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“饿死”癌细胞千真万确! 精选

已有 20624 次阅读 2015-11-25 21:57 |个人分类:科普集萃|系统分类:科普集锦| 肿瘤, 生酮饮食

昨天,我根据一个网络视频写了“饿得死”的癌细 一文,借助微信传播和网站转载,“流毒”甚广,一时间弄得“谣言”满天飞!有人质疑,生酮饮食真的可以把癌细胞饿死吗?那个视频并非严格的科学报道,何足为凭?那些说法有没有严格的科学论证?

生酮饮食“饿死”癌细胞的实验源于何时?

现在我恰好准备写一篇有关胰岛素及葡萄糖影响垂体瘤细胞生长的论文,于是带着以上质疑检索了部分研究文献,尤其关注人类肿瘤的临床试验部分的实验结果。不查不知道,一查吓一跳!原来早在1995年(也就是20年前)美国科学家就开展了生酮饮食治疗儿童脑肿瘤的临床试验。

在经过短短7天的生酮饮食试验后,两例脑肿瘤女童患者的血糖比正常水平低,而血中酮体水平升高20-30倍,肿瘤部位的葡萄糖吸收平均降低了21.8%。其中一名患者又追加了12个月的生酮饮食试验,结果未发现肿瘤进展的迹象(参考文献1)。


生酮饮食抗肿瘤的动物实验结果如何?

从1995年到2010年,在脑肿瘤动物模型中开展了大量生酮饮食与脑肿瘤生长相关性的研究,得出的结论都是生酮饮食可以抑制脑肿瘤生长,而且做出了非常乐观的预期:生酮饮食是“有效治疗恶性脑肿瘤的替代方法”(an effective alternative therapy for malignant brain tumor)(参考文献2)。


生酮饮食或配合放化疗能治疗人体肿瘤吗?

到了2010年,意大利科学家在人体试验中用生酮饮食(脂肪:碳水化合物+蛋白质=4:1,每日600千卡)治疗多形性胶质母细胞瘤(GBM)。经过两个月治疗后,患者体重减轻20%,而且脑中无可见肿瘤组织。可是,在停止治疗后10周内,肿瘤就复发了(参考文献3)。


2014年,美国匹兹堡大学癌症研究所的研究人员配合放疗、化疗开展生酮饮食治疗多形性胶质母细胞瘤临床试验,结果在6名参加生酮饮食疗法的患者中,有4人在14个月的随访中全部存活下来(参考文献4)。


生酮饮食是否只对脑肿瘤有效?

大家注意到,以往开展的生酮饮食抗肿瘤的临床试验都是针对脑肿瘤的,莫非该疗法对其他肿瘤无效?还是让数据来说话吧!在人乳腺癌、胰腺癌和前列腺癌细胞移植肿瘤动物模型中,生酮饮食是有明确治疗效果的(参考文献5、6、7)。显然,生酮饮食对脑肿瘤以外的其他肿瘤的治疗效果,还有赖今后开展人体试验进行验证。

生酮饮食抗癌疗法有无大型临床试验数据支持?

迄今在美国NIH挂上号并已完成I期临床试验的是德国图平根大学开展的复发性胶质母细胞瘤研究(Ketogenic diet for Recurrent Glioblastoma,ERGO),从2007年开始,2010年结束,历时3年(有图为证,原文网址:https://clinicaltrials.gov/show/NCT00575146)。


在项目完成后,他们于2014年在《国际肿瘤学杂志》(Int J Oncol)发表文章,全面总结了以上临床试验结果(参考文献8)。在总共20名参加临床试验的患者中,他们得出如下几个结论:

1、3位患者(15%)因无法耐受生酮饮食而放弃;

2、未观察到生酮饮食引起的严重副作用;

3、接受测试的13位患者中有12位(92%)至少一次尿检酮体阳性;

4、1位患者稍有起色,2位患者6周后病情稳定;

5、所有患者的平均无肿瘤进展存活期(PFS)为5周,最短3周,最长13周;

6、平均存活期从试验开始至32周;

7、7位接受贝伐珠单抗与生酮饮食联合治疗的患者中有6位(86%)表现全部或部分客观反应。


由于I期临床试验的主要目的是观察人体对新药的耐受程度,以便为制定给药方案提供依据,也就意味着该试验的生酮饮食的配方及食用方法并非最佳,最终导致17位接受生酮饮食治疗的患者出现病情进展。

在这些肿瘤复发患者中,13位未实施拯救方案,8位接受药物拯救治疗,并继续辅以生酮饮食,其中1位用ACNU/teniposide,4位用贝伐珠单抗,3位用贝伐珠单抗和irinotecan。用贝伐珠单抗者的平均PFS为21.1周(12-124周),达到6个月PFS的人数为43%。

胰岛素如何促进肿瘤生长?

