Effects of 17-allylamino-17-demethoxygeldanamycin on the induction of apoptosis and cell cycle arrest in HCT-116 cells

Abstract

The present study investigated the effects of HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on apoptosis and the cell cycle of the HCT-116 human colon carcinoma cell line, with the aim of elucidating their underlying mechanisms. MTT was used to examine the inhibitory effects of 17-AAG on the proliferation of HCT-116 cells at various time points and doses. The cells were stained with Annexin V-fluorescein isothiocyanate/propidium iodide and evaluated by flow cytometry. The expression of signal transducer and activator of transcription (STAT)3, cyclin D1, cytochrome c (cyt-c), caspase 9 and caspase 3 at the mRNA and protein level was determined using reverse transcription-polymerase chain reaction and western blotting. Treatment with 17-AAG at a concentration of 1.25–20 mg/l for 24 and 48 h significantly inhibited the proliferation of HCT-116 cells in a time-dependent and concentration-dependent manner. Treatment with 17-AAG at concentrations of 1.25, 2.5 and 5 mg/l for 48 h significantly induced apoptosis and cell cycle arrest in HCT-116 cells. Exposure to 17-AAG at concentrations of 1.25, 2.5 and 5 mg/l for 48 h significantly downregulated the mRNA and protein expression of STAT3 and cyclin D1, but upregulated cyt-c, caspase 9 and caspase 3 in a concentration-dependent manner in HCT-116 cells. Therefore 17-AAG is able to inhibit cell proliferation, inducing apoptosis and G1 stage cell cycle arrest by downregulating the expression of cyclin D1, and promoting the mitochondria apoptosis by downregulating STAT3 in HCT-116 cells.

Anti-cancer effects of chemotherapeutic agent; 17-AAG, in combined with gold nanoparticles and irradiation in human colorectal cancer cells

“…Heat shock protein 90 (HSP90) inhibitors are considered as an efficient therapeutic approach in cancer targeted therapy [11]. 17-allylamino-17-demethoxygeldanamycin (17-AAG) is a HSP90 inhibitor that exerts cytotoxic and apoptotic effects on cancer cells [12,13].…”

Aa-Z2 triggers ROS-induced apoptosis of osteosarcoma by targeting PDK-1

“…In addition, immunohistochemical analysis revealed a substantial increase in the proportion of cell apoptosis in Aa-Z2-treated xenograft OS tissue. The imbalance of cell cycle regulation is one hallmark of cancer, and inducing cell cycle arrest may be an effective way to treat the abnormal proliferation of cancer cells [ 42 , 43 ]. According to flow cytometric analysis, the proportions of OS cells in G2/M phase increased significantly after Aa-Z2 treatment, which was also reversed by NAC.…”

Ins and Outs of Heat Shock Proteins in Colorectal Carcinoma: Its Role in Carcinogenesis and Therapeutic Perspectives

“…The first-in-class HSP90α inhibitor is 17-allylamino-17-demethoxygeldanamycin (17-AAG)—a geldanamycin derivative that specifically targets the ATP binding pocket of HSP90. 17-AAG inhibits the ATPase activity of HSP90 and consequently promotes degradation of HSP90 through proteasome mechanisms [ 78 ]. Following 17-AAG treatment, CRC cells were arrested at G 2 due to a reduction in cyclin B1 levels.…”

“…Furthermore, 17-AAG downregulates STAT3 to induce apoptosis in CRC cells [ 78 ]. To date, more than 18 different HSP90 inhibitors have reached the clinical trial stage.…”