Penella Woll

Publications (3)2.4 Total impact

• Article: Treatment with the Chk1 inhibitor Gö6976 enhances cisplatin cytotoxicity in SCLC cells.

  Ruth Thompson, Mark Meuth, Penella Woll, Yong Zhu, Sarah Danson
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  ABSTRACT: Acquired chemoresistance is a major obstacle in successful treatment of small cell lung cancer (SCLC). DNA damage responses can potentially contribute to resistance by halting the cell cycle following exposure to therapeutic agents, thereby facilitating repair of drug-induced lesions and protecting tumour cells from death. The Chk1 protein kinase is a key regulator in this response. We analysed the status of cell cycle checkpoint proteins and the effects of the Chk1 inhibitor Gö6976 on cisplatin toxicity in SCLC cell lines. IC50s for cisplatin were determined using the MTT assay in six SCLC cell lines. Effects on cell cycle distribution and apoptosis were determined by flow cytometry and caspase 3 activation in the presence or absence of the Chk1 inhibitor Gö6976. The activation of checkpoint proteins was determined by Western blotting. Cell lines were divided into chemosensitive and chemoresistant groups on the basis of our results. While checkpoint responses were detected in these cell lines through Western blotting, some of these responses were delayed or weaker than those seen in other cell types in response to DNA damage and replication stress. Gö6976 significantly (p<0.05) enhanced the levels of apoptosis seen in response to a clinically relevant dose of cisplatin (<6 µM) and decreased drug-induced G2 arrest in chemosensitive cells. Our data suggest a role for Chk1 in chemoresistance of SCLC cells and a potential approach to improve initial response of SCLC to cisplatin therapy.
  International Journal of Oncology 09/2011; 40(1):194-202. · 2.40 Impact Factor
• Chapter: Lung Tumors

  Sarah Danson, M Dawn Teare, Penella Woll
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  ABSTRACT: Whilst the hereditary components of many tumors are well described, this is not the case for thoracic malignancies and much work is ongoing in this area. A strong family history is rare but there is increasing evidence that testing for polymorphisms, especially for genes involved in detoxification and DNA repair, may one day be used to identify those at risk of lung cancer. In those that develop lung cancer, polymorphism status could be combined with tumor characteristics to design customized treatment regimens.
  08/2009: pages 183 - 192; , ISBN: 9783527627523
• Article: Effects of COX-2 inhibition on expression of vascular endothelial growth factor and interleukin-8 in lung cancer cells

  Yong Zhu, Nor Azahri, Danny Yu, Penella Woll
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  ABSTRACT: Abstract Background Cyclooxygenase (COX)-2 has been implicated in tumour progression, angiogenesis and metastasis in non-small cell lung cancer (NSCLC). We speculated that inhibition of COX-2 activity might reduce expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) in lung cancer cells. Methods The levels of IL-8, VEGF and prostaglandin E₂(PGE₂) were measured by ELISA. Expression of COX-1 and COX-2 was determined by Western blotting. Inhibition or knockdown of COX-2 was achieved by treating NSCLC cells with specific COX-2 inhibitor NS-398 or COX-2 siRNA, respectively. Results We found that NSCLC cell lines produced more IL-8 than VEGF (p < 0.001). In contrast, small cell lung cancer (SCLC) cell lines produced more VEGF than IL-8 (p < 0.001). COX-1 was expressed in all cell lines, but COX-2 was expressed only in NSCLC cell lines. Consistent with this, PGE₂was significantly higher in NSCLC cell lines than SCLC cell lines (p < 0.001). We tested these cell lines with a potent specific COX-2 inhibitor NS-398 at concentrations of 0.02, 0.2, 2, 20 μM for 24 or 48 h. The COX-2 activity was reduced in a dose-dependent fashion as shown by reduced PGE₂production. VEGF was significantly reduced following the treatment of NS-398 in A549 (by 31%) and MOR/P (by 47%) cells lines which expressing strong COX-2, but not in H460 cell line which expressing very low COX-2. However, IL-8 was not reduced in these cell lines. To confirm these results, we knocked down COX-2 expression with COX-2 siRNA in these cell lines. VEGF was significantly decreased in A549 (by 24%) and in MOR/P (by 53%), but not in H460 whereas IL-8 was not affected in any cell line. Conclusion We conclude that NSCLC cells produce much higher levels of IL-8 than SCLC cells whereas both NSCLC and SCLC cells produce similar levels of VEGF. COX-2 is only expressed in NSCLC cells, but not in SCLC cells. VEGF is produced in both NSCLC and SCLC cells regardless of COX-2 expression. However, VEGF production is, at least partly, COX-2 dependent in NSCLC cells expressing COX-2. In contrast, IL-8 production is COX-2 independent in both NSCLC and SCLC cells. We speculate that combined targeting of COX-2 and IL-8 may be useful in the treatment of patients with NSCLC and targeting VEGF may be useful in the treatment of patients with SCLC.
  BMC Cancer. 01/2008;