在实验室中开发出潜在抗癌新药

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Potential new class of cancer drugs developed in lab6 o- i5 v; [2 `  C& C
Drug takes aim at cancer metabolism, stops most kinds of cancer
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June 27, 2015
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Saint Louis University, e) `7 i$ M" J. m9 \2 s
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A new class of drug developed targets the Warburg effect to cut off cancer's energy supply, and researchers say that it has the potential to stop most kinds of cancer in its tracks.# f; }' n5 [3 c1 o) W
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SLU pharmacology researchers Thomas Burris, Ph.D., and Colin Flaveny, Ph.D., discuss their cancer research.. C# `8 i" V7 B7 L
Credit: Courtesy of Saint Louis University
8 O) }/ {$ Y- ^. @& D3 ?4 y( XIn research published in Cancer Cell, Thomas Burris, Ph.D., chair of pharmacology and physiology at Saint Louis University, has, for the first time, found a way to stop cancer cell growth by targeting the Warburg Effect, a trait of cancer cell metabolism that scientists have been eager to exploit.
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Unlike recent advances in personalized medicine that focus on specific genetic mutations associated with different types of cancer, this research targets a broad principle that applies to almost every kind of cancer: its energy source.8 `. _2 c4 x% r9 I4 w3 }( p9 z
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The Saint Louis University study, which was conducted in animal models and in human tumor cells in the lab, showed that a drug developed by Burris and colleagues at Scripps Research Institute can stop cancer cells without causing damage to healthy cells or leading to other severe side effects.( Z1 [7 ~. o9 I( c5 r/ v3 _" p# i! e6 ^

: N9 ]  J4 g' `) W1 q/ ZThe Warburg Effect
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5 v1 X& `" k3 l5 X7 _* qMetabolism -- the ability to use energy -- is a feature of all living things. Cancer cells aggressively ramp up this process, allowing mutated cells to grow unchecked at the expense of surrounding tissue.
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( w3 c2 m3 a) _5 @' m9 l. M- _"Targeting cancer metabolism has become a hot area over the past few years, though the idea is not new," Burris said.
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, g: s) X0 M- f" r% G/ b: ISince the early 1900s, scientists have known that cancer cells prefer to use glucose as fuel even if they have plenty of other resources available. In fact, this is how doctors use PET (positron emission tomography) scan images to spot tumors. PET scans highlight the glucose that cancer cells have accumulated.
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5 ]1 x9 S; o) D- D! |7 ], pThis preference for using glucose as fuel is called the Warburg effect, or glycolysis.
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In his paper, Burris reports that the Warburg effect is the metabolic foundation of oncogenic (cancer gene) growth, tumor progression and metastasis as well as tumor resistance to treatment.
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Cancer's goal: to grow and divide& G. i/ K6 {9 B; f+ e. e
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Cancer cells have one goal: to grow and divide as quickly as possible. And, while there are a number of possible molecular pathways a cell could use to find food, cancer cells have a set of preferred pathways.! C, ?3 b( d9 {/ x: C% {; D2 N" y* D

( ?7 S0 m/ [2 G5 M; b; i6 @"In fact, they are addicted to certain pathways," Burris said. "They need tools to grow fast and that means they need to have all of the parts for new cells and they need new energy."
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"Cancer cells look for metabolic pathways to find the parts to grow and divide. If they don't have the parts, they just die," said Burris. "The Warburg effect ramps up energy use in the form of glucose to make chemicals required for rapid growth and cancer cells also ramp up another process, lipogenesis, that lets them make their own fats that they need to rapidly grow.": j: \# V9 e# V: v" o

8 H% t$ l* _0 F' j1 nIf the Warburg effect and lipogenesis are key metabolic pathways that drive cancer progression, growth, survival, immune evasion, resistance to treatment and disease recurrence, then, Burris hypothesizes, targeting glycolysis and lipogenesis could offer a way to stop a broad range of cancers.. s; N; S  h7 N! O& O
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Cutting off the energy supply
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$ A5 k2 q0 ?  `; y+ OBurris and his colleagues created a class of compounds that affect a receptor that regulates fat synthesis. The new compound, SR9243, which started as an anti-cholesterol drug candidate, turns down fat synthesis so that cells can't produce their own fat. This also impacts the Warburg pathway, turning cancer cells into more normal cells. SR9243 suppresses abnormal glucose consumption and cuts off cancer cells' energy supply.
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When cancer cells don't get the parts they need to reproduce through glucose or fat, they simply die.
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. u  y/ L8 Q- ~- [Because the Warburg effect is not a feature of normal cells and because most normal cells can acquire fat from outside, SR9243 only kills cancer cells and remains non-toxic to healthy cells.! W1 o3 i9 A) q# u/ J

