title: Sulfasalazine suppresses drug resistance and invasiveness of lung adenocarcinoma cells expressing AXL.
abstract: Metastasis and drug resistance are the major causes of mortality in patients with non-small cell lung cancer (NSCLC). Several receptor tyrosine kinases (RTKs), including AXL, are involved in the progression of NSCLC. The AXL/MER/SKY subfamily is involved in cell adhesion, motility, angiogenesis, and signal transduction and may play a significant role in the invasiveness of cancer cells. Notably, no specific inhibitors of AXL have been described. A series of CL1 sublines with progressive invasiveness established from a patient with NSCLC has been identified that positively correlates with AXL expression and resistance to chemotherapeutic drugs. The ectopic overexpression of AXL results in elevated cell invasiveness and drug resistance. Nuclear factor-kappaB (NF-kappaB) signaling activity is associated with AXL expression and may play an important role in the enhancement of invasiveness and doxorubicin resistance, as shown by using the NF-kappaB inhibitor, sulfasalazine, and IkappaB dominant-negative transfectants. In the current study, sulfasalazine exerted a synergistic anticancer effect with doxorubicin and suppressed cancer cell invasiveness in parallel in CL1 sublines and various AXL-expressing cancer cell lines. Phosphorylation of AXL and other RTKs (ErbB2 and epidermal growth factor receptor) was abolished by sulfasalazine within 15 min, suggesting that the inhibition of NF-kappaB and the kinase activity of RTKs are involved in the pharmacologic effects of sulfasalazine. Our study suggests that AXL is involved in NSCLC metastasis and drug resistance and may therefore provide a molecular basis for RTK-targeted therapy using sulfasalazine to enhance the efficacy of chemotherapy in NSCLC.
authors: Institute of Cancer Research and Division of Clinical Research, National Health Research Institutes, No. 161 Min-Chuan East Road Section 6, Taipei 114, Taiwan.
authors: Jong-Ding
authors: JD
authors: Lay
authors: Chih-Chen
authors: CC
authors: Hong
authors: Jhy-Shrian
authors: JS
authors: Huang
authors: Ya-Yu
authors: YY
authors: Yang
authors: Chung-Yi
authors: CY
authors: Pao
authors: Ching-Hang
authors: CH
authors: Liu
authors: Yi-Pin
authors: YP
authors: Lai
authors: Gi-Ming
authors: GM
authors: Lai
authors: Ann-Lii
authors: AL
authors: Cheng
authors: Ih-Jen
authors: IJ
authors: Su
authors: Shuang-En
authors: SE
authors: Chuang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009361:Neoplasm Invasiveness; D015513:Oncogene Proteins / Q000096:biosynthesis* / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000378:metabolism; D015398:Signal Transduction; D012460:Sulfasalazine / Q000008:administration & dosage / Q000494:pharmacology*; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D016328:NF-kappa B; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D012460:Sulfasalazine; D004317:Doxorubicin; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human