Chun Kyung-Hee, Kosmeder Jerome W, Sun Shihua, Pezzuto John M, Lotan Reuben, Hong Waun Ki, Lee Ho-Young
Box 432, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
J Natl Cancer Inst. 2003 Feb 19;95(4):291-302. doi: 10.1093/jnci/95.4.291.
Because lung cancer is the leading cause of cancer-related death, new approaches for preventing and controlling the disease are needed. Chemoprevention approaches are both feasible and effective. We evaluated the potential of deguelin, a natural plant product, as a lung cancer chemopreventive agent and investigated its mechanism of action.
The effects of deguelin on proliferation and apoptosis of normal, premalignant, and malignant human bronchial epithelial (HBE) cells were assessed by using the MTT assay, a flow cytometry-based TUNEL assay, and western blot analyses. The effects of deguelin on the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways were assessed by western blot analyses and with adenoviral vectors that expressed constitutively active Akt.
Deguelin treatment in vitro at doses attainable in vivo inhibited the growth of and induced apoptosis of premalignant and malignant HBE cells but had minimal effects on normal HBE cells. Levels of phosphorylated Akt (pAkt) were higher in premalignant HBE cells than in normal HBE cells. In premalignant HBE cells, deguelin inhibited PI3K activity and reduced pAkt levels and activity but had mimimal effects on the MAPK pathway. Although overexpression of a constitutively active Akt in premalignant and malignant HBE cells had no effect on growth inhibition mediated by N-(4-hydroxyphenyl)retinamide (4-HPR), a novel chemopreventive retinoid, it blocked deguelin-induced growth arrest and apoptosis.
The ability of deguelin to inhibit PI3K/Akt-mediated signaling pathways may contribute to the potency and specificity of this pro-apoptotic drug. Because both premalignant and malignant HBE cells are more sensitive to deguelin than normal HBE cells, deguelin may have potential as both a chemopreventive agent for early stages of lung carcinogenesis and a therapeutic agent against lung cancer.
由于肺癌是癌症相关死亡的主要原因，因此需要预防和控制该疾病的新方法。化学预防方法既可行又有效。我们评估了天然植物产物鱼藤素作为肺癌化学预防剂的潜力，并研究了其作用机制。
使用MTT法、基于流式细胞术的TUNEL法和蛋白质印迹分析评估鱼藤素对正常、癌前和恶性人支气管上皮（HBE）细胞增殖和凋亡的影响。通过蛋白质印迹分析和使用组成型活性Akt的腺病毒载体评估鱼藤素对磷脂酰肌醇3-激酶（PI3K）/Akt和丝裂原活化蛋白激酶（MAPK）途径的影响。
体内可达到的剂量的鱼藤素体外处理可抑制癌前和恶性HBE细胞的生长并诱导其凋亡，但对正常HBE细胞的影响最小。癌前HBE细胞中磷酸化Akt（pAkt）的水平高于正常HBE细胞。在癌前HBE细胞中，鱼藤素抑制PI3K活性并降低pAkt水平和活性，但对MAPK途径影响最小。尽管在癌前和恶性HBE细胞中组成型活性Akt的过表达对新型化学预防类视黄醇N-(4-羟基苯基)视黄酰胺（4-HPR）介导的生长抑制没有影响，但它阻断了鱼藤素诱导的生长停滞和凋亡。
鱼藤素抑制PI3K/Akt介导的信号通路的能力可能有助于这种促凋亡药物的效力和特异性。由于癌前和恶性HBE细胞对鱼藤素均比正常HBE细胞更敏感，鱼藤素可能具有作为肺癌发生早期化学预防剂和抗肺癌治疗剂的潜力。