1 F+ C& {) a3 r  J* B7 IThe drug also has a good safety profile; it is effective without causing weight loss, liver toxicity, or inflammation.0 V! m8 U7 Z% u/ b5 U

* m8 X7 |! s0 z9 ^3 A& _Promising Results So far, SR9243 has been tested in cultured cancer cells and in human tumor cells grown in animal models. Because the Warburg pathway is a feature of almost every kind of cancer, researchers are testing it on a number of different cancer models.5 J% l/ E9 E4 A7 j8 |
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"It works in a wide range of cancers both in culture and in human tumors developing in animal models," Burris said. "Some are more sensitive to it than others. In several of these pathways, cells had been reprogramed by cancer to support cancer cell growth. This returns the metabolism to that of more normal cells."
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4 W0 [5 w% _! l" g  r1 N3 f& @& PIn human tumors grown in animal models, Burris said, "It worked very well on lung, prostate, and colorectal cancers, and it worked to a lesser degree in ovarian and pancreatic cancers."
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It also seems to work on glioblastoma, an extremely difficult to treat form of brain cancer, though it isn't able to cross the brain/blood barrier very effectively. The challenge for researchers in this scenario will be to find a way to allow the drug to cross this barrier, the body's natural protection for the brain, which can make it difficult for drug treatments to reach their target.
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And, in even more promising news, it appears that when SR9243 is used in combination with existing chemotherapy drugs, it increases their effectiveness, in a mechanism apart from SR9243's own cancer fighting ability.4 K  M# P! s& d* ?$ x3 o) o

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The above post is reprinted from materials provided by Saint Louis University. Note: Materials may be edited for content and length.
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Journal Reference:2 b( a3 L+ g2 x* O) k7 _* O% B, O

  R9 S6 V8 l' T' _, _# z7 |Colin A. Flaveny, Kristine Griffett, Bahaa El-Dien M. El-Gendy, Melissa Kazantzis, Monideepa Sengupta, Antonio L. Amelio, Arindam Chatterjee, John Walker, Laura A. Solt, Theodore M. Kamenecka, Thomas P. Burris. Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis. Cancer Cell, 2015; DOI: 10.1016/j.ccell.2015.05.007
, s" h0 k( t$ V. |, Z  O. V在实验室中开发出潜在抗癌新药
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- m- [3 d2 j% V3 t3 @; g4 j（药品靶向癌细胞能量代谢，可以阻止大多数种类癌症的生长）9 H/ _2 b! F" T3 F
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概要：科学家开发出新的抗癌药物，靶向Warburg效应，可以切断癌细胞的能量供应。研究人员表示该药物可能可以阻断大多数种类癌症的生长。
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Thomas Burris, Ph.D., chair of pharmacology and physiology at Saint Louis University最近在Cancer Cell上发表了相关文章，首次公布了以癌症细胞代谢特征Warburg效应为靶点进而抑制肿瘤生长的方法。Warburg效应是癌症细胞的代谢特征，正常细胞没有这一代谢特征，所以被很多科学家研究，希望借此能找出治疗癌症的方法。+ b3 h& M, E/ b0 J

5 Y7 p1 P' s' j针对Warburg效应开发的药物可以适用几乎所有的癌症，因为它靶向几乎所有癌症细胞都具有的一个宽泛的特征，即能量代谢特点。这与最近比较火的肿瘤个体化治疗不同，它们是通过对不同个体癌细胞的测序分析，确定不同癌症病人的特异性突变，然后给予针对性的治疗。3 Q& T' \" n0 S6 S1 J6 G" V

