Combination of a STAT3 Inhibitor and an mTOR Inhibitor Against a Temozolomide-resistant Glioblastoma Cell Line

• Published in: Cancer genomics & proteomics Vol. 14; no. 1; pp. 83 - 91
• Main Authors: Miyata, Haruo, Ashizawa, Tadashi, Iizuka, Akira, Kondou, Ryota, Nonomura, Chizu, Sugino, Takashi, Urakami, Kenichi, Asai, Akira, Hayashi, Nakamasa, Mitsuya, Koichi, Nakasu, Yoko, Yamaguchi, Ken, Akiyama, Yasuto
• Format: Journal Article
• Language: English
• Published: Greece International Institute of Anticancer Research 01.01.2017
• Subjects: Animals; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Chitinase-3-Like Protein 1 - genetics; Chitinase-3-Like Protein 1 - metabolism; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; Disease Models, Animal; Drug Resistance, Neoplasm - genetics; Exome; Glioblastoma - genetics; Glioblastoma - metabolism; High-Throughput Nucleotide Sequencing; Humans; Male; Oxadiazoles - pharmacology; Protein Kinase Inhibitors - pharmacology; Quinolines - pharmacology; Signal Transduction - drug effects; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - metabolism; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; mTOR inhibitor; temozolomide resistance; glioblastoma; STAT3 inhibitor
• ISSN: 1109-6535; 1790-6245
• DOI: 10.21873/cgp.20021

Temozolomide-resistant (TMZ-R) glioblastoma is very difficult to treat, and a novel approach to overcome resistance is needed. The efficacy of a combination treatment of STAT3 inhibitor, STX-0119, with rapamycin was investigated against our established TMZ-resistant U87 cell line. The growth-inhibitory effect of the combination treatment was significant against the TMZ-R U87 cell line (IC : 78 μM for STX-0119, 30.5 μM for rapamycin and 11.3 μM for combination of the two). Western blotting analysis demonstrated that the inhibitory effect of STX-0119 on S6 and 4E-BP1 activation through regulation of YKL-40 expression occurred in addition to the inhibitory effect of rapamycin against the mTOR pathway. These results suggest that the STAT3 pathway is associated with the mTOR downstream pathway mediated by YKL-40 protein, and the combination therapy of the STAT3 inhibitor and rapamycin could be worth developing as a novel therapeutic approach against TMZ-resistant relapsed gliomas.