Identification of a pyridine derivative inducing senescence in ovarian cancer cell lines via P21 activation

Abstract

Cellular senescence is a state of irreversible cell growth arrest. Increasing evidence suggests that cellular senescence contribute to tumour suppression in vivo. However, only a few anti-cancer drugs have been discovered to induce cellular senescence. Searching for new compounds which can inhibit cancer cell growth by inducing senescence is becoming one of the most attractive research fields. To test the effects of candidate compounds on cancer cell growth, cell proliferation assays, senescence-associated β-galactosidase (SA-β-gal) staining, and flow cytometry assay were performed. Immunofluorescence, western blot, and qRT-PCR experiments were used to further study the molecular mechanisms of the candidate compounds. We demonstrated that a pyridine derivative, 4-(4-fluorophenyl)-2-phenyl-5, 6, 7, 8-tetrahydroquinoline (FPTHQ), from a pool of 46 compounds can induce senescence of ovarian cancer cells in a dose-dependent manner. FPTHQ caused growth inhibition by inducing G0/G1 cell cycle arrest in A2780 cells. Increased activities of SA-β-gal were observed in FPTHQ-treated A2780, OVCAR-3 and SKOV-3 cell lines. In addition, FPTHQ treatment increased the protein levels of MMP3 and the mRNA levels of IL-6 and IL-8 in A2780 cells, indicating the appearance of senescence-associated secretary phenotype (SASP) in the cells. Furthermore, we found that p21 was up-regulated and DNA damage was accumulated in FPTHQ-treated ovarian cancer cells. So far, our data suggest that FPTHQ can induce senescence in multiple ovarian cancer cell lines through activation of p21 signalling pathway by causing excessive DNA damage.

Artemether Attenuates the Progression of Non-small Cell Lung Cancer by Inducing Apoptosis, Cell Cycle Arrest and Promoting Cellular Senescence

“…7) Recent studies have shown that cellular senescence contributes to the anticancer effects of chemotherapeutic drugs, and cellular senescence-inducing agents might be a feasible strategy. 8,9,30) In the current study, we found that low concentration of ART promotes cellular senescence in NSCLC cells. As cellular senescence can be controlled by CDK inhibitor p16 INK4a (p16), and affects the outcome of cancer therapy.…”

“…6) Cellular senescence has been considered as an important factor in aging and age-related disease, and it is a seductive target for therapeutic exploitation. 7) Increasing studies have revealed that cellular senescence leads to tumor suppres-sion, 8,9) and only a few anti-tumor agents have been developed to promote cellular senescence. Therefore, developing new agents to disturb cancer cell proliferation by promoting cellular senescence is becoming a research focus.…”

Interleukin-22 derived from cervical cancer-associated fibroblasts accelerates senescence of normal fibroblasts and promotes expression of tumorigenesis-related factors in HeLa cells

“…Senescent cells typically display an enlarged morphology and an enhanced SA-β-gal activity. The specific molecular characteristics of senescent cells include the upregulation of p16 and α-SMA [28,29]. All these features were observed in the CAFs isolated in this study, indicating that the CAFs were more senescent than the NFs.…”

Interleukin-1β Drives Cellular Senescence of Rat Astrocytes Induced by Oligomerized Amyloid β Peptide and Oxidative Stress

“…The endogenous control was β-actin. Immunoblotting was performed using the antibodies listed in Supplementary Table 1 , and as described in previous studies ( 45 , 46 ). β-actin was used as an internal control.…”

“…SA-β-Gal staining was performed as previously described (45)(46)(47). Briefly, treated cells were fixed in 2% formaldehyde/0.2% glutaraldehyde in PBS for 5 min at room temperature.…”