紫草素诱导人肝细胞肝癌程序性死亡及其分子机制研究
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摘要
癌症是目前人类面临的重大健康问题。其中,肝癌死亡率高、预后差,中国是肝癌患病的高发区。肝癌的治疗手段主要包括手术切除、放射疗法、化学药物治疗等,现今临床上用于肝癌治疗的药物十分有限,发现新型抗肝癌药物意义重大。传统中药是抗癌药物的潜在宝库,从紫草中提取的一种萘醌类物质——紫草素,被证明具有抗肿瘤活性,但其抗癌机制一直不明。本研究对紫草素在体内、体外的抗肝癌活性及其机制进行了初步研究。
细胞程序性死亡是化疗药物有效杀伤肿瘤细胞的重要机制,主要包括细胞凋亡和细胞自噬。本研究结果显示：较低浓度紫草素(≤2.5μM)处理肝癌细胞和正常肝细胞12小时诱导细胞自噬产生。LC3转换检测、GFP-LC3荧光点聚集和吖啶橙染色自噬泡证明了紫草素促进细胞自噬的产生；细胞自噬早期抑制剂3-MA能有效阻断紫草素诱导的细胞自噬；LC3周转和p62降解则从动态上证明了自噬潮的产生。另一方面,Western blot检测细胞凋亡标志蛋白以及Annexin-V FITC/PI双染检测结果表明,较高浓度紫草素(6-8μM)处理24小时可有效诱导肝癌细胞凋亡,但不影响非恶化的肝细胞存活。CASPASE广‘谱抑制剂z-VAD预处理细胞可阻止紫草素诱导的肝癌细胞凋亡,紫草素诱导的细胞凋亡依赖于CASPASE蛋白的剪切。以上实验结果初步表明紫草素能在体外能诱导肝癌细胞发生细胞凋亡和细胞自噬。
诱导活性氧自由基ROS是一些化疗药物诱导肿瘤细胞凋亡的重要分子机制。对紫草素诱导肝癌细胞凋亡和自噬的分子机制研究发现,紫草素处理可导致细胞内ROS积累,并参与细胞凋亡与细胞自噬的调控过程,ROS的清除剂能拯救其诱导的细胞凋亡和细胞自噬。
Akt、RIP/NF-κB等信号分子是影响细胞死活命运的重要蛋白。对紫草素诱导肝癌细胞凋亡的分子机制研究发现,较高浓度(≥4μM)紫草素可抑制Akt、RIP/NF-κB活性,并参与调节紫草素诱导的细胞凋亡。外源过表达这些蛋白能部分拯救紫草素诱导的细胞凋亡,其抑制剂则能与紫草素协同诱导细胞凋亡。此外,我们研究还发现ROS的积累是这些信号通路的上游事件。
Akt/mTOR、MAPK、ATG家族蛋白等是调节细胞自噬的重要通路。对紫草素诱导的肝癌细胞自噬分子机制研究发现,ERK、ATG7参与了紫草素诱导的细胞自噬过程,较低浓度(≤2.5μM)紫草素处理可激活ERK与ATG7,降低其活性可抑制细胞自噬。另外,RIP通路也部分参与了紫草素诱导的细胞自噬过程,过表达RIP可抑制细胞自噬的发生,RIP抑制剂Nec-1能与紫草素协同诱导细胞自噬。在紫草素诱导细胞自噬的过程中,ROS的积累也发生在RIP和ERK的上游。
除体外细胞培养实验外,我们还通过建立Huh7肝癌细胞裸鼠异种移植瘤模型,研究紫草素在体内对肝癌细胞的影响。通过比较肿瘤生长曲线、动物存活率、肿瘤重量,我们发现紫草素在体内也有很好的抑癌效果。动物体重变化曲线和血清谷丙转氨酶活性分析表明紫草素对动物的毒性较低。细胞自噬相关蛋白表达分析和电子显微镜观察结果表明,较低浓度紫草素(每千克裸鼠体重灌胃2.5-5mg)可诱导体内肿瘤发生细胞自噬；细胞凋亡相关蛋白表达分析和TUNEL染色结果表明,在较高浓度紫草素(每千克裸鼠体重灌胃5-10mg)作用下,肿瘤细胞发生细胞凋亡。此外,体内信号通路变化,如细胞凋亡标志蛋白的剪切、LC3的转换、Akt、RIP在细胞凋亡过程中的下调,以及ERK、ATG7在细胞自噬过程中的上调等,也与体外细胞培养的实验结果保持一致。
综上所述,我们研究发现,紫草素既可可通过ROS/Akt、ROS/RIP/NF-κB通路诱导CASPASE依赖的细胞凋亡,也可通过ROS/ERK、ROS/RIP以及ATG7通路诱导细胞自噬发生。因此,本研究表明紫草素可作为细胞凋亡与细胞自噬的诱导剂,在肝癌化学治疗中具有潜在的应用前景。
Cancer is one of the biggest health issues around the world. Most cases of hepatocellular carcinoma (HCC) occur in China, with high mortality rate and bad prognosis. The treatments of hepatocellular carcinoma contain majorly surgical resection, radiotherapy, chemotherapy, and so on. As there are limited types of drugs on clinical treatment for HCC now, it is very important to develop novel anti-HCC drugs. The traditional Chinese medicine (TCM) is a great source for anti-tumor agents. Shikonin a naphthoquinone derived from the Chinese medicinal plant Lithospermum erythrorhizon, shows anti-cancer capability. However, the detailed mechanism is still unclear. In the presented research, we investigated the inhibition effect of shikonin on HCC in vivo and in vitro.
Programmed cell death (PCD) is an essential mechanism for chemotherapeutics killing tumor cells effectively, which mainly contains apoptosis and autophagy. Our results indicated that a low dose of shikonin (2-2.5μM) treatment for a short time (12hours) induced HCC and normal liver cells autophagy, which was determined by LC3conversion assay, GFP-LC3puncta formation, and AV staining.3-MA could block early autophagosome formation induced by shikonin. Autophagic flux was confirmed by LC3turnover assay and degradation of p62. On the other hand, results from Western blot analysis of apoptosis-related proteins and Annexin-V FITC/PI staining plus FACS analysis referred that shikonin treatment at a high dose (6-8μM) and for a long time (24hours) might induce HCC cells but not normal cells apoptotic cell death. Shikonin-induced apoptosis could be blocked by z-VAD, a CASPASE pan-inhibitor, thus it was CASPASE-dependent. Our results showed that shikonin could trigger HCC cell lines apoptosis and autophagy in vitro.
As ROS was reported to be involved in mechanisms of some anti-cancer drugs inducing apoptosis, we next investigated the mechanism and found ROS accumulation after shikonin treatment. The ROS scavengers NAC and Tiron completely blocked apoptosis and autophagy. Therefore, the ROS accumulation played an essential role in shikonin-induced apoptosis and autophagy.
Akt and RIP/NF-κB are important in cell fate decision. In our studies on the mechanism of shikonin-induced apoptosis, downregulation of Akt and RIP/NF-κB activity was found to be involved in shikonin-induced apoptosis. Because ectopic expression of Akt or RIP partly abrogated the effects of shikonin, and downregulation by Akt inhibitor and RIP inhibitor synergistically induced apoptosis in conjunction with shikonin treatment. Moreover, ROS scavengers blocked shikonin-induced inactivation of Akt and RIP/NF-κB, but Akt or RIP/NF-κB did not regulate ROS generation, suggesting that Akt and RIP/NF-κB signals are downstream of ROS generation.
On the other hand, we found that activated the ERK and ATG7are connected to shikonin-induced autophagy, since downregulation of these two pathways led to block of autophagy, and ERK inhibitor enhanced shikonin-induced autophagy. Meanwhile, RIP pathway was involved in autophagy as well, as RIP inhibitor plus shikonin cotreatment triggered enhanced autophagy, and RIP overexpression inhibited autophagy. ROS accumulation was found to be an upper stream event of RIP and ERK pathways as well.
Moreover, experiments in vivo revealed similar results: shikonin treatment in Huh7tumor xenograft model of nude mice caused suppression of tumor growth with a low toxicity to animals. Shikonin induced tumor cells autophagy at a low dose (2.5-5mg/kg body weight) and apoptosis at a high dose (5-10mg/kg body weight in vivo, via the similar pathways as in vitro.
Taken together, our findings suggest that shikonin is an inducer of autophagy and apoptosis, and may be a promising agent in the treatment of liver cancer. The molecular mechanisms of shikonin are induction of apoptosis through ROS/Akt and ROS/RIP/NF-κB pathways, and triggering autophagy via. ROS/ERK、ROS/RIP、 ATG7pathways.