一种被称为莱昂综合征(Laron's syndrome)的遗传性侏儒症,源于生长激素受体基因缺陷。有趣的是,这些病人患癌症及糖尿病的风险极低,推测生长激素与胰岛素样生长因子可能促进肿瘤增殖。同时也发现,胰岛素及胰岛素生长因子可以通过活化PI3K信号转导通路促进葡萄糖向细胞内的运输,而此过程受肿瘤抑制因子PTEN拮抗。

当PTEN突变导致PI3K过度激活时,细胞就倾向于摄入大量葡萄糖用于无氧呼吸(瓦勃效应),使代谢活性增高10-20倍,结果产生过量活性氧自由基,致使DNA损伤加剧,从而引起高频率的细胞癌变。还发现糖尿病治疗药物二甲双胍(甲福明)可使癌症发生率降低25%-40%,其间胰岛素水平显著降低,推测高水平胰岛素增大致癌风险。

在摄入高脂低糖的生酮饮食时,由于血糖水平降低,胰岛素分泌随之减少,于是将胰岛素致癌或促癌的风险降至最低。相反,生糖饮食可以大幅提高胰岛素水平,促癌能力当然有所提升了。由此可见,胰岛素抵抗及2型糖尿病患者的致癌风险很高。

生糖饮食为何提高致癌风险?

不过,究竟是高胰岛素血症还是高葡萄糖血症促进肿瘤细胞生长尚无定论,也许不同肿瘤及不同细胞有所差异。有人认为高糖环境可以通过多条途径促进肿瘤进展。例如,高糖通过上调葡萄糖转运蛋白GLUT1和GLUT3、生长因子及其受体、其他生长促进信号,可以加速肿瘤细胞增殖。高糖通过上调缺氧诱导因子、脯氨酸水化酶和细胞色素c,也与肿瘤细胞的抗凋亡活性有关(参考文献9)。

我们也发现,胰岛素不仅不能促进脑垂体瘤细胞的生长及其肿瘤标志物的表达,反而抑制生长与表达。倒是高浓度的葡萄糖却促进脑垂体瘤细胞的快速增殖,并伴随肿瘤标志物表达上调以及细胞凋亡率下降等现象(论文数据整理中)。

两点初步结论

鉴于肿瘤细胞具有线粒体功能缺陷的特点,限制葡萄糖供应肯定不利于肿瘤的增殖和转移。作为化疗或放疗的辅助手段,以生酮饮食为代表的代谢干预可能进一步加剧肿瘤细胞的死亡。

不过,体内代谢状况复杂,肿瘤细胞的生命力旺盛,单纯的生酮饮食可能不足以完全制服肿瘤恶变,而且可能还表现组织、类型、时期差异性,如肝癌是否会得益于肝脏的糖异生作用,也是今后需要深入研究的问题。


参考文献

1. Nebeling LC et al. 1995. Effects of a ketogenic diet on tumor metabolism and nutrational status in pediatric oncology patients: two case reports. J Am Coll Nutri 14: 202-208

2. Zhou W et al. 2007. The calorically restricted diet, an effective alternative therapy for malignant brain tumor. Nutr Metab (London) 4: 5

3. Zuccoli G et al. 2010. Metabolic management of glioblastoma multiforme using standard therapy with a restricted ketogenic diet: case report. Nutr Metab (London) 7: 33

4. Champe CE et al. 2014. Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. J Neurooncol 117: 125-131

5. Gluschnaider U et al. 2014. Long-chain fatty acid analogues suppress breast tumorigenesis and progression. Cancer Res 74: 6991-7002

6. Masko EM et al. 2010. Low-carbohydrate diets and prostate cancer: how low is "low enough"? Cancer Prev Res (Phila) 3: 1124-1131 

7.Shukla SK et al. 2014. Metabolism reprogramming induced by ketone bodies diminishes the pancreatic cancer cachexia. Cancer Metab 2: 18

8. Rieger J et al. 2014. ERGO: a pilot study of ketogenic diet in recurrent glioblastoma. Int J Oncol 44: 1843-1852

9. Ryu TY et al. 2014. Hyperglycemia as a risk factor for cancer progression. Diabetes Metab J 38: 330-336


附:CBN视频的文字材料


Starving Cancer: Ketogenic Diet a Key to Recovery

Many people are frustrated with today's cancer treatments. They are expensive, painful and often just don't work.

However, there is a new cancer treatment that is free, has virtually no side effects, and can be used in conjunction with other cancer treatments.

It involves cutting out carbohydrates, beginning with the worst carb of all - sugar.

