由哥伦布俄亥俄州大学Yan Liu教授领导的科学家报道塞来昔布通过阻断白介素6信号转导因子及STAT3激活通路引起肝癌细胞凋亡，从而起到治疗肝癌的作用。发布在Cancer Prevention Research上的一篇文章，COX-2阻断剂塞来昔布已显示对结肠、肺、前列腺肿瘤有治疗作用，最近发现该药对肝癌可能也有治疗功能。科学家通过对人类肝细胞肝癌研究得出本次结论。
俄亥俄州大学儿科副教授兼本次研究主要高级作者Jiayuh Lin博士透露，他今后将提倡服用COX-2抑制剂作为肝癌的预防措施。
根据塞来昔布阻断STAT3及COX-2的作用，该药可能对癌症患者有获益作用。
Jiayuh Lin博士解释说，近年不断有证据显示慢性肝脏炎症与肝癌之间有联系。STAT3是联系炎症与细胞转化的桥梁，在肝癌组织中有活化，而在正常肝脏却没有类似表现。
研究者发现，塞来昔布通过降低STAT3磷酸化，使肝癌细胞走向自毁。同时，他们还发现，塞来昔布阻断外源性白介素诱导的STAT3磷酸化及核转位。
重要的是，他们观察到，当塞来昔布联合多柔比星或索拉非尼用药时，培养中的肝癌细胞出现更多的凋亡。
Jiayuh Lin博士指出：“多柔比星及索拉非尼这两种化疗药各自都有降低肿瘤细胞生长的作用，但当其中一个联合塞来昔布时，更强的生长抑制作用发生了。因此，我们推测通过联合塞来昔布可以降低化疗药耐受现象的发生。”
本研究为COX-2阻断剂治疗多种癌症的作用提供了进一步的证据。
然而，心血管方面的副作用是这类药物长期以来的隐忧。
在2008年美国癌症研究年会上，来自马萨诸塞州波士顿布里格姆妇女医院的Monica Bertagnolli 博士发表了一份研究，报道了塞来昔布降低服药3年的进展期结直肠腺癌的高危患者5年死亡率(?)达41%。
然而，由于心血管系统安全问题开始出现，受试者被迫停止服用塞来昔布。虽然如此，塞来昔布对腺癌的保护作用并没有因为停药而终止。Monica Bertagnolli博士总结道，COX-2阻断剂对有患腺癌风险而没有心血管疾病风险的患者来说是一个理想药物。
在同年发表在美国临床肿瘤协会年会的另一分研究中，德克萨斯州休斯顿的安德森癌症中心的Edward Kim博士报道塞来昔布可以降低Ki-67的表达，从而获得对抗肺癌的化学保护作用。Ki-67 已知与支气管癌前病变相关。
这份研究通过对至少有20 包年吸烟史的烟民进行研究，中途由于塞来昔布对心血管毒副作用的担忧而中止，后来获得FDA顾问批准继续研究。
伯明翰阿拉巴马大学皮肤病学系主任Craig A. Elmets教授应邀对COX-2抑制剂的化学预防作用进行评价。
“我认为我们应该把肝细胞肝癌列入对非甾体类抗炎药有反应的肿瘤类别里。”
Elmets博士最近主持了一项多中心随机对照试验，发现塞来昔布对鳞癌和光化学损害和有非黑色素瘤高危风险的基底细胞癌患者可能存在预防作用。
“我们对非黑色素瘤患者治疗了9个月，用塞来昔布治疗的患者在新发肿瘤的数目要比对照组低50%。”
Elemets博士介绍，在他的研究的起始阶段，心血管副作用方面的影响并未出现。与其他的试验类似，当相关副作用出现时，他被迫停止了研究。然而，在治疗的9个月里，这些服用塞来昔布的患者并未因此增加心血管疾病的患病风险。
Elmets博士承认，COX-2抑制剂如果可以被用于预防肿瘤，那么其相关的心血管副作用将是一个重要的问题。
“患者需要长期服用以取得预防获益。”他解释道，“塞来昔布阻断COX-2 酶，但也有其他很多药物同样有阻断COX-2而具有较小的心血管副作用，这些药物可能成为预防多种肿瘤的理想药物。”
舒林酸(奇诺力)是其中之一，Elmets博士介绍道，“与二氟甲基鸟氨酸联合服用，可以大大降低结直肠腺癌的数目，所以我认为这里面肯定有着一种机制，使此类药物能起着化学预防的作用。”
COX-2抑制剂对乙肝病毒阳性、具有发展为肝细胞肝癌倾向的患者可能有独特的预防作用。
“肝细胞肝癌在美国并不常见，但对乙肝病毒阳性的患者来说，这类药物值得考虑，因为肝细胞肝癌的死亡率还是相当高的。”
“萘普生比其他非甾体类抗炎药有着相对较小的心血管副作用，所以值得我们关注。”
低剂量的非甾体类抗炎药或对有心血管疾病风险的患者进行筛查将会是推广这类药物作为化学预防制剂的重要举措。“所以，间断服用或联合其他药物小剂量使用可能是一个合理的选择方案。”
原文阅读：
The cyclooxygenase 2 (COX-2) inhibitor celecoxib, which has shown anticancer effects in malignancies of the colon, lung, and prostate, may also be a candidate for the treatment of liver cancer, according to new research published online April 13 in Cancer Prevention Research.
