Open Access
ARTICLE
Nelfinavir and Ritonavir Kill Bladder Cancer Cells Synergistically by Inducing Endoplasmic Reticulum Stress
Akinori Sato, Takako Asano, Kazuki Okubo, Makoto Isono, Tomohiko Asano
Department of Urology, National Defense Medical College, Tokorozawa, Saitama, Japan
Oncology Research 2018, 26(2), 323-332. https://doi.org/10.3727/096504017X14957929842972
Abstract
The human immunodeficiency virus (HIV) protease inhibitor nelfinavir acts against malignancies by inducing endoplasmic reticulum (ER) stress. The HIV protease inhibitor ritonavir, on the other hand, not only
induces ER stress but also inhibits P-glycoprotein’s pump activity and thereby enhances the effects of its
substrate drugs. We therefore postulated that ritonavir in combination with nelfinavir would kill bladder cancer cells effectively by inducing ER stress cooperatively and also enhancing nelfinavir’s effect. Nelfinavir
was shown to be a P-glycoprotein substrate, and the combination of nelfinavir and ritonavir inhibited bladder cancer cell growth synergistically. It also suppressed colony formation significantly. The combination
significantly increased the number of cells in the sub-G
1 fraction and also the number of annexin V
+
cells,
confirming robust apoptosis induction. The combination induced ER stress synergistically, as evidenced
by the increased expression of glucose-regulated protein 78, ER-resident protein 44, and endoplasmic oxidoreductin-1-like protein. It also increased the expression of the mammalian target of rapamycin (mTOR)
inhibitor AMP-activated protein kinase and caused dephosphorylation of S6 ribosomal protein, demonstrating that the combination also inhibited the mTOR pathway. We also found that the combination enhanced
histone acetylation synergistically by decreasing the expression of HDACs 1, 3, and 6.
Keywords
Cite This Article
APA Style
Sato, A., Asano, T., Okubo, K., Isono, M., Asano, T. (2018). Nelfinavir and ritonavir kill bladder cancer cells synergistically by inducing endoplasmic reticulum stress. Oncology Research, 26(2), 323-332. https://doi.org/10.3727/096504017X14957929842972
Vancouver Style
Sato A, Asano T, Okubo K, Isono M, Asano T. Nelfinavir and ritonavir kill bladder cancer cells synergistically by inducing endoplasmic reticulum stress. Oncol Res. 2018;26(2):323-332 https://doi.org/10.3727/096504017X14957929842972
IEEE Style
A. Sato, T. Asano, K. Okubo, M. Isono, and T. Asano "Nelfinavir and Ritonavir Kill Bladder Cancer Cells Synergistically by Inducing Endoplasmic Reticulum Stress," Oncol. Res., vol. 26, no. 2, pp. 323-332. 2018. https://doi.org/10.3727/096504017X14957929842972