Ueda Jun-ya, Athikomkulchai Sirivan, Miyatake Ryuta, Saiki Ikuo, Esumi Hiroyasu, Awale Suresh
Frontier Research Core for Life Sciences, Toyama, Japan ; Institute of Natural Medicine, University of Toyama, Toyama, Japan.
Faculty of Pharmacy, Srinakharinwirot University, Nakhon Nayok, Thailand, Japan.
Drug Des Devel Ther. 2013 Dec 18;8:39-47. doi: 10.2147/DDDT.S52168. eCollection 2014.
Human pancreatic tumors are known to be highly resistant to nutrient starvation, and this prolongs their survival in the hypovascular (austere) tumor microenvironment. Agents that retard this tolerance to nutrient starvation represent a novel antiausterity strategy in anticancer drug discovery. (+)-Grandifloracin (GF), isolated from Uvaria dac, has shown preferential toxicity to PANC-1 human pancreatic cancer cells under nutrient starvation, with a PC50 value of 14.5 μM. However, the underlying mechanism is not clear. In this study, GF was found to preferentially induce PANC-1 cell death in a nutrient-deprived medium via hyperactivation of autophagy, as evidenced by a dramatic upregulation of microtubule-associated protein 1 light chain 3. No change was observed in expression of the caspase-3 and Bcl-2 apoptosis marker proteins. GF was also found to strongly inhibit the activation of Akt, a key regulator of cancer cell survival and proliferation. Because pancreatic tumors are highly resistant to current therapies that induce apoptosis, the alternative cell death mechanism exhibited by GF provides a novel therapeutic insight into antiausterity drug candidates.
已知人类胰腺肿瘤对营养饥饿具有高度抗性，这延长了它们在低血管（贫瘠）肿瘤微环境中的存活时间。延缓对营养饥饿耐受性的药物代表了抗癌药物发现中的一种新型抗贫瘠策略。从紫玉盘属植物中分离出的（+）-大花弗拉辛（GF）在营养饥饿条件下对PANC-1人胰腺癌细胞表现出优先毒性，半数致死浓度（PC50）值为14.5μM。然而，其潜在机制尚不清楚。在本研究中，发现GF通过自噬的过度激活在营养缺乏的培养基中优先诱导PANC-1细胞死亡，微管相关蛋白1轻链3的显著上调证明了这一点。半胱天冬酶-3和Bcl-2凋亡标记蛋白的表达未观察到变化。还发现GF强烈抑制Akt的激活，Akt是癌细胞存活和增殖的关键调节因子。由于胰腺肿瘤对目前诱导凋亡的疗法具有高度抗性，GF表现出的替代性细胞死亡机制为抗贫瘠候选药物提供了新的治疗思路。
