NVP-BEZ235, a dual PI3K/mTOR inhibitor synergistically potentiates the antitumor effects of cisplatin in bladder cancer cells

Du Geon Moon, Sang E. Lee, Mi-Mi Oh, Sang C. Lee, Seong J. Jeong, Sung K. Hong, Cheol Y. Yoon, Seok S. Byun, Hong Seok Park, Jun Cheon

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

The PI3K/Akt/mTOR pathway is a prototypic survival pathway and constitutively activated in many malignant conditions. Moreover, activation of the PI3K/Akt/mTOR pathway confers resistance to various cancer therapies and is often associated with a poor prognosis. In this study, we explored the antitumor effect of NVP-BEZ235, a dual PI3K/mTOR inhibitor in cisplatin-resistant human bladder cancer cells and its synergistic interaction with cisplatin. A human bladder cancer cell line with cisplatin resistance was exposed to escalating doses of NVP-BEZ235 alone or in combination with cisplatin and antitumor effects was determined by the CCK-8 assay. Based on a dose-response study, synergistic interaction between NVP-BEZ235 and cisplatin was evaluated by combination index (CI), three-dimensional model and clonogenic assay. The combination of NVP-BEZ235 and cisplatin caused significant synergistic antitumor effect in cisplatin-resistant bladder cancer cells over a wide dose range and reduced the IC50 of NVP-BEZ235 and cisplatin by 5.6- and 3.6-fold, respectively. Three-dimensional synergy analysis resulted in a synergy volume of 388.25 μM/ml2% indicating a strong synergistic effect of combination therapy. The combination therapy caused cell cycle arrest and caspase-dependent apoptosis. Although NVP-BEZ235 suppressed PI3K/mTOR signaling without any paradoxical induction of Akt activity, it caused MEK/ERK pathway activation. The present study demonstrated that the PI3K/mTOR dual inhibitor NVP-BEZ235 can synergistically potentiate the antitumor effects of cisplatin in cisplatin-resistant bladder cancer cells though the suppression of cell cycle progression and the survival pathway as well as induction of caspase-dependent apoptosis.

Original languageEnglish
Pages (from-to)1027-1035
Number of pages9
JournalInternational Journal of Oncology
Volume45
Issue number3
DOIs
Publication statusPublished - 2014 Jan 1

Fingerprint

Phosphatidylinositol 3-Kinases
Urinary Bladder Neoplasms
Cisplatin
Caspases
dactolisib
Apoptosis
Sincalide
Survival
MAP Kinase Signaling System
Cell Cycle Checkpoints
Inhibitory Concentration 50
Cell Cycle
Therapeutics
Cell Line

Keywords

  • Carcinoma
  • Cisplatin
  • NVP-BEZ235
  • Resistance
  • Urinary bladder

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

NVP-BEZ235, a dual PI3K/mTOR inhibitor synergistically potentiates the antitumor effects of cisplatin in bladder cancer cells. / Moon, Du Geon; Lee, Sang E.; Oh, Mi-Mi; Lee, Sang C.; Jeong, Seong J.; Hong, Sung K.; Yoon, Cheol Y.; Byun, Seok S.; Park, Hong Seok; Cheon, Jun.

In: International Journal of Oncology, Vol. 45, No. 3, 01.01.2014, p. 1027-1035.

Research output: Contribution to journalArticle

Moon, Du Geon ; Lee, Sang E. ; Oh, Mi-Mi ; Lee, Sang C. ; Jeong, Seong J. ; Hong, Sung K. ; Yoon, Cheol Y. ; Byun, Seok S. ; Park, Hong Seok ; Cheon, Jun. / NVP-BEZ235, a dual PI3K/mTOR inhibitor synergistically potentiates the antitumor effects of cisplatin in bladder cancer cells. In: International Journal of Oncology. 2014 ; Vol. 45, No. 3. pp. 1027-1035.
@article{661d6313b5aa479e94b90a4cc47da4e2,
title = "NVP-BEZ235, a dual PI3K/mTOR inhibitor synergistically potentiates the antitumor effects of cisplatin in bladder cancer cells",
abstract = "The PI3K/Akt/mTOR pathway is a prototypic survival pathway and constitutively activated in many malignant conditions. Moreover, activation of the PI3K/Akt/mTOR pathway confers resistance to various cancer therapies and is often associated with a poor prognosis. In this study, we explored the antitumor effect of NVP-BEZ235, a dual PI3K/mTOR inhibitor in cisplatin-resistant human bladder cancer cells and its synergistic interaction with cisplatin. A human bladder cancer cell line with cisplatin resistance was exposed to escalating doses of NVP-BEZ235 alone or in combination with cisplatin and antitumor effects was determined by the CCK-8 assay. Based on a dose-response study, synergistic interaction between NVP-BEZ235 and cisplatin was evaluated by combination index (CI), three-dimensional model and clonogenic assay. The combination of NVP-BEZ235 and cisplatin caused significant synergistic antitumor effect in cisplatin-resistant bladder cancer cells over a wide dose range and reduced the IC50 of NVP-BEZ235 and cisplatin by 5.6- and 3.6-fold, respectively. Three-dimensional synergy analysis resulted in a synergy volume of 388.25 μM/ml2{\%} indicating a strong synergistic effect of combination therapy. The combination therapy caused cell cycle arrest and caspase-dependent apoptosis. Although NVP-BEZ235 suppressed PI3K/mTOR signaling without any paradoxical induction of Akt activity, it caused MEK/ERK pathway activation. The present study demonstrated that the PI3K/mTOR dual inhibitor NVP-BEZ235 can synergistically potentiate the antitumor effects of cisplatin in cisplatin-resistant bladder cancer cells though the suppression of cell cycle progression and the survival pathway as well as induction of caspase-dependent apoptosis.",
keywords = "Carcinoma, Cisplatin, NVP-BEZ235, Resistance, Urinary bladder",
author = "Moon, {Du Geon} and Lee, {Sang E.} and Mi-Mi Oh and Lee, {Sang C.} and Jeong, {Seong J.} and Hong, {Sung K.} and Yoon, {Cheol Y.} and Byun, {Seok S.} and Park, {Hong Seok} and Jun Cheon",
year = "2014",
month = "1",
day = "1",
doi = "10.3892/ijo.2014.2505",
language = "English",
volume = "45",
pages = "1027--1035",
journal = "International Journal of Oncology",
issn = "1019-6439",
publisher = "Spandidos Publications",
number = "3",