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这个来着圣路易斯大学的研究团队在实验室中利用动物模型和人癌细胞进行药物的研究。Burris和他来自Scripps Research Institute的同事制造了一种药物可以抑制癌细胞而且不损伤正常细胞，也没有导致其他严重的副作用。
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8 [# r' y  o, l' u: i: e4 t7 ^5 q3 g% L9 YWarburg效应$ _) J3 @9 [2 H. e# K
代谢就是利用能量，每个活着生命都具有这一功能。癌细胞对于能量代谢是极其贪婪的，从而使癌细胞大量繁殖占据周围的组织。Burris说：”最近几年，靶向癌细胞的代谢是一个很热门的研究领域，虽然这个想法并不新颖“。
/ c: e5 `) Z: T# \* @& n在20世纪初，科学家就已经发现癌细胞偏好利用葡萄糖作为能量来源，即使它们有足够的其他可用能源物质。事实上，这也是为什么医生可以使用PET（正电子发射断层扫描）图像扫描来发现肿瘤。PET扫描时癌细胞中大量堆积的葡萄糖会凸显出来。这种偏爱使用葡萄糖作为能量来源的现象被称为Warburg效应，即糖酵解。
  A. E# _" S( z( X( M在论文中，Burris 指出Warburg效应是癌细胞（癌症基因）生长，肿瘤进展（？），癌细胞转移和肿瘤治疗耐药性产生的代谢基础。
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癌细胞的目标：生长和分裂
! G4 U$ F& K& ]5 V癌细胞有一个目标：尽可能快地分裂和生长。虽然细胞有许多的分子途径用来寻找食物，但癌细胞在这方面有偏好性。（偏食厌食很危险哦……）Burris说：“事实上，它们沉迷于某种能量代谢途径（这种途径可以满足它们的欲望……）。它们需要材料来实现快速生长，这意味着它们不仅仅需要新的能源，还需要组成新细胞的各种原料。癌细胞们找寻能量代谢途径来获得细胞生长和分裂的原料，如果它们没有找到，就会死亡（最后活下来的癌细胞都是找的这一途径的……优胜略汰）。Warburg效应能够利用大量的葡萄糖产生能量并且提供细胞快速生长的其他化学成分，同时还可以进行脂肪合成来满足癌细胞的快速生长。”
+ F+ A8 u) V, y4 d! _0 X如果Warburg效应和脂肪生成是推动癌症的发展，生长，存活，免疫逃避，抵抗治疗和复发的关键代谢途径，那么，Burris 推测，靶向糖酵解和脂肪生成可能可以作为一种新的方法用于各种癌症的治疗。
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5 o/ V* ^- ?+ [2 D5 m切断能源供应（兵法云：给老子把它们的粮草断了）* \: r; w0 |  ?9 p
Burris和他的同事们制造了一些化合物，可以影响调控脂肪合成的一个受体。新的化合物，SR9243，开始时被作为抗胆固醇的候选药物，可以下调脂肪的合成，使细胞不能产生自己的脂肪。它也会影响Warburg途径，把癌细胞的代谢状态变得和正常细胞一样。 SR9243可以抑制不正常的葡萄糖消耗从而切断肿瘤细胞的能量供应。  O, `, T0 d- Y3 n* s& z
当癌细胞无法从葡萄糖代谢或脂肪合成中得到复制所需的原料，就只能死了。
& S9 H2 p0 {+ Q8 \因为Warburg效应是不正常细胞的特征，大多数正常细胞可以从外界获得脂肪，所以SR9243只杀死癌细胞，对正常细胞无毒性。
0 J7 W; S, o+ `* \该药物也具有良好的安全性;它不会引起体重减轻，肝毒性，或炎症。" b6 o. W' Z6 T. l1 \7 Z1 q' w$ B
SR9243已在培养的癌细胞和有人肿瘤细胞生长的动物模型中进行试验，到目前为止的实验结果让人满意。因为Warburg 途径几乎是每一种癌症细胞的特征，所以研究人员正在使用许多不同种类癌症的模型进行测试。2 V- O% p, Q& Z8 F
Burris 说“该药物适用于各种体外培养的癌细胞和人类肿瘤动物模型，有一些癌症细胞比其他癌细胞要敏感。癌细胞会让周围的正常细胞进行与癌细胞相同的代谢途径，从而制造一个利于癌症生长的环境。这个药物可以让这些它们恢复更正常的代谢途径。”
! c  p) W* ^: m5 J& _& t" s在人类癌症动物模型的研究中， Burris说，“它对于肺癌，前列腺癌和大肠癌的治疗效果都很好，对卵巢癌和胰腺癌的效果稍逊。”1 E- @+ h4 ^" V5 z0 L+ _
虽然它不能够很有效地穿过血脑屏障，但似乎还是对胶质母细胞瘤（一种极其难以治疗的脑癌）有一定的作用。研究人员在这种情况下面临的挑战是找到一种方法，使药物能够跨越这个机体为了保护大脑而建立的屏障，因为这个屏障使药物很难到达病灶发动攻击。
1 k$ v& m) j# x# R: f3 j, ~更有前进的消息是，当SR9243与现有化疗药物组合使用时，它可以增强化疗药物的有效性，这个机制和SR9243自身的抗癌能力无关。
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4 }, g% `2 w8 Q0 V记得之前看过一篇paper是讲白血病细胞和正常造血干细胞的代谢差别的，也是第一次接触wb效应，不知道这个药物对血液癌症的效果如何……