NSK-01105 inhibits proliferation and induces apoptosis of prostate cancer cells by blocking the Raf/MEK/ERK and PI3K/Akt/mTOR signal pathways.
The purposes of this study are to investigate the antitumor activities of NSK-01105, a novel sorafenib derivative, in in vitro and in vivo models, and explore the potential mechanisms. The effects of NSK-01105 on proliferation and apoptosis of prostate cancer cells were established by cytotoxicity assays, apoptosis analysis, flow cytometry analysis, and Western blot analysis. Two xenograft tumor models were used to verify the therapeutic effect of NSK-01105 in vivo. NSK-01105 exhibited broad-spectrum antitumor activity, particularly in prostate cancer cells. Characterization of apoptosis morphology was observed, and the percentage of apoptosis-positive cells significantly increased after NSK-01105 treatment for 24 h. Furthermore, a significant increase of the "sub-G1" population in LNCaP and PC-3 cells after NSK-01105 treatment was determined by cell cycle analysis. Tumor growth was significantly suppressed by once daily oral 30 mg/kg dose of NSK-01105 with the inhibition rates of 63.82% in LNCaP models and 64.29% in PC-3 models, respectively. The activation of Raf-1 kinase and epidermal growth factor receptor was downregulated by NSK-01105 at 10 μmol/L. Consequently, the dual inhibitions of Raf/MEK/ERK and PI3K/Akt/mTOR signal pathways were observed by Western blot analysis. Collectively, our results suggest a role of NSK-01105 in treatment for human prostate tumors by inhibiting cell proliferation and inducing apoptosis. NSK-01105 appears to be a promising orally active anticancer drug and deserves further investigation.
School of Life Science and Bio-pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China.
Pengfei
P
Yu
Liang
L
Ye
Hongbo
H
Wang
Guangying
G
Du
Jianzhao
J
Zhang
Jinghai
J
Zhang
Jingwei
J
Tian
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D061986:MCF-7 Cells; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D009536:Niacinamide; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D011799:Quinazolines; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases; C000601029:NSK-01105; C546842:MTOR protein, human