A novel PI3K inhibitor displays potent preclinical activity against an androgen-independent and PTEN-deficient prostate cancer model established from the cell line PC3.
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.
Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China; Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
Min
M
Shi
Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215106, China.
Xiumin
X
Zhou
Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China; Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
Zubin
Z
Zhang
Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China; Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
Man
M
Wang
Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China; Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
Guodong
G
Chen
Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China; Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
Kunkun
K
Han
Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China; Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
Biyin
B
Cao
Department of Organic Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
Zhaopeng
Z
Liu
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.
Xinliang
X
Mao
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
C584755:6-bromo-8-ethoxy-3-nitro-2H-chromene; D000970:Antineoplastic Agents; D001578:Benzopyrans; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D058539:Phosphatidylinositol 3-Kinase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C505407:CASP3 protein, human; D053148:Caspase 3
Androgen-independence; BENC-511; PI3K/AKT; PTEN; Prostate cancer