Scientists, led by Yan Liu, PhD, from Ohio State University in Columbus, report that celecoxib may have anticancer activity because it blocks the interleukin 6/signal transducer and activator of transcription 3 (STAT3) pathway and causes apoptosis in liver cancer cells.
They made their discovery in human hepatocellular carcinoma (HCC) cells.
Jiayuh Lin, PhD, an associate professor of paediatrics at Ohio State and senior author of the study, told Medscape Medical News he would advocate taking a COX-2 inhibitor as a preventive measure.
"Based on the ability of celecoxib to inhibit both STAT3 and COX-2, it may have some beneficial effects in cancer prevention," he said.
Dr. Lin explained that there is growing evidence demonstrating an association between chronic liver inflammation and HCC development. STAT3, which is associated with inflammation and cellular transformation, is activated in human HCC tissue but not in normal human liver tissues.
The researchers found that celecoxib decreased STAT3 phosphorylation to cause the liver cancer cells to self-destruct. They also found that celecoxib blocked exogenous interleukin-6–induced STAT3 phosphorylation and nuclear translocation.
Importantly, they also observed that when celecoxib was combined with doxorubicin or sorafenib, more HCC cells in culture were killed.
"Each chemotherapy drug alone will reduce the growth of cancer cells, but when each drug was combined with celecoxib, a greater growth suppression effect was observed," Dr. Lin said. "Therefore, we believe that celecoxib can be combined with other anticancer drugs to reduce drug resistance caused by interleukin-6 STAT3 signals."
This research adds to the growing evidence for a possible role for COX-2 inhibition in various cancers.
Cardiovascular Concerns
However, cardiovascular concerns have long been an issue with this class of drugs.
In a study that was presented at the 2008 Annual Meeting of the American Association for Cancer Research, Monica Bertagnolli, MD, from Brigham and Women's Hospital in Boston, Massachusetts, reported that celecoxib reduced the 5-year rate of advanced colorectal adenomas by 41% in high-risk patients who took the drug for 3 years.
However, subjects had to discontinue taking the drug as concerns about cardiovascular safety began to emerge.
Nevertheless, the protection from adenomas continued after use of the drug was stopped, and Dr. Bertagnolli concluded that COX-2 inhibitors are promising in patients who are at risk of developing adenomas and who do not have cardiovascular risk factors.
In another study that was presented the same year at the Annual Meeting of the American Society of Clinical Oncology, Edward Kim, MD, from the M.D. Anderson Cancer Center in Houston, Texas, reported that celecoxib was able to reduce the expression of Ki-67, a biomarker associated with bronchial premalignant lesions, and could have a chemoprotective effect against lung cancer.
The study, which was conducted in current or former smokers with at least a 20 pack-year smoking history, was also halted because of fears of cardiovascular toxic effects but resumed after advisers to the US Food and Drug Administration recommended that it be continued.
Medscape Medical News invited Craig A. Elmets, MD, professor and chair, Department of Dermatology, University of Alabama at Birmingham, to comment on the use of COX-2 inhibitors for chemoprevention.
"I think we can add hepatocellular carcinoma to the potential types of cancer which will respond to NSAIDs [nonsteroidal anti-inflammatory drugs]," he said.
Dr. Elmets recently headed a multicenter randomized controlled trial that found that celecoxib may be effective for prevention of squamous cell carcinomas and basal cell carcinomas in individuals who have extensive actinic damage and are at high risk for development of nonmelanoma skin cancers.
"We treated patients with nonmelanoma skin cancers for 9 months, and in the patients who received celecoxib there was a greater than 50% reduction in the number of new nonmelanoma skin cancers that developed compared to a control group that didn't receive celecoxib," he said in an interview.
Dr. Elemets said that when his study was started, concerns about the cardiovascular adverse effects with celecoxib had not yet surfaced. Similar to the other trials, his was stopped when these concerns came to light. However, during the 9 months that patients took celecoxib no increase in cardiovascular risk was seen, he noted.
Possible Alternatives to Celecoxib
Dr. Elmets admitted that if the COX-2 inhibitors are going to be taken to prevent cancer, then the cardiovascular risk they pose could become an issue.
"People need to be on these drugs on a chronic basis for preventive benefit," he explained. "Celecoxib blocks the cyclooxygenase 2 enzyme, but there are a number of other drugs that also block COX-2 that have much less of a cardiovascular risk, so these may be ideal for prevention of various types of cancers."
Sulindac (Clinoril, Merck) is one, he said. "Combined with difluoromethylornithine, it produces a dramatic reduction in the number of colorectal adenomas, so I think that there is definitely something going on here with regard to chemoprevention."
A COX-2 inhibitor may be particularly useful in hepatitis B–positive patients who are at risk for HCC.
"Hepatocellular carcinoma is not a common malignancy in the US, but in patients who are hepatitis B positive, this may be a drug that should be considered because mortality rate for hepatocellular carcinoma is really quite high," he said.
"Naproxen has much less of a cardiovascular effect than the other NSAIDs, so there would be quite a bit of interest in looking at naproxen," he added.
Using lower NSAID doses or screening people for cardiovascular risk factors may be other strategies that will enable these drugs to be used as effective chemopreventive agents. "So might using these drugs intermittently or using them in combination with other drugs at much lower doses than are normally used," Dr. Elmets said.
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