A novel PI3K/mTOR dual inhibitor, CMG002, overcomes the chemoresistance in ovarian cancer

Autor: Ju Yeon Park, Kyung Soon Park, Se Hwa Kim, Hee Jung An, Hyeon Ju Cho, Hye Joung Choi, Yong Wha Moon, Jin Sung Kim, Ju Yeon Jeong, Jin Hyung Heo
Rok vydání: 2018
Předmět:
0301 basic medicine
Paclitaxel
Pyridines
Mice
Nude
03 medical and health sciences
chemistry.chemical_compound
Mice
Phosphatidylinositol 3-Kinases
0302 clinical medicine
Piperidines
In vivo
Cell Line
Tumor
Antineoplastic Combined Chemotherapy Protocols
medicine
Animals
Humans
Protein kinase B
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Phosphoinositide-3 Kinase Inhibitors
Cisplatin
Ovarian Neoplasms
Mice
Inbred BALB C
Cell growth
business.industry
TOR Serine-Threonine Kinases
Obstetrics and Gynecology
Drug Synergism
medicine.disease
G1 Phase Cell Cycle Checkpoints
Xenograft Model Antitumor Assays
030104 developmental biology
Pyrimidines
Oncology
chemistry
Apoptosis
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Cancer research
Female
Ovarian cancer
business
medicine.drug
Signal Transduction
Zdroj: Gynecologic oncology. 153(1)
ISSN: 1095-6859
Popis: Objective Ovarian cancer is the leading cause of gynecologic-related mortality worldwide. Despite successful initial treatment, overall survival rates are very low because tumors develop resistance to chemotherapeutic drugs. The PI3K/mTOR pathway is a key signaling pathway involved in drug resistance of ovarian cancer cells. The aim of this study was to examine the effect of a newly developed PI3K/mTOR dual inhibitor, CMG002, on chemoresistant ovarian cancer cells. Methods We examined the effects of CMG002, and its synergistic effects when combined with paclitaxel or cisplatin, on cell viability, cell cycle arrest, and apoptosis of PTX-resistant SKpac17 or cisplatin-resistant A2780cis ovarian cancer cells in vitro. Western blot analysis was performed to assess expression of PI3K, p-mTOR, p-Akt, p-S6, Bim, and caspase-3. In vivo studies were carried out in a xenograft mouse model, followed by TUNEL and immunohistochemical staining of excised tumor tissue. Results CMG002 showed marked toxicity against chemoresistant ovarian cancer cells and re-sensitized these cells to chemotherapeutic agents by suppressing cell proliferation and inducing G1 cell cycle arrest and apoptosis. In vivo xenograft studies revealed that treatment with CMG002, either alone or in combination with paclitaxel or cisplatin, led to a marked reduction in tumor growth. CMG002 caused marked suppression of mTOR (Ser2448), Akt (Ser473), Akt (Thr308), and S6 (Ser235/236) phosphorylation, both in vitro and in vivo. Conclusion Taken together, CMG002, a very potent PI3K/mTOR dual inhibitor, induced cytotoxicity in chemoresistant ovarian cancer cells, suggesting that this novel inhibitor might be a new therapeutic strategy for chemoresistant ovarian cancer.
Databáze: OpenAIRE
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