细胞程序性死亡是化疗药物有效杀伤肿瘤细胞的重要机制,主要包括细胞凋亡和细胞自噬。本研究结果显示：较低浓度紫草素(≤2.5μM)处理肝癌细胞和正常肝细胞12小时诱导细胞自噬产生。LC3转换检测、GFP-LC3荧光点聚集和吖啶橙染色自噬泡证明了紫草素促进细胞自噬的产生；细胞自噬早期抑制剂3-MA能有效阻断紫草素诱导的细胞自噬；LC3周转和p62降解则从动态上证明了自噬潮的产生。另一方面,Western blot检测细胞凋亡标志蛋白以及Annexin-V FITC/PI双染检测结果表明,较高浓度紫草素(6-8μM)处理24小时可有效诱导肝癌细胞凋亡,但不影响非恶化的肝细胞存活。CASPASE广‘谱抑制剂z-VAD预处理细胞可阻止紫草素诱导的肝癌细胞凋亡,紫草素诱导的细胞凋亡依赖于CASPASE蛋白的剪切。以上实验结果初步表明紫草素能在体外能诱导肝癌细胞发生细胞凋亡和细胞自噬。
诱导活性氧自由基ROS是一些化疗药物诱导肿瘤细胞凋亡的重要分子机制。对紫草素诱导肝癌细胞凋亡和自噬的分子机制研究发现,紫草素处理可导致细胞内ROS积累,并参与细胞凋亡与细胞自噬的调控过程,ROS的清除剂能拯救其诱导的细胞凋亡和细胞自噬。
Akt、RIP/NF-κB等信号分子是影响细胞死活命运的重要蛋白。对紫草素诱导肝癌细胞凋亡的分子机制研究发现,较高浓度(≥4μM)紫草素可抑制Akt、RIP/NF-κB活性,并参与调节紫草素诱导的细胞凋亡。外源过表达这些蛋白能部分拯救紫草素诱导的细胞凋亡,其抑制剂则能与紫草素协同诱导细胞凋亡。此外,我们研究还发现ROS的积累是这些信号通路的上游事件。
Akt/mTOR、MAPK、ATG家族蛋白等是调节细胞自噬的重要通路。对紫草素诱导的肝癌细胞自噬分子机制研究发现,ERK、ATG7参与了紫草素诱导的细胞自噬过程,较低浓度(≤2.5μM)紫草素处理可激活ERK与ATG7,降低其活性可抑制细胞自噬。另外,RIP通路也部分参与了紫草素诱导的细胞自噬过程,过表达RIP可抑制细胞自噬的发生,RIP抑制剂Nec-1能与紫草素协同诱导细胞自噬。在紫草素诱导细胞自噬的过程中,ROS的积累也发生在RIP和ERK的上游。
除体外细胞培养实验外,我们还通过建立Huh7肝癌细胞裸鼠异种移植瘤模型,研究紫草素在体内对肝癌细胞的影响。通过比较肿瘤生长曲线、动物存活率、肿瘤重量,我们发现紫草素在体内也有很好的抑癌效果。动物体重变化曲线和血清谷丙转氨酶活性分析表明紫草素对动物的毒性较低。细胞自噬相关蛋白表达分析和电子显微镜观察结果表明,较低浓度紫草素(每千克裸鼠体重灌胃2.5-5mg)可诱导体内肿瘤发生细胞自噬；细胞凋亡相关蛋白表达分析和TUNEL染色结果表明,在较高浓度紫草素(每千克裸鼠体重灌胃5-10mg)作用下,肿瘤细胞发生细胞凋亡。此外,体内信号通路变化,如细胞凋亡标志蛋白的剪切、LC3的转换、Akt、RIP在细胞凋亡过程中的下调,以及ERK、ATG7在细胞自噬过程中的上调等,也与体外细胞培养的实验结果保持一致。
综上所述,我们研究发现,紫草素既可可通过ROS/Akt、ROS/RIP/NF-κB通路诱导CASPASE依赖的细胞凋亡,也可通过ROS/ERK、ROS/RIP以及ATG7通路诱导细胞自噬发生。因此,本研究表明紫草素可作为细胞凋亡与细胞自噬的诱导剂,在肝癌化学治疗中具有潜在的应用前景。
Cancer is one of the biggest health issues around the world. Most cases of hepatocellular carcinoma (HCC) occur in China, with high mortality rate and bad prognosis. The treatments of hepatocellular carcinoma contain majorly surgical resection, radiotherapy, chemotherapy, and so on. As there are limited types of drugs on clinical treatment for HCC now, it is very important to develop novel anti-HCC drugs. The traditional Chinese medicine (TCM) is a great source for anti-tumor agents. Shikonin a naphthoquinone derived from the Chinese medicinal plant Lithospermum erythrorhizon, shows anti-cancer capability. However, the detailed mechanism is still unclear. In the presented research, we investigated the inhibition effect of shikonin on HCC in vivo and in vitro.
Programmed cell death (PCD) is an essential mechanism for chemotherapeutics killing tumor cells effectively, which mainly contains apoptosis and autophagy. Our results indicated that a low dose of shikonin (2-2.5μM) treatment for a short time (12hours) induced HCC and normal liver cells autophagy, which was determined by LC3conversion assay, GFP-LC3puncta formation, and AV staining.3-MA could block early autophagosome formation induced by shikonin. Autophagic flux was confirmed by LC3turnover assay and degradation of p62. On the other hand, results from Western blot analysis of apoptosis-related proteins and Annexin-V FITC/PI staining plus FACS analysis referred that shikonin treatment at a high dose (6-8μM) and for a long time (24hours) might induce HCC cells but not normal cells apoptotic cell death. Shikonin-induced apoptosis could be blocked by z-VAD, a CASPASE pan-inhibitor, thus it was CASPASE-dependent. Our results showed that shikonin could trigger HCC cell lines apoptosis and autophagy in vitro.
As ROS was reported to be involved in mechanisms of some anti-cancer drugs inducing apoptosis, we next investigated the mechanism and found ROS accumulation after shikonin treatment. The ROS scavengers NAC and Tiron completely blocked apoptosis and autophagy. Therefore, the ROS accumulation played an essential role in shikonin-induced apoptosis and autophagy.
Akt and RIP/NF-κB are important in cell fate decision. In our studies on the mechanism of shikonin-induced apoptosis, downregulation of Akt and RIP/NF-κB activity was found to be involved in shikonin-induced apoptosis. Because ectopic expression of Akt or RIP partly abrogated the effects of shikonin, and downregulation by Akt inhibitor and RIP inhibitor synergistically induced apoptosis in conjunction with shikonin treatment. Moreover, ROS scavengers blocked shikonin-induced inactivation of Akt and RIP/NF-κB, but Akt or RIP/NF-κB did not regulate ROS generation, suggesting that Akt and RIP/NF-κB signals are downstream of ROS generation.
On the other hand, we found that activated the ERK and ATG7are connected to shikonin-induced autophagy, since downregulation of these two pathways led to block of autophagy, and ERK inhibitor enhanced shikonin-induced autophagy. Meanwhile, RIP pathway was involved in autophagy as well, as RIP inhibitor plus shikonin cotreatment triggered enhanced autophagy, and RIP overexpression inhibited autophagy. ROS accumulation was found to be an upper stream event of RIP and ERK pathways as well.
Moreover, experiments in vivo revealed similar results: shikonin treatment in Huh7tumor xenograft model of nude mice caused suppression of tumor growth with a low toxicity to animals. Shikonin induced tumor cells autophagy at a low dose (2.5-5mg/kg body weight) and apoptosis at a high dose (5-10mg/kg body weight in vivo, via the similar pathways as in vitro.
Taken together, our findings suggest that shikonin is an inducer of autophagy and apoptosis, and may be a promising agent in the treatment of liver cancer. The molecular mechanisms of shikonin are induction of apoptosis through ROS/Akt and ROS/RIP/NF-κB pathways, and triggering autophagy via. ROS/ERK、ROS/RIP、 ATG7pathways.
引文
Ajani JA (2008) Optimizing docetaxel chemotherapy in patients with cancer of the gastric and gastroesophageal junction:evolution of the docetaxel, cisplatin, and 5-fluorouracil regimen. Cancer 113(5):945-955.
Arany I, Megyesi JK, Kaneto H, Price PM and Safirstein RL (2004) Cisplatin-induced cell death is EGFR/src/ERK signaling dependent in mouse proximal tubule cells. American journal of physiology Renal physiology 287(3):F543-549.
Ariff B, Lloyd CR, Khan S, Shariff M, Thillainayagam AV, Bansi DS, Khan SA, Taylor-Robinson SD and Lim AK (2009) Imaging of liver cancer. World journal of gastroenterology: WJG 15(11):1289-1300.
Arzumanyan A, Reis HM and Feitelson MA (2013) Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nature reviews Cancer 13(2):123-135.
Bekaii-Saab T, Markowitz J, Prescott N, Sadee W, Heerema N, Wei L, Dai Z, Papp A, Campbell A, Culler K, Balint C, O'Neil B, Lee RM, Zalupski M, Dancey J, Chen H, Grever M, Eng C and Villalona-Calero M (2009) A multi-institutional phase II study of the efficacy and tolerability of lapatinib in patients with advanced hepatocellular carcinomas. Clinical cancer research: an official journal of the American Association for Cancer Research 15(18): 5895-5901.
Belghiti J, Cortes A, Abdalla EK, Regimbeau JM, Prakash K, Durand F, Sommacale D, Dondero F, Lesurtel M, Sauvanet A, Farges O and Kianmanesh R (2003) Resection prior to liver transplantation for hepatocellular carcinoma. Annals of surgery 238(6):885-892; discussion 892-883.
