Preclinical Evaluation of Application of Sclareol for Adjuvant Therapy of Cisplatin-Resistant Non-Small Cell Lung Cancer

Cancer is always ranked first among the top 10 leading causes of death in Taiwan. Of that, the incidence of lung cancer is highest in the population of all cancers. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and hardly cured. To date, the platinum-based chemotherapy has become a common clinical regimen for first-line use in NSCLC. However, these drugs possessed many clinical side effects and toxicity as well as potential problem in drug resistance. Thus, it will be a practicable approaches to resolve the problem mention above by developing a compound with adjuvant therapeutic potential in combination with cisplatin. Sclareol, a natural bioactive compound, has been reported to possess the effects of immunomodulation and cancer cell cytotoxicity. Our studies also suggested that sclareol exhibited anti-inflammation, anti-angiogenesis, and synergistic cytotoxicity with cisplatin. Thereby, it has more potential application to use as a cisplatin-based adjuvant medicine for clinical therapy of NSCLC. Accordingly, this project will be divided into three years to perform: In 1st year, (1) To evaluate the regulatory effects of sclareol on the generation, proliferation, differentiation, migration, invasion and epitheilial-to-mesenchymal transition (EMT) of cancer stem cells as well as its pharmacological and molecular mechanisms; (2) To establish a acquired cisplatin-resistant NSCLC cell line (CisR-A549 cells) for used in the experiments of drug resistance (in 2nd year); (3) For establishment of cisplatin-resistant tumor model (in 3th year) and real-time evaluation of synergistic efficacy of sclareol in combination with cisplatin in a living system, an luciferase-based expression vector (pcDNA3.1(+)- Luc2) will be constructed and transferred into CisR-A549 cells to select and generate a luciferase-stable expression cell line. In 2nd year, (1) To evaluate the regulatory effects of sclareol on cell proliferation, migration, and invasion of CisR-A549 cells and its molecular mechanisms. (2) To investigate the regulatory activities of sclareol on drug resistances to cisplatin and anti-angiogenesis as well as its pharmacological and molecular mechanisms. In 3th year, (1) To acquire the blood pharmacokinetic parameters and to evaluate possible toxicity of sclareol. (2) Using the non-invasive in vivo imaging system (IVIS) to evaluate the inhibitory and improving efficacy of sclareol in combination with cisplatin on tumor growth and metastasis, and to analyze the its pharmacological mechanisms and histopathological changes. Currently, the emergence of cancer drug resistance is still a comprehensive problem in cancer chemotherapy. Thereby, developing an adjuvant drugs targeting on cancer stem cells or drug-resistant cells will augment clinical effectiveness of primary chemotherapeutic agent (e.g. cisplatin) and thus to reduce its dosage and then to decrease side effects and toxicity. These adjuvant drugs developed by such strategy certainly will effectively improve clinical therapy outcome and survival rate of NSCLC.