A novel PI3K inhibitor displays potent preclinical activity against an androgen-independent and PTEN-deficient prostate cancer model established from the cell line PC3

Min Shi; Xiumin Zhou; Zubin Zhang; Man Wang; Guodong Chen; Kunkun Han; Biyin Cao; Zhaopeng Liu; Xinliang Mao

doi:10.1016/j.toxlet.2014.05.003

A novel PI3K inhibitor displays potent preclinical activity against an androgen-independent and PTEN-deficient prostate cancer model established from the cell line PC3

Toxicol Lett. 2014 Aug 4;228(3):133-9. doi: 10.1016/j.toxlet.2014.05.003. Epub 2014 May 14.

Authors

Min Shi¹, Xiumin Zhou², Zubin Zhang¹, Man Wang¹, Guodong Chen¹, Kunkun Han¹, Biyin Cao¹, Zhaopeng Liu³, Xinliang Mao⁴

Affiliations

¹ Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China; Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
² Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215106, China.
³ Department of Organic Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
⁴ Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China; Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China; The Collaborative Innovation Center of Hematology, China. Electronic address: Xinliangmao@suda.edu.cn.

PMID: 24831963
DOI: 10.1016/j.toxlet.2014.05.003

Abstract

Recent studies demonstrated that targeting the phosphatidylinositide 3-kinase (PI3K)/AKT signaling pathway is a major strategy for the treatment of androgen-independent prostate cancer. In the present study, we developed an analog BENC-511 from a recently reported PI3K inhibitor S14161 by structural optimization. Using PC3 and DU145 as the model cell lines, we found PTEN-deficient PC3 cells were more sensitive than PTEN-expressing DU145 ones in terms of cell proliferation, apoptosis, and caspase-3 activation. These findings were consistent with the inhibition on PI3K/AKT signals. BENC-511 preferably suppressed AKT activation in PC3 over DU145 cells. Notably, PTEN restoration attenuated BENC-511 induced apoptosis. Moreover, BENC-511 displayed great therapeutic efficacy in a PC3-derived prostate cancer model in nude mice. With an oral dosage of 50mg/kg, BENC-511 decreased tumor growth more than 50% in 27 days, which was accompanied with PARP cleavage, but did not show overt toxicity. This study lays a solid rationale for the development of BENC-511 as a drug for the treatment of PTEN-deficient and androgen-independent prostate cancers.

Keywords: Androgen-independence; BENC-511; PI3K/AKT; PTEN; Prostate cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Benzopyrans / administration & dosage
Benzopyrans / pharmacology*
Caspase 3 / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Enzyme Activation
Humans
Male
Mice
Mice, Nude
PTEN Phosphohydrolase / deficiency*
PTEN Phosphohydrolase / genetics
Phosphatidylinositol 3-Kinase / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Poly(ADP-ribose) Polymerases / metabolism
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / enzymology
Prostatic Neoplasms / genetics
Prostatic Neoplasms / pathology
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / pharmacology*
Signal Transduction / drug effects
Time Factors
Transfection
Tumor Burden
Xenograft Model Antitumor Assays

Substances

6-bromo-8-ethoxy-3-nitro-2H-chromene
Antineoplastic Agents
Benzopyrans
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Poly(ADP-ribose) Polymerases
Phosphatidylinositol 3-Kinase
PTEN Phosphohydrolase
PTEN protein, human
CASP3 protein, human
Caspase 3