Bosch FX, Ribes J, Diaz M and Cleries R (2004) Primary liver cancer: worldwide incidence and trends. Gastroenterology 127(5 Suppl 1):S5-S16.
Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, Metivier D, Meley D, Souquere S, Yoshimori T, Pierron G, Codogno P and Kroemer G (2005) Inhibition of macroautophagy triggers apoptosis. Molecular and cellular biology 25(3):1025-1040.
Breitenstein S, Apestegui C, Petrowsky H and Clavien PA (2009) "State of the art" in liver resection and living donor liver transplantation:a worldwide survey of 100 liver centers. World J Surg 33(4):797-803.
Bruix J, Sherman M and American Association for the Study of Liver D (2011) Management of hepatocellular carcinoma: an update. Hepatology 53(3):1020-1022.
Budihardjo I, Oliver H, Lutter M, Luo X and Wang X (1999) Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 15: 269-290.
Cagnol S and Chambard JC (2010) ERK and cell death: mechanisms of ERK-induced cell death--apoptosis, autophagy and senescence. The FEBS journal 277(1):2-21.
Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, Franklin RA and McCubrey JA (2003) Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 17(3):590-603.
Chen MS, Li JQ, Zheng Y, Guo RP, Liang HH, Zhang YQ, Lin XJ and Lau WY (2006) A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Annals of surgery 243(3):321-328.
Chen X, Yang L, Oppenheim JJ and Howard MZ (2002) Cellular pharmacology studies of shikonin derivatives. Phytotherapy research:PTR 16(3):199-209.
Christofferson DE and Yuan J (2010) Necroptosis as an alternative form of programmed cell death. Current opinion in cell biology 22(2):263-268.
Cillo U, Vitale A, Bassanello M, Boccagni P, Brolese A, Zanus G, Burra P, Fagiuoli S, Farinati F, Rugge M and D'Amico DF (2004) Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma. Annals of surgery 239(2):150-159.
Dank M, Zaluski J, Barone C, Valvere V, Yalcin S, Peschel C, Wenczl M, Goker E, Cisar L, Wang K and Bugat R (2008) Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Annals of oncology:official journal of the European Society for Medical Oncology/ESMO 19(8): 1450-1457.
Das BB, Shoemaker L, Subramanian S, Johnsrude C, Recto M and Austin EH (2007) Acute sirolimus pulmonary toxicity in an infant heart transplant recipient: case report and literature review. The Journal of heart and lung transplantation:the official publication of the International Society for Heart Transplantation 26(3):296-298.
de Lope CR, Tremosini S, Forner A, Reig M and Bruix J (2012) Management of HCC. Journal of hepatology 56 Suppl 1:S75-87.
Declercq W, Vanden Berghe T and Vandenabeele P (2009) RIP kinases at the crossroads of cell death and survival. Cell 138(2):229-232.
Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA and Yuan J (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature chemical biology 1(2):112-119.
Degterev A, Maki JL and Yuan J (2013) Activity and specificity of necrostatin-1, small-molecule inhibitor of RIP 1 kinase. Cell death and differentiation 20(2):366.
Deora AA, Hajjar DP and Lander HM (2000) Recruitment and activation of Raf-1 kinase by nitric oxide-activated Ras. Biochemistry 39(32):9901-9908.
Devin A, Lin Y and Liu ZG (2003) The role of the death-domain kinase RIP in tumour-necrosis-factor-induced activation of mitogen-activated protein kinases. EMBO reports 4(6):623-627.
Di Tommaso L, Sangiovanni A, Borzio M, Park YN, Farinati F and Roncalli M (2013) Advanced precancerous lesions in the liver. Best practice & research Clinical gastroenterology 27(2):269-284.
Dice JF (2007) Chaperone-mediated autophagy. Autophagy 3(4):295-299.
Djavaheri-Mergny M, Amelotti M, Mathieu J, Besancon F, Bauvy C and Codogno P (2007) Regulation of autophagy by NFkappaB transcription factor and reactives oxygen species. Autophagy 3(4):390-392.
Djavaheri-Mergny M, Amelotti M, Mathieu J, Besancon F, Bauvy C, Souquere S, Pierron G and Codogno P (2006) NF-kappaB activation represses tumor necrosis factor-alpha-induced autophagy. The Journal of biological chemistry 281(41):30373-30382.
Fattovich G, Stroffolini T, Zagni I and Donato F (2004) Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127(5 Suppl 1):S35-50.
Festjens N, Vanden Berghe T, Cornelis S and Vandenabeele P (2007) PIP1, a kinase on the crossroads of a cell's decision to live or die. Cell Death Differ 14(3):400-410.
Fukuda T, Ahearn M, Roberts A, Mattaliano RJ, Zaal K, Ralston E, Plotz PH and Raben N (2006) Autophagy and mistargeting of therapeutic enzyme in skeletal muscle in Pompe disease. Molecular therapy: the journal of the American Society of Gene Therapy 14(6):831-839.
Galluzzi L, Kepp O and Kroemer G (2009) RIP kinases initiate programmed necrosis. J Mol Cell Biol 1(1):8-10.
Gozuacik D and Kimchi A (2004) Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23(16):2891-2906.
Guo XP, Zhang XY and Zhang SD (1991) [Clinical trial on the effects of shikonin mixture on later stage lung cancer]. Zhong Xi Yi Jie He Za Zhi 11(10):598-599,580.
Haber DA, Bell DW, Sordella R, Kwak EL, Godin-Heymann N, Sharma SV, Lynch TJ and Settleman J (2005) Molecular targeted therapy of lung cancer: EGFR mutations and response to EGFR inhibitors. Cold Spring Harbor symposia on quantitative biology 70:419-426.
Heinzelmann S and Bauer G Multiple protective functions of catalase against intercellular apoptosis-inducing ROS signaling of human tumor cells. Biol Chem.
Hsu H, Huang J, Shu HB, Baichwal V and Goeddel DV (1996) TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 4(4):387-396.
Hsu PC, Huang YT, Tsai ML, Wang YJ, Lin JK and Pan MH (2004) Induction of apoptosis by shikonin through coordinative modulation of the Bcl-2 family, p27, and p53, release of cytochrome c, and sequential activation of caspases in human colorectal carcinoma cells. Journal of agricultural and food chemistry 52(20):6330-6337.
Jacobson MD (1996) Reactive oxygen species and programmed cell death. Trends Biochem Sci 21(3):83-86.
Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D (2011) Global cancer statistics. CA: a cancer journal for clinicians 61(2):69-90.
Jeong SW, Jang JY and Chung RT (2012) Hepatitis C virus and hepatocarcinogenesis. Clinical and molecular hepatology 18(4):347-356.
Jiang C, Wang Z, Ganther H and Lu J (2001) Caspases as key executors of methyl selenium-induced apoptosis (anoikis) of DU-145 prostate cancer cells. Cancer Res 61(7): 3062-3070.
Kane RC, Farrell AT, Madabushi R, Booth B, Chattopadhyay S, Sridhara R, Justice R and Pazdur R (2009) Sorafenib for the treatment of unresectable hepatocellular carcinoma. The oncologist 14(1):95-100.
Kelley RK (2013) Brivanib and FOLFOX in Hepatocellular Carcinoma:Finding the Common Themes Among Negative Trials. Journal of clinical oncology:official journal of the American Society of Clinical Oncology 31(28):3483-3486.
Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ and Leder P (1998) The death domain kinase RIP mediates the TNF-induced NF-kappaB signal. Immunity 8(3):297-303.
Kensler TW, Roebuck BD, Wogan GN and Groopman JD (2011) Aflatoxin: a 50-year odyssey of mechanistic and translational toxicology. Toxicological sciences:an official journal of the Society of Toxicology 120 Suppl 1:S28-48.
Khan SA, Davidson BR, Goldin RD, Heaton N, Karani J, Pereira SP, Rosenberg WM, Tait P, Taylor-Robinson SD, Thillainayagam AV, Thomas HC, Wasan H and British Society of G (2012) Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update. Gut 61(12): 1657-1669.
Kim Y, Suh N, Sporn M and Reed JC (2002) An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis. JBiol Chem 277(25):22320-22329.
Kimmelman AC (2011) The dynamic nature of autophagy in cancer. Genes & development 25(19):1999-2010.
Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S, Hamazaki J, Nishito Y, Iemura S, Natsume T, Yanagawa T, Uwayama J, Warabi E, Yoshida H, Ishii T, Kobayashi A, Yamamoto M, Yue Z, Uchiyama Y, Kominami E and Tanaka K (2007) Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131(6):1149-1163.
Lee HS, Kim JS, Choi IJ, Chung JW, Park JH and Kim CY (1997) The safety and efficacy of transcatheter arterial chemoembolization in the treatment of patients with hepatocellular carcinoma and main portal vein obstruction. A prospective controlled study. Cancer 79(11): 2087-2094.
Lee JH, Jung KM, Bae IH, Cho S, Seo DB, Lee SJ, Park YH and Lim KM (2009) Anti-inflammatory and barrier protecting effect of Lithospermum erythrorhizon extracts in chronic oxazolone-induced murine atopic dermatitis. Journal of dermatological science 56(1):64-66.