}

TY - JOUR

T1 - NVP-BEZ235, a dual PI3K/mTOR inhibitor synergistically potentiates the antitumor effects of cisplatin in bladder cancer cells

AU - Moon, Du Geon

AU - Lee, Sang E.

AU - Oh, Mi-Mi

AU - Lee, Sang C.

AU - Jeong, Seong J.

AU - Hong, Sung K.

AU - Yoon, Cheol Y.

AU - Byun, Seok S.

AU - Park, Hong Seok

AU - Cheon, Jun

PY - 2014/1/1

Y1 - 2014/1/1

N2 - The PI3K/Akt/mTOR pathway is a prototypic survival pathway and constitutively activated in many malignant conditions. Moreover, activation of the PI3K/Akt/mTOR pathway confers resistance to various cancer therapies and is often associated with a poor prognosis. In this study, we explored the antitumor effect of NVP-BEZ235, a dual PI3K/mTOR inhibitor in cisplatin-resistant human bladder cancer cells and its synergistic interaction with cisplatin. A human bladder cancer cell line with cisplatin resistance was exposed to escalating doses of NVP-BEZ235 alone or in combination with cisplatin and antitumor effects was determined by the CCK-8 assay. Based on a dose-response study, synergistic interaction between NVP-BEZ235 and cisplatin was evaluated by combination index (CI), three-dimensional model and clonogenic assay. The combination of NVP-BEZ235 and cisplatin caused significant synergistic antitumor effect in cisplatin-resistant bladder cancer cells over a wide dose range and reduced the IC50 of NVP-BEZ235 and cisplatin by 5.6- and 3.6-fold, respectively. Three-dimensional synergy analysis resulted in a synergy volume of 388.25 μM/ml2% indicating a strong synergistic effect of combination therapy. The combination therapy caused cell cycle arrest and caspase-dependent apoptosis. Although NVP-BEZ235 suppressed PI3K/mTOR signaling without any paradoxical induction of Akt activity, it caused MEK/ERK pathway activation. The present study demonstrated that the PI3K/mTOR dual inhibitor NVP-BEZ235 can synergistically potentiate the antitumor effects of cisplatin in cisplatin-resistant bladder cancer cells though the suppression of cell cycle progression and the survival pathway as well as induction of caspase-dependent apoptosis.

AB - The PI3K/Akt/mTOR pathway is a prototypic survival pathway and constitutively activated in many malignant conditions. Moreover, activation of the PI3K/Akt/mTOR pathway confers resistance to various cancer therapies and is often associated with a poor prognosis. In this study, we explored the antitumor effect of NVP-BEZ235, a dual PI3K/mTOR inhibitor in cisplatin-resistant human bladder cancer cells and its synergistic interaction with cisplatin. A human bladder cancer cell line with cisplatin resistance was exposed to escalating doses of NVP-BEZ235 alone or in combination with cisplatin and antitumor effects was determined by the CCK-8 assay. Based on a dose-response study, synergistic interaction between NVP-BEZ235 and cisplatin was evaluated by combination index (CI), three-dimensional model and clonogenic assay. The combination of NVP-BEZ235 and cisplatin caused significant synergistic antitumor effect in cisplatin-resistant bladder cancer cells over a wide dose range and reduced the IC50 of NVP-BEZ235 and cisplatin by 5.6- and 3.6-fold, respectively. Three-dimensional synergy analysis resulted in a synergy volume of 388.25 μM/ml2% indicating a strong synergistic effect of combination therapy. The combination therapy caused cell cycle arrest and caspase-dependent apoptosis. Although NVP-BEZ235 suppressed PI3K/mTOR signaling without any paradoxical induction of Akt activity, it caused MEK/ERK pathway activation. The present study demonstrated that the PI3K/mTOR dual inhibitor NVP-BEZ235 can synergistically potentiate the antitumor effects of cisplatin in cisplatin-resistant bladder cancer cells though the suppression of cell cycle progression and the survival pathway as well as induction of caspase-dependent apoptosis.

KW - Carcinoma

KW - Cisplatin

KW - NVP-BEZ235

KW - Resistance

KW - Urinary bladder

UR - http://www.scopus.com/inward/record.url?scp=84904397559&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84904397559&partnerID=8YFLogxK

U2 - 10.3892/ijo.2014.2505

DO - 10.3892/ijo.2014.2505

M3 - Article

C2 - 24969552

AN - SCOPUS:84904397559

VL - 45

SP - 1027

EP - 1035

JO - International Journal of Oncology

JF - International Journal of Oncology

SN - 1019-6439

IS - 3

ER -