The Role of Hedgehog Signaling in Anticancer Agent-Induced Cytotoxicity in Non-Small Cell Lung Cancer Cells and the Efficacy of Combination Therapy(1/2)

Non-small cell lung cancer (NSCLC) is the major cause of cancer mortality each year in Taiwan and worldwide. Despite the identification of many therapeutic agents for NSCLC treatment, their value in extending patient survival remains suboptimal, and there is still much room for improving NSCLC treatment. The Hedgehog pathway is associated with NSCLC progression and therapeutic resistance through a variety of mechanisms, such as upregulation of ATP-binding cassette transporter efflux pumps and activation of the PI3K/Akt and Bcl-2 pathways. Hyperactivation of antioxidant enzymes is also associated with resistance to a variety of chemotherapeutic agents in NSCLC. However, it remains unclear whether the Hedgehog pathway promotes therapeutic resistance by modulating oxidative stress and regulating antioxidant enzymes. To test this possibility, the following specific aims will be addressed: 1. To examine the effect of different anticancer agents (chemotherapeutic agents and antimicrobial peptides) on Hedgehog pathway activation in NSCLC cancer cells. 2. To investigate whether the Hedgehog pathway is involved in regulating anticancer agent (chemotherapeutics and antimicrobial peptide)-induced oxidative stress in NSCLC cancer cells. 3. To evaluate whether the Hedgehog pathway promotes therapeutic resistance by modulating antioxidant enzymes in NSCLC cancer cells. 4. To examine the anticancer effects of combined Hedgehog pathway inhibitors and anticancer agents (chemotherapeutic agents and antimicrobial peptide) on NSCLC cell lines.