Levine B and Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132(1): 27-42.
Li X, Yan J, Wang L, Xiao F, Yang Y, Guo X and Wang H (2013) Beclinl inhibition promotes autophagy and decreases gemcitabine-induced apoptosis in Miapaca2 pancreatic cancer cells. Cancer cell international 13(1):26.
Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M, Kondo S, Dumont DJ, Gutterman JU, Walker CL, Slingerland JM and Mills GB (2007) The energy sensing LKB1-AMPK pathway regulates p27(kipl) phosphorylation mediating the decision to enter autophagy or apoptosis. Nature cell biology 9(2):218-224.
Liu B, Cheng Y, Zhang B, Bian HJ and Bao JK (2009) Polygonatum cyrtonema lectin induces apoptosis and autophagy in human melanoma A375 cells through a mitochondria-mediated ROS-p38-p53 pathway. Cancer letters 275(1):54-60.
Liu Yan ME-m, Ni Jiati-rehemu (2006) Protective Effects of Arnebia euchroma (Royle) Johnston Extracts Against CC14-induced Acute Liver Injury in Mice. Lishizhen Medicine and Materia Medica Research 17(9).
Llovet JM, Burroughs A and Bruix J (2003) Hepatocellular carcinoma. Lancet 362(9399): 1907-1917.
Long S, GuangZhi Y, BaoJie G, Wei X, YanYong H, YingLi W, Yang Z and LiHua L (2012) Shikonin derivatives protect immune organs from damage and promote immune responses in vivo in tumour-bearing mice. Phytotherapy research: PTR 26(1):26-33.
Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, Bikbov B, Bin Abdulhak A, Birbeck G, Blyth F, Bolliger I, Boufous S, Bucello C, Burch M, Burney P, Carapetis J, Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahodwala N, De Leo D, Degenhardt L, Delossantos A, Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Ezzati M, Feigin V, Flaxman AD, Forouzanfar MH, Fowkes FG, Franklin R, Fransen M, Freeman MK, Gabriel SE, Gakidou E, Gaspari F, Gillum RF, Gonzalez-Medina D, Halasa YA, Haring D, Harrison JE, Havmoeller R, Hay RJ, Hoen B, Hotez PJ, Hoy D, Jacobsen KH, James SL, Jasrasaria R, Jayaraman S, Johns N, Karthikeyan G, Kassebaum N, Keren A, Khoo JP, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lipnick M, Lipshultz SE, Ohno SL, Mabweijano J, MacIntyre MF, Mallinger L, March L, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGrath J, Mensah GA, Merriman TR, Michaud C, Miller M, Miller TR, Mock C, Mocumbi AO, Mokdad AA, Moran A, Mulholland K, Nair MN, Naldi L, Narayan KM, Nasseri K, Norman P, O'Donnell M, Omer SB, Ortblad K, Osborne R, Ozgediz D, Pahari B, Pandian JD, Rivero AP, Padilla RP, Perez-Ruiz F, Perico N, Phillips D, Pierce K, Pope CA, 3rd, Porrini E, Pourmalek F, Raju M, Ranganathan D, Rehm JT, Rein DB, Remuzzi G, Rivara FP, Roberts T, De Leon FR, Rosenfeld LC, Rushton L, Sacco RL, Salomon JA, Sampson U, Sanman E, Schwebel DC, Segui-Gomez M, Shepard DS, Singh D, Singleton J, Sliwa K, Smith E, Steer A, Taylor JA, Thomas B, Tleyjeh IM, Towbin JA, Truelsen T, Undurraga EA, Venketasubramanian N, Vijayakumar L, Vos T, Wagner GR, Wang M, Wang W, Watt K, Weinstock MA, Weintraub R, Wilkinson JD, Woolf AD, Wulf S, Yeh PH, Yip P, Zabetian A, Zheng ZJ, Lopez AD, Murray CJ, AlMazroa MA and Memish ZA (2012) Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010:a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380(9859): 2095-2128.
Luo X, Budihardjo I, Zou H, Slaughter C and Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94(4):481-490.
Mahmut-Maierdan LY, Hujia-Gulixian, Zhang Guo-qing (2007) The hepatoprotective effects of Arnebia euchroma (Royle) Johnston extracts against alcohol-induced acute liver injury in mice. Chinese Remedies & Clinics 7(4).
Maiuri MC, Zalckvar E, Kimchi A and Kroemer G (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nature reviews Molecular cell biology 8(9):741-752.
Mao X, Yu CR, Li WH and Li WX (2008) Induction of apoptosis by shikonin through a ROS/JNK-mediated process in Bcr/Abl-positive chronic myelogenous leukemia (CML) cells. Cell research 18(8):879-888.
Marciniak SJ and Lomas DA (2010) Alphal-antitrypsin deficiency and autophagy. The New England journal of medicine 363(19):1863-1864.
Martinet W, Agostinis P, Vanhoecke B, Dewaele M and De Meyer GR (2009) Autophagy in disease: a double-edged sword with therapeutic potential. Clinical science 116(9):697-712.
Mathew R and White E (2011) Autophagy in tumorigenesis and energy metabolism:friend by day, foe by night. Current opinion in genetics & development 21(1):113-119.
McAlister VC, Mahalati K, Peltekian KM, Fraser A and MacDonald AS (2002) A clinical pharmacokinetic study of tacrolimus and sirolimus combination immunosuppression comparing simultaneous to separated administration. Therapeutic drug monitoring 24(3):346-350.
Meylan E and Tschopp J (2005) The RIP kinases: crucial integrators of cellular stress. Trends Biochem Sci 30(3):151-159.
Min R, Tong J, Wenjun Y, Wenhu D, Xiaojian Z, Jiacai H, Jian Z, Wantao C and Chenping Z (2008) Growth inhibition and induction of apoptosis in human oral squamous cell carcinoma Tca-8113 cell lines by Shikonin was partly through the inactivation of NF-kappaB pathway. Phytotherapy research: PTR 22(3):407-415.
Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME and Dixit VM (1996) FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. Cell 85(6):817-827.
Obed A, Tsui TY, Schnitzbauer AA, Obed M, Schlitt HJ, Becker H and Lorf T (2008) Liver transplantation as curative approach for advanced hepatocellular carcinoma:is it justified? Langenbeck's archives of surgery/Deutsche Gesellschaft fur Chirurgie 393(2):141-147.
Oliver FJ, de la Rubia G, Rolli V, Ruiz-Ruiz MC, de Murcia G and Murcia J M (1998) Importance of poly(ADP-ribose) polymerase and its cleavage in apoptosis. Lesson from an uncleavable mutant. JBiol Chem 273(50):33533-33539.
Organization WH (2006) Cancer.
Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Overvatn A, Bjorkoy G and Johansen T (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. The Journal of biological chemistry 282(33): 24131-24145.
Papaiahgari S, Zhang Q, Kleeberger SR, Cho HY and Reddy SP (2006) Hyperoxia stimulates an Nrf2-ARE transcriptional response via ROS-EGFR-PI3K-Akt/ERK MAP kinase signaling in pulmonary epithelial cells. Antioxid Redox Signal 8(1-2):43-52.
Papathanasiou K, Papageorgiou C, Panidis D and Mantalenakis S (1999) Our experience in laparoscopic diagnosis and management in women with chronic pelvic pain. Clin Exp Obstet Gynecol 26(3-4):190-192.
Park KJ, Lee SH, Lee CH, Jang JY, Chung J, Kwon MH and Kim YS (2009) Upregulation of Beclin-1 expression and phosphorylation of Bcl-2 and p53 are involved in the JNK-mediated autophagic cell death. Biochemical and biophysical research communications 382(4):726-729.
Pelicano H, Carney D and Huang P (2004) ROS stress in cancer cells and therapeutic implications. Drug resistance updates:reviews and commentaries in antimicrobial and anticancer chemotherapy 7(2):97-110.
Pham PT, Pham PC, Danovitch GM, Ross DJ, Gritsch HA, Kendrick EA, Singer J, Shah T and Wilkinson AH (2004) Sirolimus-associated pulmonary toxicity. Transplantation 77(8): 1215-1220.
Pimentel-Muinos FX and Seed B (1999) Regulated commitment of TNF receptor signaling: a molecular switch for death or activation. Immunity 11(6):783-793.
Powers RW, 3rd, Kaeberlein M, Caldwell SD, Kennedy BK and Fields S (2006) Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes & development 20(2): 174-184.
Qing G, Yan P and Xiao G (2006) Hsp90 inhibition results in autophagy-mediated proteasome-independent degradation of IkappaB kinase (IKK). Cell research 16(11):895-901.
Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y, Cattoretti G and Levine B (2003) Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. The Journal of clinical investigation 112(12): 1809-1820.
Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, Jimenez-Sanchez M, Korolchuk VI, Lichtenberg M, Luo S, Massey DC, Menzies FM, Moreau K, Narayanan U, Renna M, Siddiqi FH, Underwood BR, Winslow AR and Rubinsztein DC (2010) Regulation of mammalian autophagy in physiology and pathophysiology. Physiological reviews 90(4):1383-1435.
