PMID- 28560953
OWN - NLM
STAT- MEDLINE
DCOM- 20180827
LR  - 20210217
IS  - 1555-3906 (Electronic)
IS  - 0965-0407 (Print)
IS  - 0965-0407 (Linking)
VI  - 26
IP  - 2
DP  - 2018 Mar 5
TI  - Nelfinavir and Ritonavir Kill Bladder Cancer Cells Synergistically by Inducing 
      Endoplasmic Reticulum Stress.
PG  - 323-332
LID - 10.3727/096504017X14957929842972 [doi]
AB  - 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-G1 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.
FAU - Sato, Akinori
AU  - Sato A
AD  - Department of Urology, National Defense Medical College, Tokorozawa, Saitama, 
      Japan.
FAU - Asano, Takako
AU  - Asano T
AD  - Department of Urology, National Defense Medical College, Tokorozawa, Saitama, 
      Japan.
FAU - Okubo, Kazuki
AU  - Okubo K
AD  - Department of Urology, National Defense Medical College, Tokorozawa, Saitama, 
      Japan.
FAU - Isono, Makoto
AU  - Isono M
AD  - Department of Urology, National Defense Medical College, Tokorozawa, Saitama, 
      Japan.
FAU - Asano, Tomohiko
AU  - Asano T
AD  - Department of Urology, National Defense Medical College, Tokorozawa, Saitama, 
      Japan.
LA  - eng
PT  - Journal Article
DEP - 20170526
PL  - United States
TA  - Oncol Res
JT  - Oncology research
JID - 9208097
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Histones)
RN  - HO3OGH5D7I (Nelfinavir)
RN  - O3J8G9O825 (Ritonavir)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
MH  - Acetylation/drug effects
MH  - Antineoplastic Agents/metabolism/*pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Drug Synergism
MH  - Endoplasmic Reticulum Stress/*drug effects
MH  - Histones/metabolism
MH  - Humans
MH  - Nelfinavir/metabolism/*pharmacology
MH  - Ritonavir/metabolism/*pharmacology
MH  - Urinary Bladder Neoplasms/*metabolism
PMC - PMC7844765
EDAT- 2017/06/01 06:00
MHDA- 2018/08/28 06:00
PMCR- 2018/03/05
CRDT- 2017/06/01 06:00
PHST- 2017/06/01 06:00 [pubmed]
PHST- 2018/08/28 06:00 [medline]
PHST- 2017/06/01 06:00 [entrez]
PHST- 2018/03/05 00:00 [pmc-release]
AID - OR1145 [pii]
AID - 10.3727/096504017X14957929842972 [doi]
PST - ppublish
SO  - Oncol Res. 2018 Mar 5;26(2):323-332. doi: 10.3727/096504017X14957929842972. Epub 
      2017 May 26.