timosaponin-aiii and Lung-Neoplasms

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Ferroptosis; HSP90 Heat-Shock Proteins; Humans; Iron; Lung Neoplasms; Mice; Mice, Inbred C57BL; Mice, Nude; Reactive Oxygen Species; Saponins; Steroids; Ubiquitination

Timosaponin AIII (TAIII), an active component with anti-tumor activity from Anemarrhena asphodeloides Bunge, can induce both autophagy and apoptosis of cancer cells. The present study aimed to reveal the promoting or inhibiting role of TAIII-induced autophagy on TAIII-induced apoptosis, to determine the respective upstream signaling pathways for TAIII-induced autophagy and apoptosis; and to observe the therapeutic potential of TAIII in human non-small cell lung cancer in vivo.. WST-1 assay was used to determine the effect of TAIII on cell growth and proliferation. Apoptosis was detected by DAPI staining and flow cytometry. Autophagy was verified by immunofluorescence and transmission electron microscopy. Western blot was used to determine the levels of protein expression. Furthermore, the anti-tumor activity of TAIII was observed in nude mice.. TAIII at high concentrations from 10 μM to 30 μM induced both autophagy and apoptosis in human non-small cell lung cancer cells in a time- and concentration-dependent manner. TAIII at low concentration (1 μM) only induced autophagy. The AMP-activated protein kinase (AMPK) signaling pathway was identified to be responsible for TAIII-induced autophagy both at high or low concentrations. The MAPK/Erk1/2 signaling pathway was identified to be responsible for TAIII-induced apoptosis at the high concentration (20 μM). TAIII-induced autophagy protected cancer cells from apoptosis, and combination of TAIII and autophagy inhibitor showed higher anti-cancer activity.

Topics: A549 Cells; AMP-Activated Protein Kinases; Animals; Antineoplastic Agents; Apoptosis; Autophagy; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Humans; Lung Neoplasms; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mice, Nude; Saponins; Signal Transduction; Steroids

Timosaponin AIII (TAIII) is a type of steroidal saponins isolated from Anemarrhena asphodeloides. It was known to improve learning and memory deficits through anti-inflammatory effects. TAIII was also reported to induce autophagy preceding mitochondria-mediated apoptosis in HeLa cancer cells and inhibit the growth of human colorectal cancer cells, thus regarded as a potential candidate for anti-cancer agent. In this study, we verified apoptosis-inducing and cell-cycle-arresting effects of TAIII in A549 human non-small-cell lung cancer (NSCLC) cells. Then, we report that TAIII suppresses migration and invasion of A549 human NSCLC cells. We propose that two matrix metalloproteinases (MMPs), MMP-2 and MMP-9, which are well known to be involved in cancer-metastasis, are attenuated by the treatment of TAIII. TAIII exerts its suppressive effects on MMP-2 and MMP-9 via inhibitions of ERK1/2, Src/FAK and β-catenin signalings which are closely related with the regulations of MMP-2 and MMP-9.

Topics: A549 Cells; Anemarrhena; Apoptosis; beta Catenin; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Movement; Focal Adhesion Kinase 1; Humans; Lung Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Saponins; Signal Transduction; src-Family Kinases; Steroids