Rosen HR (2011) Clinical practice. Chronic hepatitis C infection. The New England journal of medicine 364(25):2429-2438.
Samuelsen JT, Dahl JE, Karlsson S, Morisbak E and Becher R (2007) Apoptosis induced by the monomers HEMA and TEGDMA involves formation of ROS and differential activation of the MAP-kinases p38, JNK and ERK. Dental materials: official publication of the Academy of Dental Materials 23(1):34-39.
Seger R and Krebs EG (1995) The MAPK signaling cascade. FASEB J 9(9):726-735.
Shaw RJ (2008) mTOR signaling: RAG GTPases transmit the amino acid signal. Trends in biochemical sciences 33(12):565-568.
Simon HU, Haj-Yehia A and Levi-Schaffer F (2000) Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5(5):415-418.
Slee EA, Zhu H, Chow SC, MacFarlane M, Nicholson DW and Cohen GM (1996) Benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (Z-VAD.FMK) inhibits apoptosis by blocking the processing of CPP32. Biochem J 315 (Pt 1):21-24.
Song J, Qu Z, Guo X, Zhao Q, Zhao X, Gao L, Sun K, Shen F, Wu M and Wei L (2009) Hypoxia-induced autophagy contributes to the chemoresistance of hepatocellular carcinoma cells. Autophagy 5(8):1131-1144.
Sun Z, Ming L, Zhu X and Lu J (2002) Prevention and control of hepatitis B in China. Journal of medical virology 67(3):447-450.
Sun ZJ, Chen G, Hu X, Zhang W, Liu Y, Zhu LX, Zhou Q and Zhao YF Activation of PI3K/Akt/IKK-alpha/NF-kappaB signaling pathway is required for the apoptosis-evasion in human salivary adenoid cystic carcinoma:its inhibition by quercetin. Apoptosis.
Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C, Waguri S, Eishi Y, Hino O, Tanaka K and Mizushima N (2011) Autophagy-deficient mice develop multiple liver tumors. Genes & development 25(8):795-800.
Talloczy Z, Virgin HWt and Levine B (2006) PKR-dependent autophagic degradation of herpes simplex virus type 1. Autophagy 2(1):24-29.
Thangapazham RL, Singh AK, Seth P, Misra N, Mathad VT, Raj K and Maheshwari RK (2008) Shikonin analogue (SA) 93/637 induces apoptosis by activation of caspase-3 in U937 cells. Front Biosci 13:561-568.
Thyagarajan A, Jedinak A, Nguyen H, Terry C, Baldridge LA, Jiang J and Sliva D (2010) Triterpenes from Ganoderma Lucidum induce autophagy in colon cancer through the inhibition of p38 mitogen-activated kinase (p38 MAPK). Nutrition and cancer 62(5):630-640.
Ting AT, Pimentel-Muinos FX and Seed B (1996) RIP mediates tumor necrosis factor receptor 1 activation of NF-kappaB but not Fas/APO-1-initiated apoptosis. The EMBO journal 15(22):6189-6196.
Trachootham D, Alexandre J and Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms:a radical therapeutic approach? Nat Rev Drug Discov 8(7):579-591.
Tsang WP, Chau SP, Kong SK, Fung KP and Kwok TT (2003) Reactive oxygen species mediate doxorubicin induced p53-independent apoptosis. Life Sci 73(16):2047-2058.
Underwood BR, Imarisio S, Fleming A, Rose C, Krishna G, Heard P, Quick M, Korolchuk VI, Renna M, Sarkar S, Garcia-Arencibia M, O'Kane CJ, Murphy MP and Rubinsztein DC (2010) Antioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease. Human molecular genetics 19(17):3413-3429.
Vandenabeele P, Grootjans S, Callewaert N and Takahashi N (2013) Necrostatin-1 blocks both RIPK1 and IDO: consequences for the study of cell death in experimental disease models. Cell death and differentiation 20(2):185-187.
Vindis C, Seguelas MH, Lanier S, Parini A and Cambon C (2001) Dopamine induces ERK activation in renal epithelial cells through H2O2 produced by monoamine oxidase. Kidney international 59(1):76-86.
Vivanco I and Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2(7):489-501.
Wang Z, Liu T, Gan L, Wang T, Yuan X, Zhang B, Chen H and Zheng Q (2010) Shikonin protects mouse brain against cerebral ischemia/reperfusion injury through its antioxidant activity. European journal of pharmacology 643(2-3):211-217.
White E and DiPaola RS (2009) The double-edged sword of autophagy modulation in cancer. Clinical cancer research: an official journal of the American Association for Cancer Research 15(17):5308-5316.
Wu Z, Wu L, Li L, Tashiro S, Onodera S and Ikejima T (2004a) p53-mediated cell cycle arrest and apoptosis induced by shikonin via a caspase-9-dependent mechanism in human malignant melanoma A375-S2 cells. Journal of pharmacological sciences 94(2):166-176.
Wu Z, Wu LJ, Li LH, Tashiro S, Onodera S and Ikejima T (2004b) Shikonin regulates HeLa cell death via caspase-3 activation and blockage of DNA synthesis. Journal of Asian natural products research 6(3):155-166.
Xie X, Le L, Fan Y, Lv L and Zhang J (2012) Autophagy is induced through the ROS-TP53-DRAM1 pathway in response to mitochondrial protein synthesis inhibition. Autophagy 8(7):1071-1084.
Yamamoto A, Morisawa Y, Verloes A, Murakami N, Hirano M, Nonaka I and Nishino I (2001a) Infantile autophagic vacuolar myopathy is distinct from Danon disease. Neurology 57(5): 903-905.
Yamamoto J, Okada S, Shimada K, Okusaka T, Yamasaki S, Ueno H and Kosuge T (2001b) Treatment strategy for small hepatocellular carcinoma: comparison of long-term results after percutaneous ethanol injection therapy and surgical resection. Hepatology 34(4 Pt 1):707-713.
Yang H, Zhou P, Huang H, Chen D, Ma N, Cui QC, Shen S, Dong W, Zhang X, Lian W, Wang X, Dou QP and Liu J (2008) Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivo. Int J Cancer.
Yeh CC, Kuo HM, Li TM, Lin JP, Yu FS, Lu HF, Chung JG and Yang JS (2007) Shikonin-induced apoptosis involves caspase-3 activity in a human bladder cancer cell line (T24). In vivo 21(6):1011-1019.
Youle RJ and Strasser A (2008) The BCL-2 protein family:opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9(1):47-59.
Yue Z, Jin S, Yang C, Levine AJ and Heintz N (2003) Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proceedings of the National Academy of Sciences of the United States of America 100(25):15077-15082.
Zellerhoff C, Schneider S, Senges J, Pfannebecker T, Hamm C and Tebbe U (2008) Sirolimus-eluting stents in the treatment of chronic total coronary occlusions:results from the prospective multi-center German Cypher Stent Registry. Clinical research in cardiology:official journal of the German Cardiac Society 97(4):253-259.
Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J, Fan ST, Luk JM, Wigler M, Hannon GJ, Mu D, Lucito R, Powers S and Lowe SW (2006) Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125(7): 1253-1267.
Zhan Y, Gong K, Chen C, Wang H and Li W (2012) P38 MAP kinase functions as a switch in MS-275-induced reactive oxygen species-dependent autophagy and apoptosis in human colon cancer cells. Free radical biology & medicine 53(3):532-543.
Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, Dong MQ and Han J (2009) RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325(5938):332-336.
Zhang P, Wang YZ, Kagan E and Bonner JC (2000) Peroxynitrite targets the epidermal growth factor receptor, Raf-1, and MEK independently to activate MAPK. The Journal of biological chemistry 275(29):22479-22486.
Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, Lecker SH and Goldberg AL (2007) Fox03 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell metabolism 6(6):472-483.
Zhou L, Liu J and Luo F (2006) Serum tumor markers for detection of hepatocellular carcinoma. World journal of gastroenterology:WJG 12(8):1175-1181.
Zhu AX, Sahani DV, Duda DG, di Tomaso E, Ancukiewicz M, Catalano OA, Sindhwani V, Blaszkowsky LS, Yoon SS, Lahdenranta J, Bhargava P, Meyerhardt J, Clark JW, Kwak EL, Hezel AF, Miksad R, Abrams TA, Enzinger PC, Fuchs CS, Ryan DP and Jain RK (2009) Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase Ⅱstudy. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 27(18):3027-3035.
Arany I, Megyesi JK, Kaneto H, Price PM and Safirstein RL (2004) Cisplatin-induced cell death is EGFR/src/ERK signaling dependent in mouse proximal tubule cells. American journal of physiology Renal physiology 287(3):F543-549.
Ariff B, Lloyd CR, Khan S, Shariff M, Thillainayagam AV, Bansi DS, Khan SA, Taylor-Robinson SD and Lim AK (2009) Imaging of liver cancer. World journal of gastroenterology: WJG 15(11):1289-1300.
Arzumanyan A, Reis HM and Feitelson MA (2013) Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nature reviews Cancer 13(2):123-135.
