| Summary: | 碩士 === 國立陽明大學 === 生物藥學研究所 === 103 === Lung cancer is the leading cause of cancer death around the world. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. In the present clinical treatment, patients receive cisplatin plus gemcitabine or pemetrexed for lung squamous carcinoma or lung adenocarcinoma with EGFR wild-type. However, NSCLC patients resistant to chemotherapeutic treatment might be due to cancer stem cells theory. Therefore, it is important to find potential drugs to kill CSCs and to overcome drug resistance and. From connectivity map, phenothiazine derivatives were revealed to have potential to reverse CSCs gene signature. But the effects of drug P in NSCLC are still unclear. In the present study, gene signatures of drug P in NSCLC cell lines via L1000 microarray were used to query CPDB and LINCS database to figure out its inhibitory effects. From bioinformatics analysis, drug P potentially induced cell cycle, autophagy, senescence, and EGFR signaling. These results indicated that drug P inhibited the cell viability of NSCLC parental and spheroid cells, but did not affect the original target, dopamine receptor D2. Drug P also showed inhibitory effects on CSC characteristics and decreased CSC markers in lung cancer spheres. Microarray analysis and microscopy observation showed that dramatic changes in combination with pemetrexed to induce DNA damage. Drug P alone or in combination with various chemo- or target therapy drugs suppressed tumorigenesis in vivo. Taken together, drug P is a potent anti-cancer and anti-cancer stem cell drug in NSCLC, and warrants for clinical trials in the future.
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