mechanisms in cisplatin-resistant human oral cancer CAR cells via AKT signaling

  • Authors:
    • Hui-Ping Chang
    • Chi-Cheng Lu
    • Jo-Hua Chiang
    • Fuu-Jen Tsai
    • Yu-Ning Juan
    • Je-Wei Tsao
    • Hong-Yi Chiu
    • Jai-Sing Yang
  • View Affiliations

  • Published online on: March 2, 2018     https://doi.org/10.3892/ijo.2018.4298
  • Pages: 1504-1514
  • Copyright: © Chang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pterostilbene is a natural polyphenolic compound that is primarily found in fruits, such as blueberries and has a similar structure to resveratrol. Pterostilbene exhibits antioxidant, anti-inflammatory and antitumor activity but the effects of pterostilbene on drug-resistant oral cancer cells and its underlying mechanisms of action have not yet been explored. Therefore, the present study was performed to clarify the anticancer effects of pterostilbene on cisplatin-resistant human oral cancer CAR cells. The results demonstrated that CAR cells exhibited marked shrinkage, cell membrane breakage and autophagic vacuole formation following treatment with pterostilbene. Pterostilbene also effectively inhibited cell viability and suppressed cell confluence in a time- and concentration-dependent manner. Probing with acridine orange, monodansylcadaverine and LysoTracker Red demonstrated that the number of acidic vesicular organelles was increased, indicating increased autophagy. Furthermore, Heochst 33342 staining determined that DNA condensation, a characteristic of apoptosis, was enhanced following treatment with pterostilbene. Furthermore, pterostilbene upregulated mRNA levels of LC3-II and Atg12, as well as the expression of Atgs/Beclin-1/LC3-associated signaling, suggesting that it enhances autophagy. The autophagy inhibitors 3-methyladenine and chloroquine were used to confirm that pterostilbene induces autophagy. It was also determined that pterostilbene triggered caspase-dependent apoptosis by directly testing DNA breakage and using the pan-caspase inhibitor carbobenzoxyvalyl-alanyl-aspartyl fluoromethyl ketone. The results demonstrated that pterostilbene mediates the apoptosis of CAR cells via the intrinsic apoptotic cascade. In addition, pterostilbene inhibited MDR1 expression and the phosphorylation of AKT on the Ser473 site in CAR cells. Therefore, pterostilbene may elicit an oral anticancer response in drug-resistant cells and may be used as a chemotherapeutic adjuvant to treat patients with oral cancer.
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May-2018
Volume 52 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Chang H, Lu C, Chiang J, Tsai F, Juan Y, Tsao J, Chiu H and Yang J: Pterostilbene modulates the suppression of multidrug resistance protein 1 and triggers autophagic and apoptotic mechanisms in cisplatin-resistant human oral cancer CAR cells via AKT signaling. Int J Oncol 52: 1504-1514, 2018.
APA
Chang, H., Lu, C., Chiang, J., Tsai, F., Juan, Y., Tsao, J. ... Yang, J. (2018). Pterostilbene modulates the suppression of multidrug resistance protein 1 and triggers autophagic and apoptotic mechanisms in cisplatin-resistant human oral cancer CAR cells via AKT signaling. International Journal of Oncology, 52, 1504-1514. https://doi.org/10.3892/ijo.2018.4298
MLA
Chang, H., Lu, C., Chiang, J., Tsai, F., Juan, Y., Tsao, J., Chiu, H., Yang, J."Pterostilbene modulates the suppression of multidrug resistance protein 1 and triggers autophagic and apoptotic mechanisms in cisplatin-resistant human oral cancer CAR cells via AKT signaling". International Journal of Oncology 52.5 (2018): 1504-1514.
Chicago
Chang, H., Lu, C., Chiang, J., Tsai, F., Juan, Y., Tsao, J., Chiu, H., Yang, J."Pterostilbene modulates the suppression of multidrug resistance protein 1 and triggers autophagic and apoptotic mechanisms in cisplatin-resistant human oral cancer CAR cells via AKT signaling". International Journal of Oncology 52, no. 5 (2018): 1504-1514. https://doi.org/10.3892/ijo.2018.4298