Bekaii-Saab T, Markowitz J, Prescott N, Sadee W, Heerema N, Wei L, Dai Z, Papp A, Campbell A, Culler K, Balint C, O'Neil B, Lee RM, Zalupski M, Dancey J, Chen H, Grever M, Eng C and Villalona-Calero M (2009) A multi-institutional phase II study of the efficacy and tolerability of lapatinib in patients with advanced hepatocellular carcinomas. Clinical cancer research: an official journal of the American Association for Cancer Research 15(18): 5895-5901.
Belghiti J, Cortes A, Abdalla EK, Regimbeau JM, Prakash K, Durand F, Sommacale D, Dondero F, Lesurtel M, Sauvanet A, Farges O and Kianmanesh R (2003) Resection prior to liver transplantation for hepatocellular carcinoma. Annals of surgery 238(6):885-892; discussion 892-883.
Bosch FX, Ribes J, Diaz M and Cleries R (2004) Primary liver cancer: worldwide incidence and trends. Gastroenterology 127(5 Suppl 1):S5-S16.
Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, Metivier D, Meley D, Souquere S, Yoshimori T, Pierron G, Codogno P and Kroemer G (2005) Inhibition of macroautophagy triggers apoptosis. Molecular and cellular biology 25(3):1025-1040.
Breitenstein S, Apestegui C, Petrowsky H and Clavien PA (2009) "State of the art" in liver resection and living donor liver transplantation:a worldwide survey of 100 liver centers. World J Surg 33(4):797-803.
Bruix J, Sherman M and American Association for the Study of Liver D (2011) Management of hepatocellular carcinoma: an update. Hepatology 53(3):1020-1022.
Budihardjo I, Oliver H, Lutter M, Luo X and Wang X (1999) Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 15: 269-290.
Cagnol S and Chambard JC (2010) ERK and cell death: mechanisms of ERK-induced cell death--apoptosis, autophagy and senescence. The FEBS journal 277(1):2-21.
Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, Franklin RA and McCubrey JA (2003) Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 17(3):590-603.
Chen MS, Li JQ, Zheng Y, Guo RP, Liang HH, Zhang YQ, Lin XJ and Lau WY (2006) A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Annals of surgery 243(3):321-328.
Chen X, Yang L, Oppenheim JJ and Howard MZ (2002) Cellular pharmacology studies of shikonin derivatives. Phytotherapy research:PTR 16(3):199-209.
Christofferson DE and Yuan J (2010) Necroptosis as an alternative form of programmed cell death. Current opinion in cell biology 22(2):263-268.
Cillo U, Vitale A, Bassanello M, Boccagni P, Brolese A, Zanus G, Burra P, Fagiuoli S, Farinati F, Rugge M and D'Amico DF (2004) Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma. Annals of surgery 239(2):150-159.
Dank M, Zaluski J, Barone C, Valvere V, Yalcin S, Peschel C, Wenczl M, Goker E, Cisar L, Wang K and Bugat R (2008) Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Annals of oncology:official journal of the European Society for Medical Oncology/ESMO 19(8): 1450-1457.
Das BB, Shoemaker L, Subramanian S, Johnsrude C, Recto M and Austin EH (2007) Acute sirolimus pulmonary toxicity in an infant heart transplant recipient: case report and literature review. The Journal of heart and lung transplantation:the official publication of the International Society for Heart Transplantation 26(3):296-298.
de Lope CR, Tremosini S, Forner A, Reig M and Bruix J (2012) Management of HCC. Journal of hepatology 56 Suppl 1:S75-87.
Declercq W, Vanden Berghe T and Vandenabeele P (2009) RIP kinases at the crossroads of cell death and survival. Cell 138(2):229-232.
Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA and Yuan J (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature chemical biology 1(2):112-119.
Degterev A, Maki JL and Yuan J (2013) Activity and specificity of necrostatin-1, small-molecule inhibitor of RIP 1 kinase. Cell death and differentiation 20(2):366.
Deora AA, Hajjar DP and Lander HM (2000) Recruitment and activation of Raf-1 kinase by nitric oxide-activated Ras. Biochemistry 39(32):9901-9908.
Devin A, Lin Y and Liu ZG (2003) The role of the death-domain kinase RIP in tumour-necrosis-factor-induced activation of mitogen-activated protein kinases. EMBO reports 4(6):623-627.
Di Tommaso L, Sangiovanni A, Borzio M, Park YN, Farinati F and Roncalli M (2013) Advanced precancerous lesions in the liver. Best practice & research Clinical gastroenterology 27(2):269-284.
Dice JF (2007) Chaperone-mediated autophagy. Autophagy 3(4):295-299.
Djavaheri-Mergny M, Amelotti M, Mathieu J, Besancon F, Bauvy C and Codogno P (2007) Regulation of autophagy by NFkappaB transcription factor and reactives oxygen species. Autophagy 3(4):390-392.
Djavaheri-Mergny M, Amelotti M, Mathieu J, Besancon F, Bauvy C, Souquere S, Pierron G and Codogno P (2006) NF-kappaB activation represses tumor necrosis factor-alpha-induced autophagy. The Journal of biological chemistry 281(41):30373-30382.
Fattovich G, Stroffolini T, Zagni I and Donato F (2004) Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127(5 Suppl 1):S35-50.
Festjens N, Vanden Berghe T, Cornelis S and Vandenabeele P (2007) PIP1, a kinase on the crossroads of a cell's decision to live or die. Cell Death Differ 14(3):400-410.
Fukuda T, Ahearn M, Roberts A, Mattaliano RJ, Zaal K, Ralston E, Plotz PH and Raben N (2006) Autophagy and mistargeting of therapeutic enzyme in skeletal muscle in Pompe disease. Molecular therapy: the journal of the American Society of Gene Therapy 14(6):831-839.
Galluzzi L, Kepp O and Kroemer G (2009) RIP kinases initiate programmed necrosis. J Mol Cell Biol 1(1):8-10.
Gozuacik D and Kimchi A (2004) Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23(16):2891-2906.
Guo XP, Zhang XY and Zhang SD (1991) [Clinical trial on the effects of shikonin mixture on later stage lung cancer]. Zhong Xi Yi Jie He Za Zhi 11(10):598-599,580.
Haber DA, Bell DW, Sordella R, Kwak EL, Godin-Heymann N, Sharma SV, Lynch TJ and Settleman J (2005) Molecular targeted therapy of lung cancer: EGFR mutations and response to EGFR inhibitors. Cold Spring Harbor symposia on quantitative biology 70:419-426.
Heinzelmann S and Bauer G Multiple protective functions of catalase against intercellular apoptosis-inducing ROS signaling of human tumor cells. Biol Chem.
Hsu H, Huang J, Shu HB, Baichwal V and Goeddel DV (1996) TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 4(4):387-396.
Hsu PC, Huang YT, Tsai ML, Wang YJ, Lin JK and Pan MH (2004) Induction of apoptosis by shikonin through coordinative modulation of the Bcl-2 family, p27, and p53, release of cytochrome c, and sequential activation of caspases in human colorectal carcinoma cells. Journal of agricultural and food chemistry 52(20):6330-6337.
Jacobson MD (1996) Reactive oxygen species and programmed cell death. Trends Biochem Sci 21(3):83-86.
Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D (2011) Global cancer statistics. CA: a cancer journal for clinicians 61(2):69-90.
Jeong SW, Jang JY and Chung RT (2012) Hepatitis C virus and hepatocarcinogenesis. Clinical and molecular hepatology 18(4):347-356.
Jiang C, Wang Z, Ganther H and Lu J (2001) Caspases as key executors of methyl selenium-induced apoptosis (anoikis) of DU-145 prostate cancer cells. Cancer Res 61(7): 3062-3070.
Kane RC, Farrell AT, Madabushi R, Booth B, Chattopadhyay S, Sridhara R, Justice R and Pazdur R (2009) Sorafenib for the treatment of unresectable hepatocellular carcinoma. The oncologist 14(1):95-100.
Kelley RK (2013) Brivanib and FOLFOX in Hepatocellular Carcinoma:Finding the Common Themes Among Negative Trials. Journal of clinical oncology:official journal of the American Society of Clinical Oncology 31(28):3483-3486.
Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ and Leder P (1998) The death domain kinase RIP mediates the TNF-induced NF-kappaB signal. Immunity 8(3):297-303.
Kensler TW, Roebuck BD, Wogan GN and Groopman JD (2011) Aflatoxin: a 50-year odyssey of mechanistic and translational toxicology. Toxicological sciences:an official journal of the Society of Toxicology 120 Suppl 1:S28-48.
Khan SA, Davidson BR, Goldin RD, Heaton N, Karani J, Pereira SP, Rosenberg WM, Tait P, Taylor-Robinson SD, Thillainayagam AV, Thomas HC, Wasan H and British Society of G (2012) Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update. Gut 61(12): 1657-1669.
Kim Y, Suh N, Sporn M and Reed JC (2002) An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis. JBiol Chem 277(25):22320-22329.
Kimmelman AC (2011) The dynamic nature of autophagy in cancer. Genes & development 25(19):1999-2010.
Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S, Hamazaki J, Nishito Y, Iemura S, Natsume T, Yanagawa T, Uwayama J, Warabi E, Yoshida H, Ishii T, Kobayashi A, Yamamoto M, Yue Z, Uchiyama Y, Kominami E and Tanaka K (2007) Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131(6):1149-1163.
Lee HS, Kim JS, Choi IJ, Chung JW, Park JH and Kim CY (1997) The safety and efficacy of transcatheter arterial chemoembolization in the treatment of patients with hepatocellular carcinoma and main portal vein obstruction. A prospective controlled study. Cancer 79(11): 2087-2094.
Lee JH, Jung KM, Bae IH, Cho S, Seo DB, Lee SJ, Park YH and Lim KM (2009) Anti-inflammatory and barrier protecting effect of Lithospermum erythrorhizon extracts in chronic oxazolone-induced murine atopic dermatitis. Journal of dermatological science 56(1):64-66.
Levine B and Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132(1): 27-42.
Li X, Yan J, Wang L, Xiao F, Yang Y, Guo X and Wang H (2013) Beclinl inhibition promotes autophagy and decreases gemcitabine-induced apoptosis in Miapaca2 pancreatic cancer cells. Cancer cell international 13(1):26.
Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M, Kondo S, Dumont DJ, Gutterman JU, Walker CL, Slingerland JM and Mills GB (2007) The energy sensing LKB1-AMPK pathway regulates p27(kipl) phosphorylation mediating the decision to enter autophagy or apoptosis. Nature cell biology 9(2):218-224.
Liu B, Cheng Y, Zhang B, Bian HJ and Bao JK (2009) Polygonatum cyrtonema lectin induces apoptosis and autophagy in human melanoma A375 cells through a mitochondria-mediated ROS-p38-p53 pathway. Cancer letters 275(1):54-60.
Liu Yan ME-m, Ni Jiati-rehemu (2006) Protective Effects of Arnebia euchroma (Royle) Johnston Extracts Against CC14-induced Acute Liver Injury in Mice. Lishizhen Medicine and Materia Medica Research 17(9).
Llovet JM, Burroughs A and Bruix J (2003) Hepatocellular carcinoma. Lancet 362(9399): 1907-1917.
Long S, GuangZhi Y, BaoJie G, Wei X, YanYong H, YingLi W, Yang Z and LiHua L (2012) Shikonin derivatives protect immune organs from damage and promote immune responses in vivo in tumour-bearing mice. Phytotherapy research: PTR 26(1):26-33.
Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, Bikbov B, Bin Abdulhak A, Birbeck G, Blyth F, Bolliger I, Boufous S, Bucello C, Burch M, Burney P, Carapetis J, Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahodwala N, De Leo D, Degenhardt L, Delossantos A, Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Ezzati M, Feigin V, Flaxman AD, Forouzanfar MH, Fowkes FG, Franklin R, Fransen M, Freeman MK, Gabriel SE, Gakidou E, Gaspari F, Gillum RF, Gonzalez-Medina D, Halasa YA, Haring D, Harrison JE, Havmoeller R, Hay RJ, Hoen B, Hotez PJ, Hoy D, Jacobsen KH, James SL, Jasrasaria R, Jayaraman S, Johns N, Karthikeyan G, Kassebaum N, Keren A, Khoo JP, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lipnick M, Lipshultz SE, Ohno SL, Mabweijano J, MacIntyre MF, Mallinger L, March L, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGrath J, Mensah GA, Merriman TR, Michaud C, Miller M, Miller TR, Mock C, Mocumbi AO, Mokdad AA, Moran A, Mulholland K, Nair MN, Naldi L, Narayan KM, Nasseri K, Norman P, O'Donnell M, Omer SB, Ortblad K, Osborne R, Ozgediz D, Pahari B, Pandian JD, Rivero AP, Padilla RP, Perez-Ruiz F, Perico N, Phillips D, Pierce K, Pope CA, 3rd, Porrini E, Pourmalek F, Raju M, Ranganathan D, Rehm JT, Rein DB, Remuzzi G, Rivara FP, Roberts T, De Leon FR, Rosenfeld LC, Rushton L, Sacco RL, Salomon JA, Sampson U, Sanman E, Schwebel DC, Segui-Gomez M, Shepard DS, Singh D, Singleton J, Sliwa K, Smith E, Steer A, Taylor JA, Thomas B, Tleyjeh IM, Towbin JA, Truelsen T, Undurraga EA, Venketasubramanian N, Vijayakumar L, Vos T, Wagner GR, Wang M, Wang W, Watt K, Weinstock MA, Weintraub R, Wilkinson JD, Woolf AD, Wulf S, Yeh PH, Yip P, Zabetian A, Zheng ZJ, Lopez AD, Murray CJ, AlMazroa MA and Memish ZA (2012) Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010:a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380(9859): 2095-2128.
Luo X, Budihardjo I, Zou H, Slaughter C and Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94(4):481-490.
Mahmut-Maierdan LY, Hujia-Gulixian, Zhang Guo-qing (2007) The hepatoprotective effects of Arnebia euchroma (Royle) Johnston extracts against alcohol-induced acute liver injury in mice. Chinese Remedies & Clinics 7(4).
Maiuri MC, Zalckvar E, Kimchi A and Kroemer G (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nature reviews Molecular cell biology 8(9):741-752.
Mao X, Yu CR, Li WH and Li WX (2008) Induction of apoptosis by shikonin through a ROS/JNK-mediated process in Bcr/Abl-positive chronic myelogenous leukemia (CML) cells. Cell research 18(8):879-888.
Marciniak SJ and Lomas DA (2010) Alphal-antitrypsin deficiency and autophagy. The New England journal of medicine 363(19):1863-1864.
Martinet W, Agostinis P, Vanhoecke B, Dewaele M and De Meyer GR (2009) Autophagy in disease: a double-edged sword with therapeutic potential. Clinical science 116(9):697-712.
Mathew R and White E (2011) Autophagy in tumorigenesis and energy metabolism:friend by day, foe by night. Current opinion in genetics & development 21(1):113-119.
McAlister VC, Mahalati K, Peltekian KM, Fraser A and MacDonald AS (2002) A clinical pharmacokinetic study of tacrolimus and sirolimus combination immunosuppression comparing simultaneous to separated administration. Therapeutic drug monitoring 24(3):346-350.
Meylan E and Tschopp J (2005) The RIP kinases: crucial integrators of cellular stress. Trends Biochem Sci 30(3):151-159.
Min R, Tong J, Wenjun Y, Wenhu D, Xiaojian Z, Jiacai H, Jian Z, Wantao C and Chenping Z (2008) Growth inhibition and induction of apoptosis in human oral squamous cell carcinoma Tca-8113 cell lines by Shikonin was partly through the inactivation of NF-kappaB pathway. Phytotherapy research: PTR 22(3):407-415.
Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME and Dixit VM (1996) FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. Cell 85(6):817-827.
Obed A, Tsui TY, Schnitzbauer AA, Obed M, Schlitt HJ, Becker H and Lorf T (2008) Liver transplantation as curative approach for advanced hepatocellular carcinoma:is it justified? Langenbeck's archives of surgery/Deutsche Gesellschaft fur Chirurgie 393(2):141-147.
Oliver FJ, de la Rubia G, Rolli V, Ruiz-Ruiz MC, de Murcia G and Murcia J M (1998) Importance of poly(ADP-ribose) polymerase and its cleavage in apoptosis. Lesson from an uncleavable mutant. JBiol Chem 273(50):33533-33539.
Organization WH (2006) Cancer.
Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Overvatn A, Bjorkoy G and Johansen T (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. The Journal of biological chemistry 282(33): 24131-24145.
Papaiahgari S, Zhang Q, Kleeberger SR, Cho HY and Reddy SP (2006) Hyperoxia stimulates an Nrf2-ARE transcriptional response via ROS-EGFR-PI3K-Akt/ERK MAP kinase signaling in pulmonary epithelial cells. Antioxid Redox Signal 8(1-2):43-52.
Papathanasiou K, Papageorgiou C, Panidis D and Mantalenakis S (1999) Our experience in laparoscopic diagnosis and management in women with chronic pelvic pain. Clin Exp Obstet Gynecol 26(3-4):190-192.
Park KJ, Lee SH, Lee CH, Jang JY, Chung J, Kwon MH and Kim YS (2009) Upregulation of Beclin-1 expression and phosphorylation of Bcl-2 and p53 are involved in the JNK-mediated autophagic cell death. Biochemical and biophysical research communications 382(4):726-729.
Pelicano H, Carney D and Huang P (2004) ROS stress in cancer cells and therapeutic implications. Drug resistance updates:reviews and commentaries in antimicrobial and anticancer chemotherapy 7(2):97-110.
Pham PT, Pham PC, Danovitch GM, Ross DJ, Gritsch HA, Kendrick EA, Singer J, Shah T and Wilkinson AH (2004) Sirolimus-associated pulmonary toxicity. Transplantation 77(8): 1215-1220.
Pimentel-Muinos FX and Seed B (1999) Regulated commitment of TNF receptor signaling: a molecular switch for death or activation. Immunity 11(6):783-793.
Powers RW, 3rd, Kaeberlein M, Caldwell SD, Kennedy BK and Fields S (2006) Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes & development 20(2): 174-184.