Killing Cancer

Dr. Fred Hatfield is an impressive guy: a power-lifting champion, author of dozens of books, a millionaire businessman with a beautiful wife. But he'll tell you his greatest accomplishment is killing his cancer just in the nick of time.

"The doctors gave me three months to live because of widespread metastatic cancer in my skeletal structure," he recalled. "Three months, three different doctors told me that same thing."

His wife Gloria remembers it well.

"It's a horrible, horrible feeling to have someone tell you that the person you love only has three months to live and you're not going to be with him any more," she said.

While Hatfield was preparing to die, he heard about an anti-cancer diet, also known as metabolic therapy. With nothing to lose, he gave it a try and was shocked when it actually worked.

"The cancer was gone!" he exclaimed. "Completely. To this day there's no trace of it. And it's been over a year."

Starving Bad Cells

Although it wasn't easy, Hatfield stopped eating carbohydrates, which turn into glucose inside your body. Cancer cells love glucose and need it so badly, that if you stop giving it to them, they die.

"It just absolutely amazes me that medical science is just now finding this out," he said.

Hatfield's cancer recovery, however, was not a surprise to Dr. Dominic D'Agostino, who researches metabolic therapy. When he and his team of scientists at the University of South Florida removed carbohydrates from the diets of lab mice, the mice survived highly aggressive metastatic cancer even better than when they were treated with chemotherapy.

"We have dramatically increased survival with metabolic therapy," he said. "So we think it's important to get this information out."

It's not just lab mice. Dr. D'Agostino has also seen similar success in people - lots of them.

"I've been in correspondence with a number of people," he said. "At least a dozen over the last year-and-a-half to two years, and all of them are still alive, despite the odds. So this is very encouraging."

The Ketogenic Diet

All cells, including cancer cells, are fueled by glucose. But if you deprive them of glucose, they switch to the alternate fuel, ketone bodies.

Except cancer cells. A defect prevents them from making the switch to using ketone bodies as fuel and therefore, cancer cells can only survive on glucose. All other cells can use either glucose or ketone bodies.

"Your normal cells have the metabolic flexibility to adapt from using glucose to using ketone bodies. But cancer cells lack this metabolic flexibility. So we can exploit that," Dr. D'Agostino explained.

People like Hatfield, who want to deprive their cells of glucose and fuel them with ketone bodies instead, eat what's known as a ketogenic diet. It consists of almost zero carbohydrates, but lots of natural proteins and fats.

Gloria said the food on the ketogenic diet is in every grocery store and is pretty easy to prepare.

"You can go online and there's cook books," she said, "It's clean eating. Just very clean eating, none of the sugars, the salts, the trash food."

"Natural" proteins are ones that are in their original form. On the other hand, "processed" meats, like cold cuts and hot dogs, are off-limits because often carbohydrates have been added to them.

Similarly, "natural" fats are whole foods, like olive oil, avocados, and nuts. Stay away from "trans" fats, such as shortening or margarine, any oil that is hydrogenated. Trans fats are man-made.

Safe & Healthy

Sometimes people are afraid to try the ketogenic diet because they think eating fat like this is bad for your heart. But more doctors say as long as it's natural, fat is good for you, even saturated fat like coconut oil and butter.

"Is cholesterol the major cause of heart disease?" cardiologist Dr. Stephen Sinatra asked. "Absolutely not."

In his book, The Great Cholesterol Myth, Dr. Sinatra said the real cause of heart disease is inflammation, which comes from eating too many carbohydrates.

"We need to coach our patients and empower our patients about the dangers of sugar," he said. "Unfortunately, they're not hearing that. They're hearing the converse, the dangers of fat. Fat is healthy for you, as long as you avoid trans fats."

So by cutting back on carbohydrates and eating natural fats and proteins, you could improve your heart health and even wipe out cancer.

Additional Information:

The ketogenic diet has also proven successful in treating epilepsy. For more information, go to The Charlie Foundation.

For additional resources and recipes for delicious ketogenic diet foods, such as breads and cupcakes with all natural ingredients, check out the following resources:

Related Stories:

Cholesterol Myth: What Really Causes Heart Disease?

Brain Shrinkage? Trans Fats Link to Alzheimer's

Ketogenic Diet: Fatty Foods a Cure for Epilepsy?

Related Links:

Ketogenic Diet Resource

Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer

International Sports Sciences Association

Here is an e-book called “Fighting Cancer With The Ketogenic Diet"

Dr. Joseph's Mercola's interview with Professor Thomas Seyfried about the ketogenic diet as a treatment for cancer.

Research study showing Ketogenic Diet prolongs survival against metastatic cancer.

Commercial source for ketone supplements. The products on this site are STRICTLY for research only and NOT for cancer patients. This site is a resource for scientists interested in pursuing ketone research for cancer or neurological diseases.





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