Qing G, Yan P and Xiao G (2006) Hsp90 inhibition results in autophagy-mediated proteasome-independent degradation of IkappaB kinase (IKK). Cell research 16(11):895-901.
Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y, Cattoretti G and Levine B (2003) Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. The Journal of clinical investigation 112(12): 1809-1820.
Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, Jimenez-Sanchez M, Korolchuk VI, Lichtenberg M, Luo S, Massey DC, Menzies FM, Moreau K, Narayanan U, Renna M, Siddiqi FH, Underwood BR, Winslow AR and Rubinsztein DC (2010) Regulation of mammalian autophagy in physiology and pathophysiology. Physiological reviews 90(4):1383-1435.
Rosen HR (2011) Clinical practice. Chronic hepatitis C infection. The New England journal of medicine 364(25):2429-2438.
Samuelsen JT, Dahl JE, Karlsson S, Morisbak E and Becher R (2007) Apoptosis induced by the monomers HEMA and TEGDMA involves formation of ROS and differential activation of the MAP-kinases p38, JNK and ERK. Dental materials: official publication of the Academy of Dental Materials 23(1):34-39.
Seger R and Krebs EG (1995) The MAPK signaling cascade. FASEB J 9(9):726-735.
Shaw RJ (2008) mTOR signaling: RAG GTPases transmit the amino acid signal. Trends in biochemical sciences 33(12):565-568.
Simon HU, Haj-Yehia A and Levi-Schaffer F (2000) Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5(5):415-418.
Slee EA, Zhu H, Chow SC, MacFarlane M, Nicholson DW and Cohen GM (1996) Benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (Z-VAD.FMK) inhibits apoptosis by blocking the processing of CPP32. Biochem J 315 (Pt 1):21-24.
Song J, Qu Z, Guo X, Zhao Q, Zhao X, Gao L, Sun K, Shen F, Wu M and Wei L (2009) Hypoxia-induced autophagy contributes to the chemoresistance of hepatocellular carcinoma cells. Autophagy 5(8):1131-1144.
Sun Z, Ming L, Zhu X and Lu J (2002) Prevention and control of hepatitis B in China. Journal of medical virology 67(3):447-450.
Sun ZJ, Chen G, Hu X, Zhang W, Liu Y, Zhu LX, Zhou Q and Zhao YF Activation of PI3K/Akt/IKK-alpha/NF-kappaB signaling pathway is required for the apoptosis-evasion in human salivary adenoid cystic carcinoma:its inhibition by quercetin. Apoptosis.
Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C, Waguri S, Eishi Y, Hino O, Tanaka K and Mizushima N (2011) Autophagy-deficient mice develop multiple liver tumors. Genes & development 25(8):795-800.
Talloczy Z, Virgin HWt and Levine B (2006) PKR-dependent autophagic degradation of herpes simplex virus type 1. Autophagy 2(1):24-29.
Thangapazham RL, Singh AK, Seth P, Misra N, Mathad VT, Raj K and Maheshwari RK (2008) Shikonin analogue (SA) 93/637 induces apoptosis by activation of caspase-3 in U937 cells. Front Biosci 13:561-568.
Thyagarajan A, Jedinak A, Nguyen H, Terry C, Baldridge LA, Jiang J and Sliva D (2010) Triterpenes from Ganoderma Lucidum induce autophagy in colon cancer through the inhibition of p38 mitogen-activated kinase (p38 MAPK). Nutrition and cancer 62(5):630-640.
Ting AT, Pimentel-Muinos FX and Seed B (1996) RIP mediates tumor necrosis factor receptor 1 activation of NF-kappaB but not Fas/APO-1-initiated apoptosis. The EMBO journal 15(22):6189-6196.
Trachootham D, Alexandre J and Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms:a radical therapeutic approach? Nat Rev Drug Discov 8(7):579-591.
Tsang WP, Chau SP, Kong SK, Fung KP and Kwok TT (2003) Reactive oxygen species mediate doxorubicin induced p53-independent apoptosis. Life Sci 73(16):2047-2058.
Underwood BR, Imarisio S, Fleming A, Rose C, Krishna G, Heard P, Quick M, Korolchuk VI, Renna M, Sarkar S, Garcia-Arencibia M, O'Kane CJ, Murphy MP and Rubinsztein DC (2010) Antioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease. Human molecular genetics 19(17):3413-3429.
Vandenabeele P, Grootjans S, Callewaert N and Takahashi N (2013) Necrostatin-1 blocks both RIPK1 and IDO: consequences for the study of cell death in experimental disease models. Cell death and differentiation 20(2):185-187.
Vindis C, Seguelas MH, Lanier S, Parini A and Cambon C (2001) Dopamine induces ERK activation in renal epithelial cells through H2O2 produced by monoamine oxidase. Kidney international 59(1):76-86.
Vivanco I and Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2(7):489-501.
Wang Z, Liu T, Gan L, Wang T, Yuan X, Zhang B, Chen H and Zheng Q (2010) Shikonin protects mouse brain against cerebral ischemia/reperfusion injury through its antioxidant activity. European journal of pharmacology 643(2-3):211-217.
White E and DiPaola RS (2009) The double-edged sword of autophagy modulation in cancer. Clinical cancer research: an official journal of the American Association for Cancer Research 15(17):5308-5316.
Wu Z, Wu L, Li L, Tashiro S, Onodera S and Ikejima T (2004a) p53-mediated cell cycle arrest and apoptosis induced by shikonin via a caspase-9-dependent mechanism in human malignant melanoma A375-S2 cells. Journal of pharmacological sciences 94(2):166-176.
Wu Z, Wu LJ, Li LH, Tashiro S, Onodera S and Ikejima T (2004b) Shikonin regulates HeLa cell death via caspase-3 activation and blockage of DNA synthesis. Journal of Asian natural products research 6(3):155-166.
Xie X, Le L, Fan Y, Lv L and Zhang J (2012) Autophagy is induced through the ROS-TP53-DRAM1 pathway in response to mitochondrial protein synthesis inhibition. Autophagy 8(7):1071-1084.
Yamamoto A, Morisawa Y, Verloes A, Murakami N, Hirano M, Nonaka I and Nishino I (2001a) Infantile autophagic vacuolar myopathy is distinct from Danon disease. Neurology 57(5): 903-905.
Yamamoto J, Okada S, Shimada K, Okusaka T, Yamasaki S, Ueno H and Kosuge T (2001b) Treatment strategy for small hepatocellular carcinoma: comparison of long-term results after percutaneous ethanol injection therapy and surgical resection. Hepatology 34(4 Pt 1):707-713.
Yang H, Zhou P, Huang H, Chen D, Ma N, Cui QC, Shen S, Dong W, Zhang X, Lian W, Wang X, Dou QP and Liu J (2008) Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivo. Int J Cancer.
Yeh CC, Kuo HM, Li TM, Lin JP, Yu FS, Lu HF, Chung JG and Yang JS (2007) Shikonin-induced apoptosis involves caspase-3 activity in a human bladder cancer cell line (T24). In vivo 21(6):1011-1019.
Youle RJ and Strasser A (2008) The BCL-2 protein family:opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9(1):47-59.
Yue Z, Jin S, Yang C, Levine AJ and Heintz N (2003) Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proceedings of the National Academy of Sciences of the United States of America 100(25):15077-15082.
Zellerhoff C, Schneider S, Senges J, Pfannebecker T, Hamm C and Tebbe U (2008) Sirolimus-eluting stents in the treatment of chronic total coronary occlusions:results from the prospective multi-center German Cypher Stent Registry. Clinical research in cardiology:official journal of the German Cardiac Society 97(4):253-259.
Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J, Fan ST, Luk JM, Wigler M, Hannon GJ, Mu D, Lucito R, Powers S and Lowe SW (2006) Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125(7): 1253-1267.
Zhan Y, Gong K, Chen C, Wang H and Li W (2012) P38 MAP kinase functions as a switch in MS-275-induced reactive oxygen species-dependent autophagy and apoptosis in human colon cancer cells. Free radical biology & medicine 53(3):532-543.
Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, Dong MQ and Han J (2009) RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325(5938):332-336.
Zhang P, Wang YZ, Kagan E and Bonner JC (2000) Peroxynitrite targets the epidermal growth factor receptor, Raf-1, and MEK independently to activate MAPK. The Journal of biological chemistry 275(29):22479-22486.
Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, Lecker SH and Goldberg AL (2007) Fox03 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell metabolism 6(6):472-483.
Zhou L, Liu J and Luo F (2006) Serum tumor markers for detection of hepatocellular carcinoma. World journal of gastroenterology:WJG 12(8):1175-1181.
Zhu AX, Sahani DV, Duda DG, di Tomaso E, Ancukiewicz M, Catalano OA, Sindhwani V, Blaszkowsky LS, Yoon SS, Lahdenranta J, Bhargava P, Meyerhardt J, Clark JW, Kwak EL, Hezel AF, Miksad R, Abrams TA, Enzinger PC, Fuchs CS, Ryan DP and Jain RK (2009) Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase Ⅱstudy. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 27(18):3027-3035.